CN114150051A - 一种一体化全面检测五种复杂遗传病的试剂盒和方法 - Google Patents

一种一体化全面检测五种复杂遗传病的试剂盒和方法 Download PDF

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CN114150051A
CN114150051A CN202111305509.3A CN202111305509A CN114150051A CN 114150051 A CN114150051 A CN 114150051A CN 202111305509 A CN202111305509 A CN 202111305509A CN 114150051 A CN114150051 A CN 114150051A
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余永国
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Abstract

本发明提供了一种一体化全面检测五种复杂遗传病的方法和试剂盒。该检测方法和试剂盒用于检测杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症的相关基因的所有常见已知致病性变异。本发明仅需要一次实验、一种技术平台即可同时检测上述疾病单外显子水平拷贝数缺失/重复和常见临床相关已知致病性的单核苷酸变异，可以有效弥补现有基因检测方法中需要多种技术平台联用，诊断效率低下，检测费用昂贵的缺点，可显著提升医生对上述疾病临床检测的标准化程度，并为类似复杂遗传病的诊断和遗传干预提供了一种一体化、高时效性、高准确率和高操作性的分子诊断方法，从而显著提高其诊断、治疗、预后及遗传咨询水平。

Description

一种一体化全面检测五种复杂遗传病的试剂盒和方法
技术领域
本发明属于出生缺陷及遗传病综合防治领域，尤其涉及一种一体化全面检测五种复杂遗传病的试剂盒和方法。
背景技术
复杂遗传病是指致病基因多、基因长度大、基因致病机制多元化以及存在高度同源基因的遗传病，通常很难被单一临床检测技术精准识别与有效诊断，原因在于目前使用的单一临床检测技术在检测范围上都是有不足之处的，往往需要联合运用多种技术才能确诊这类遗传病。
杜氏肌营养不良DMD基因的突变中约70％都是外显子水平拷贝数变异Exon_CNV，外显子区域和侧翼区域的单核苷酸变异SNV位点，包含点突变和小片段InDel，比例只有23％，采用用全外显子测序WES数据进行拷贝数变异CNV分析的效能评估，结果显示基于NGS现有针对CNV的检测算法，WES仅在3个外显子以上的CNV准确度较高，对3个外显子以下的CNV容易漏检。临床首选多重连接探针扩增MLPA检测其外显子级别的CNV，采用Sanger测序检测SNV位点，但由于DMD基因涉及数千个位点，且无突变热点，因此多重连接探针扩增联合Sanger测序效率极低。
超过90％的α-地中海贫血是由于α珠蛋白基因(HBA1、HBA2)缺失导致的，α-地中海贫血表型严重程度与失去功能的α珠蛋白基因拷贝数直接相关，根据缺失的程度,缺失1-4个，分为α+-地中海贫血和α0-地中海贫血，非缺失型α-地中海贫血则主要是α1或α2基因发生点突变或若干碱基的缺失造成的。临床病例中仍有相当一部分患者是由未知或罕见的突变类型致病的，尤其是基因大片段缺失突变或多拷贝，常规分子诊断方法无法对这类病例作出诊断，因此需要采用基因拷贝数定量技术来弥补常规技术的不足。β-地中海贫血则以HBB基因的点突变和InDel为主，大片段缺失为辅。针对缺失型地中海贫血患者，临床首选跨越断裂点PCR(GAP-PCR)和实时PCR技术进行检测，但GAP-PCR需要根据缺失的范围设计引物，仅能检测已知突变，实时PCR仅能确定是α+-地中海贫血缺失还是α0-地中海贫血缺失，无法确定具体的突变位点，还需要进一步用MLPA来确定突变位点和未知突变。而针对非缺失型地中海贫血，则采用反向点杂交RDB和基于实时PCR的荧光标记探针的熔解曲线分析法(PCR-PMCA)，若二者均不能找到点突变，还要进行Sanger测序。尤其，对于α地贫基因簇，HBA1(α1)和HBA2(α2)基因是编码α珠蛋白的高度同源基因,同源性约94％，同时存在同源基因HBZ和假基因HBM、HBZP1、HBQ1。基因间的高度同源性和缺失变异高发，增加了单一检测技术检测地贫基因的难度。
脊髓性肌萎缩症患者中约88％～95％存在SMN1基因7号外显子的纯合缺失，且大部分同时合并第8号外显子的缺失，另有约5％-10％是SMN1基因7号外显子的杂合缺失合并SMN1基因杂合性SNV位点。对于临床高度怀疑或诊断为脊髓性肌萎缩症的患者，首选PCR-限制性片段长度多态性PCR-RFLP、MLPA和实时荧光定量PCR等进行SMN1基因第7号外显子缺失检测，但PCR-RFLP仅能检测SMN1基因第7号外显子纯合缺失，无法检测杂合缺失。对于临床高度怀疑SMN1基因7号外显子的杂合缺失，可进一步考虑检测SMN1基因内的SNV位点，通常采用长片断PCR扩增整个SMN1基因的片断之后进行亚克隆或者巢式PCR，对SMN1基因各外显子进行PCR扩增测序，检测其是否存在变异；或者直接利用患者新鲜外周血样或者建株淋巴细胞提取RNA，反转录为cDNA，对其进行特异性扩增，之后对扩增产物进行Sanger测序，然而由于cDNA仅包含SMN1基因的外显子序列，上述办法均无法检出内含子中的潜在剪切位点。也难以避免高度同源的SMN2基因的干扰。SMN1基因位于一个长度约1.5Mb的反向重复区域中,此区域靠近端粒的一侧存在与SMN1高度同源的基因SMN2，其拷贝数为0-8个，由于SMN2与SMN1基因仅有5个碱基的差异，且其中仅一个位于编码区,因此一般技术很难检测SMN2的拷贝数。由于SMN2基因约10％的转录产物可翻译成为正常长度的SMN蛋白，因此同时检测SMN2基因的拷贝数同样具有重要的临床意义，SMN2的拷贝数增加与脊髓性肌萎缩症的表型严重程度呈负相关，SMN2基因通过剂量补偿效应减轻脊髓性肌萎缩症严重程度，因此SMN2拷贝数同脊髓性肌萎缩症临床表型具有相关性,较高的SMN2基因拷贝数可通过提高SMN蛋白的产量使SMN1基因纯和缺失型患者不出现表型或者仅出现轻微表型。可将其作为预测疾病严重程度的依据之一，是脊髓性肌萎缩症患者症状及临床进展评估的重要参考，需要有针对性地同时检出。
目前已知的非综合征耳聋基因有84个，综合征耳聋基因有46个，总体突变阳性率为5％。常见的遗传性耳聋基因突变热点约数十种，如GJB2(35del G、176del16、235del C、299del AT)、SLC26A4(IVS7-2A>G、2168A>G)、GJB3(538C>T)和12SrRNA(1494C>T、1555A>G)等，对确诊听力障碍患儿6个月时实施干预后，85％的聋儿经过早期的语言康复可进入普通学校学习。但要找到引起耳聋的基因并非易事，目前耳聋基因检测常用方法基因芯片、二代测序、飞行时间质谱、限制性片段长度多态性聚合酶链反应(PCR-RFLP)、荧光PCR等，大都只针对上述常见突变热点进行设计，极易引起漏诊。
按照酶缺陷类型的不同，先天性肾上腺皮质增生症可分为21-羟化酶缺乏症(21-hydroxylase deficiency，21-OHD)、11β羟化酶缺乏症(11beta hydroxylase deficiency，11β-OHD)、17α-羟化酶缺乏症(17alpha-hydroxylase deficiency，17α-OHD)等。其中21-OHD最常见，约占先天性肾上腺皮质增生症的90％～95％；11β-OHD次之，占5％～8％；其他类型罕见。先天性肾上腺皮质增生症基因检测的主要的方法有二代测序、MLPA、等位基因特异性聚合酶链式反应(Allele-Specific PCR,AS-PCR)和变性高效液相色谱。但是21-OHD编码基因CYP21A2存在一个高度同源的CYP21P，目前常用的方法均不能有效区分真假基因，从而引起误诊和漏诊。
此类复杂疾病还包括囊性纤维化、甲型血友病、青光眼等，均是出生缺陷常见高发严重的遗传病，具有较大的危害。准确快速的检测复杂遗传病，如果做到早发现、早治疗、早防控，具有重要的临床意义。然而常规的分子诊断方法操作繁琐且效率低下，不仅消耗大量样本、费时费力、工作繁琐，而且容易导致交叉污染且诊断效率低下，更增加了患者家属的医疗支出。
对于杜氏肌营养不良DMD外显子缺失/重复的检测，目前主要使用MLPA技术。一项研究指出应用MLPA从94例DMD先证者中检测到66例DMD基因外显子缺失/重复，检出率为70.2％，121例女性亲属确诊DMD基因突变携带者48例，检出率为39.7％[1]。另一项研究应用MLPA从22例先证者中检测到15例DMD基因外显子缺失突变，4例重复突变，检出率为86.4％[2]。对于DMD基因突变则使用二代测序技术加Sanger验证的模式。在一项综合研究中，433个无亲缘关系的DMD家系，通过MLPA检测到316个家系的DMD外显子缺失/重复突变，检出率为73％，应用二代测序和Sanger测序对剩下117个家系进行检测，共有96个家系检测到点突变，检出率为82.1％。可见，综合运用MLPA，二代测序以及Sanger测序，共有412个家系得到确诊，阳性验证率为95.2％[3]。
对于脊髓性肌萎缩症，目前MLPA技术是检测其拷贝数的金标准，但是不能检测SMN1基因微小突变与SMN1[2+0]基因型，总体检出率95％左右。荧光定量PCR对于SMN2的检测需要另外设计探针，也无法检测SMN1基因微小突变与SMN1[2+0]基因型，总体检出率低于MLPA的95％[4]。
对于地中海贫血，常规筛查方法包括PCR-流式荧光杂交技术、多重Gap-PCR和PCR-RDB等，对于405例疑似地贫样本的总体阳性检出率为88.76％，而利用高通量测序的阳性符合率可达到95％以上[5]。
对于耳聋，目前主要用耳聋基因芯片和高通量测序技术进行基因检测。耳聋基因芯片对2305例危重新生儿对常见9个突变位点的检出率为3.16％[6]。而高通量测序技术结合Sanger验证在耳聋的基因诊断中，综合检出率约40～65％[7]。
对于先天性肾上腺皮质增生症，需先进行染色体核型检查，明确其性染色体，再进行基因检测。基因检测针对先天性肾上腺皮质增生症不同亚型缺陷涉及的基因种类多，也存在不同基因突变类型，需采用不同的检测方法，综合来看，结合测序，MLPA等方法，检出率在90～95％之间[8]。
参考文献：
[1]赵炜,姜楠,李朔等.假性肥大型肌营养不良症的遗传学分析及产前诊断[J].中华妇产科杂志,2019,54(4):347-351.
[2]钟青燕,严提珍,曾婷等.MLPA技术在假肥大型肌营养不良症基因检测和产前诊断中的应用[J].中国儿童保健杂志,2017,25(5):342-345.
[3]白莹,李双,宗亚楠等.杜氏/贝氏肌营养不良症433个家系的基因突变分析[J].中华医学杂志,2016,96(16):1261-1269.
[4]北京医学会医学遗传学分会.脊髓性肌萎缩症遗传学诊断专家共识.中华医学杂志,2020.100(40):3130-3140.
[5]何淑贞,蒲育栋,苏焕厚等.NGS与常规筛查对地中海贫血基因筛查的结果比较[J].西南国防医药,2018,28(5):404-406.
[6]杨淑梅,杨杰,伍燕飞等.2305例危重新生儿耳聋基因筛查[J].中国妇幼保健,2015,21(30):3662-3664.
[7]王翠翠,袁慧军.高通量测序技术在遗传性耳聋研究中的应用及研究进展[J].遗传,2017,39(3):208-219.
[8]国家卫生健康委临床检验中心新生儿遗传代谢病筛查室间质评委员会.新生儿先天性肾上腺皮质增生症筛查与诊断实验室检测技术专家共识[J].中华检验医学杂志,2019,42(12):1014-1019.
发明内容
鉴于上述现有复杂遗传病检测手段存在的问题，本发明针对杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症五种复杂遗传病，提供了一种一体化全面检测五种复杂遗传病的方法和试剂盒。利用全染色体基因分型芯片的特异性，对杜氏肌营养不良、脊髓性肌萎缩症和地中海贫血单外显子水平的缺失/重复设计了exon_cnv探针组，同时针对DMD、HBA1、HBA2、HBB、SMN1、SMN2、GJB2、GJB3、SLC26A4、PRPS1、MYO15A、MYO7A、COCH、DIABLO、TMC1、DSPP、线粒体12SrRNA、CYP21A2、CYP11B1、STAR、HSD3B2、CYP17A1、NR5A1和SRY设计了gene_variants探针组，全面覆盖了五种疾病常见临床相关常见热点SNV。
本发明的一个目的是提供一种一体化全面检测杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症的试剂盒，仅需一次实验，就可实现五种复杂疾病单外显子水平的所有常见已知致病性变异类型的全面检测，有效克服了临床现有MLPA、实时PCR和Sanger测序等分子诊断技术通量较低，需联合运用多种技术才能确诊复杂遗传病，诊断速度和效率低下且给患者家庭较大的经济压力的不足，该试剂盒包括exon_cnv和gene_variants两套探针组；
所述exon_cnv探针组包括针对所述杜氏肌营养不良的相关基因DMD的一个外显子及以上的缺失/重复设计的探针、所述地中海贫血的相关基因HBA1、HBA2、HBB的外显子缺失设计的探针；以及针对所述脊髓性肌萎缩症的主效基因SMN1内部7号外显子和8号外显子缺失设计的探针；
所述gene_variants探针组包括针对所述杜氏肌营养不良的相关基因DMD设计的探针；针对所述地中海贫血的相关基因HBA1、HBA2、HBB设计的探针；针对所述脊髓性肌萎缩症的主效基因SMN1、高度同源的基因SMN2设计的探针；针对所述遗传性耳聋的相关基因GJB2、GJB3、SLC26A4、PRPS1、MYO15A、MYO7A、COCH、DIABLO、TMC1、DSPP、12SrRNA设计的探针；针对所述先天性肾上腺皮质增生症的相关基因CYP21A2、CYP11B1、STAR、HSD3B2、CYP17A1、NR5A1、SRY设计的探针。
具体的，分类为exon_cnv的探针组包括覆盖表1区域的探针组，针对DMD基因较大片段缺失/重复，以及地贫基因HBA1、HBA2和HBB大片段缺失而设计。
表1覆盖DMD基因常见缺失/重复区域以及地贫基因常见缺失区域的exon_cnv探针组
Figure BDA0003340080970000061
Figure BDA0003340080970000071
进一步的，分类为exon_cnv探针组还包括表2的SNP探针，针对脊髓性肌萎缩症基因SMN1内部7号外显子和8号外显子缺失突变。
表2覆盖脊髓性肌萎缩症的SNP探针
Figure BDA0003340080970000072
Figure BDA0003340080970000081
Figure BDA0003340080970000091
Figure BDA0003340080970000101
Figure BDA0003340080970000111
所述gene_variants探针组包括针对所述杜氏肌营养不良的相关基因设计的探针，覆盖了脊髓性肌萎缩症相关SNV位点2128个，转录本为NM_004006.2；
针对所述地中海贫血的相关基因HBA1、HBA2、HBB设计的探针，覆盖了所述HBA1相关SNV位点151个，转录本为NM_000558.4；HBA2相关SNV位点228个，转录本为NM_000517.4；HBB相关SNV位点779个，转录本为NM_000518.4；
针对所述脊髓性肌萎缩症的主效基因SMN1、高度同源的基因SMN2设计的探针，覆盖了所述主效基因SMN1相关SNV位点91个，转录本为NM_000344.3；高度同源基因SMN2相关SNV位点1个，转录本为NM_017411.3；
针对所述遗传性耳聋的相关基因GJB2、GJB3、SLC26A4、PRPS1、MYO15A、MYO7A、COCH、DIABLO、TMC1、DSPP、12SrRNA设计的探针，覆盖了所述GJB2相关SNV位点423个，转录本为NM_004004.6；GJB3相关SNV位点39个，转录本为NM_024009.3；SLC26A4相关SNV位点585个，转录本为NM_000441.2；PRPS1相关SNV位点39个，转录本为NM_002764.3；MYO15A相关SNV位点311个，转录本为NM_016239.3；MYO7A相关SNV位点582个，转录本为NM_000260.4；COCH相关SNV位点31个，转录本为NM_004086.3；DIABLO相关SNV位点2个，转录本为NM_019887.6；TMC1相关SNV位点108个，转录本为NM_138691.3；DSPP相关SNV位点58个，转录本为NM_014208.3；12SrRNA相关SNV位点8个，转录本为NC_012920.1；
针对所述先天性肾上腺皮质增生症的相关基因CYP21A2、CYP11B1、STAR、HSD3B2、CYP17A1、NR5A1、SRY设计的探针，覆盖了所述CYP21A2相关SNV位点284个，转录本为NM_000500.9；CYP11B1相关SNV位点133个，转录本为NM_000497.3；STAR相关SNV位点83个，转录本为NM_000349.3；HSD3B2相关SNV位点70个，转录本为NM_000198.4；CYP17A1相关SNV位点133个，转录本为NM_000102.4；NR5A1相关SNV位点224个，转录本为NM_004959.5；SRY相关SNV位点108个，转录本为NM_003140.3。
进一步的，分类为gene_variants的探针组，包括DMD、HBA1、HBA2和HBB常见的临床SNV突变，其中DMD由于没有明显的突变热点，因此根据临床突变数据库ClinVar和人类基因组突变数据库HGMD报道，覆盖了常见的致病和可能致病位点，共计2128个(转录本：NM_004006.2)，如下：
c.*23_*35del、c.G10969T、c.10922-2A>G、c.C10910A、c.C10903T、c.10889delG、c.C10888T、c.C10873T、c.C10855T、c.10812delC、c.C10801T、c.10773+5G>A、c.10797+1G>A、c.G10792T、c.10787delT、c.10785delG、c.C10783T、c.10744delC、c.10722delC、c.A10705T、c.10656delT、c.C10651T、c.10624_10625del、c.10609delT、c.10608_10609insGTCG、c.10606delC、c.10599delT、c.10563delA、c.C10561A、c.10554-2A>G、NC_000023.11(chrX):g.31147536G>C、c.G10546T、c.G10543T、c.10509_10510del、c.10509delA、c.10500_10501del、c.10498_10499del、c.G10495T、c.10492_10493insAAT、c.10484_10491G、c.10489delT、c.10478delA、c.10477delC、c.C10477T、c.10454delT、c.10453_10454del、c.10453_10454TA、c.10453delC、c.10453dupC、c.10441delC、c.T10412A、c.10409dupT、c.10406_10407del、c.10406delA、c.10406_10407insAA、c.10406dupA、c.G10402T、c.10395-1G>C、c.10386delT、c.10368delT、c.10329_10331del、c.T10320A、c.C10304A、c.C10279T、c.C10279T、c.10262+1G>A、c.C10262T、c.10259_10260AA、c.10258delT、c.10231_10235del、c.10235delT、c.10231dupA、c.10230dupT、c.10225_10229del、c.10227delC、c.10227dupC、c.10224dupT、c.10224_10225insGT、c.*2T>A、c.*1G>T、c.1022delG、c.G1022C、c.G1022A、c.10223+2T>C、c.10216_10223del、c.10223+1G>T、c.10223+1G>A、c.10223+1G>C、c.G10219T、c.10210dupG、c.10203delA、c.T10202G、c.10187delC、c.10174delA、c.10171dupC、c.C10171T、c.A10149C、c.A10147T、c.C10141T、c.10137delA、c.A10135T、c.10133delA、c.A10129T、c.10126delC、c.10121delA、c.10115_10116del、c.C10108T、c.C10108T、c.10105delG、c.10101_10103del、c.A10103G、c.G10102C、c.G10102T、c.10097_10099del、c.G10096T、c.C10094A、c.10088delC、c.10087-2A>-、c.10087-2A>C、NC_000023.11(chrX):g.31180365C>G、NC_000023.11(chrX):g.31180367->A、c.10086+1G>-、c.10086+2T>A、c.10086+2T>C、c.10086+1G>A、c.10086+1G>T、c.T10077A、c.G10072T、c.10044delA、c.G10034A、c.C10033T、c.10027dupT、c.10020delC、c.C10020G、c.C10020A、c.G10019A、c.T10018C、c.10015delA、c.C10012T、c.C10011G、c.G10010A、c.T10009C、c.G10003A、c.G10003T、c.G10003C、c.T10002G、c.A9997T、c.A9997C、c.9986delT、c.C9978G、c.9975-2A>-、c.9975-1G>T、c.9975-1G>A、c.9975-2A>G、NC_000023.11(chrX):g.31182735T>C、NC_000023.11(chrX):g.31182735T>A、c.9974+2T>A、c.9974+1G>T、c.9974+1G>A、c.9974+1G>C、c.9959delC、c.C9959G、c.C9958T、c.9953_9954del、c.T9955C、c.9950_9951del、c.G9952T、c.C9948A、c.9944delT、c.9941_9942insGTAA、c.G9938T、c.T9937G、c.T9937C、c.A9934G、c.C9928T、c.A9926G、c.G9913T、c.9897_9898del、c.A9898T、c.A9896G、c.9894_9895insTCCTG、c.9893dupT、c.9885delG、c.9881_9882insTG、c.G9882A、c.G9881A、c.9854_9863del、c.9862delG、c.G9862T、c.G9851A、c.G9829T、c.9822dupA、c.9816dupT、c.9813_9814del、c.9808-1G>A、NC_000023.11(chrX):g.31182906TG>C、c.9808-2A>C、NC_000023.11(chrX):g.31201247G>A、NC_000023.11(chrX):g.31203957T>-、NC_000023.11(chrX):g.31203956C>T、c.9807+1G>C、c.9807+1G>T、c.G9748T、c.C9739T、c.9722_9723del、c.9711_9713del、c.G9695A、c.C9691T、c.9689delA、c.T9682C、c.9663delA、c.C9661T、c.9650_9654del、c.C9651A、NC_000023.11(chrX):g.31206567A>G、NC_000023.11(chrX):g.31206577C>A、NC_000023.11(chrX):g.31206577C>T、NC_000023.11(chrX):g.31206579->A、c.9649+2T>C、c.9649+1G>A、c.C9645A、c.9640_9641del、c.9619_9626del、c.9621delT、c.T9619C、c.9604_9605insTCTTTTAAAACTG、c.9600_9601del、c.9597delT、c.9596_9597del、c.9583_9584insAT、c.C9568T、c.9564_9564TT、c.9564-1G>A、c.9564-2A>T、NC_000023.11(chrX):g.31206697T>A、NC_000023.11(chrX):g.31207094A>C、NC_000023.11(chrX):g.31208283T>C、NC_000023.11(chrX):g.31209491TACGTAC>AT、NC_000023.11(chrX):g.31209493C>G、c.9563+1G>A、c.9562delA、c.A9560G、c.A9560G、c.9551dupA、c.G9542A、c.C9522A、c.9471_9474del、c.9461delT、c.T9461A、c.9457delT、c.9454_9457del、c.C9445T、c.9432delC、c.9429_9430del、c.C9427T、c.9421_9422del、c.C9403T、c.C9380G、c.9364delG、c.9362-2A>C、NC_000023.11(chrX):g.31210914T>C、NC_000023.11(chrX):g.31222930T>C、NC_000023.11(chrX):g.31223042C>G、c.9361+1G>-、c.9361+1->T、c.9361+1G>A、c.C9360A、c.9358delT、c.9358dupT、c.9352delG、c.9348dupG、c.A9349G、c.C9346T、c.9328_9337del、c.G9338A、c.C9337T、c.9333delA、c.9312_9322del、c.9319_9320insAA、c.9300_9301insTAAT、c.9287-1G>A、c.9287-2A>G、c.T9284G、c.9278_9279insAAATGACAGAGCTCTACCA、c.C9277T、c.C9276A、c.9269_9273TCTTTTACCAAAATGACAGT、c.9262delA、c.G9249A、c.G9248A、c.9228_9229insA、c.9225-1G>A、c.9225-2A>C、NC_000023.11(chrX):g.31261026A>T、NC_000023.11(chrX):g.31261176T>C、NC_000023.11(chrX):g.31261301T>C、NC_000023.11(chrX):g.31261303G>T、NC_000023.11(chrX):g.31261663T>C、NC_000023.11(chrX):g.31261664T>C、NC_000023.11(chrX):g.31314406G>T、NC_000023.11(chrX):g.31323593C>G、c.9224+1G>C、c.9224+1G>A、c.9224+1G>T、c.9221_9222insAT、c.C9216A、c.C9216G、c.9210_9214del、c.9204_9207del、c.9197_9198insATCTC、c.C9197A、c.G9183A、c.G9182A、c.9176delG、c.G9176A、c.9173delA、c.9164_9164del、c.9164-1G>A、c.9164-1G>T、c.9164-2A>G、c.9163+1G>A、c.9158_9161del、c.9156dupT、c.9153delC、c.9131_9147del、c.C9148T、c.9135delT、c.9133_9134insCAGGGACT、c.C9109T、c.9103_9104insGACCGAG、c.C9100T、c.9090delC、c.9085-1G>A、NC_000023.11(chrX):g.31364153C>A、c.C9082T、c.G9072A、c.9052delG、c.9035_9041del、c.T9036A、c.C9029G、c.9021delT、c.9009delC、c.C9001T、c.8970_8971del、c.8955dupT、c.G8947T、c.C8944T、NC_000023.11(chrX):g.31444636A>T、c.8937+2T>C、c.G8937C、c.8931dupA、c.8912_8913del、c.8910_8913del、c.C8914T、c.8898_8899insTC、c.G8880A、c.8877delC、c.G8872T、c.8868delC、c.C8854T、c.8828_8829insTTCAAGAGGCCAC、c.G8812T、c.G8810A、c.8807_8808del、c.G8791T、c.8785dupA、c.C8776T、c.G8775A、c.G8774A、c.8754delG、c.8751dupA、c.G8746T、c.G8745A、c.G8744A、c.G8740T、c.8729_8734TGGTCG、c.8733delC、c.A8734G、c.8732_8733insA、c.A8729T、c.G8728T、c.8711_8715AGG、c.C8713T、c.C8692T、c.A8686T、c.G8680T、c.8669-1G>C、c.8669-2A>T、NC_000023.11(chrX):g.31478980T>A、c.8668_8668del、c.8668+2T>C、c.8668+1G>A、c.G8668A、c.G8668A、c.C8656T、c.8652_8653del、c.8641delC、c.G8628A、c.C8608T、c.8605_8606del、c.8601dupG、c.8597_8598del、c.G8575T、c.G8560T、c.8548-1G>C、c.8542delC、c.A8527T、c.8514dupT、c.C8491T、c.T8483G、c.G8479T、c.G8476A、c.8473delG、c.8465delA、c.C8464T、c.G8460A、c.G8459A、c.C8443T、c.8438delC、c.A8422T、c.G8420A、c.A8417G、c.C8416T、c.8392_8402del、c.8391-1G>A、c.8391-1G>C、c.8390+2T>C、c.8390+2T>G、c.8390+1G>C、c.8390+1G>A、c.G8390A、c.G8390C、c.G8390A、c.8388delT、c.8374_8375del、c.A8374T、c.A8371T、c.G8357A、c.8355delG、c.A8353T、c.G8333A、c.8324delT、c.G8299T、c.8297delT、c.8291_8292del、c.8287delC、c.8284dupA、c.G8269T、c.8259delC、c.8249delA、c.8233delA、c.G8230T、c.8228delG、c.C8224T、c.8221delC、c.A8219G、c.8218-1G>T、c.8218-2A>G、NC_000023.11(chrX):g.31595570C>A、NC_000023.11(chrX):g.31609621T>C、NC_000023.11(chrX):g.31627667ACTT>-、NC_000023.11(chrX):g.31627668C>T、NC_000023.11(chrX):g.31627670->A、c.8217+2T>G、c.8217+2T>C、c.8215_8216insT、c.C8215T、c.G8214A、c.8210_8211insCA、c.C8209T、c.8196delA、c.G8197T、c.A8194T、c.8184_8185insT、c.8178delA、c.G8176T、c.8171dupT、c.8167delA、c.A8161T、c.8159delG、c.8145_8146insTA、c.C8146T、c.8138delA、c.G8111A、c.8103delT、c.8098_8099del、c.A8098T、c.8087delT、c.8086delC、c.8086dupC、c.8081delT、c.C8074T、c.8064_8065del、c.G8053T、c.8038dupC、c.8034_8037del、c.C8038T、c.8028-1G>C、NC_000023.11(chrX):g.31657979G>A、c.8027+2T>A、c.8027+2T>C、c.8027+1G>A、c.7997_8025del、c.7999_8009del、c.G8010A、c.G8009A、c.7992_7993del、c.A7969T、c.7948delG、c.7922delA、c.7908_7909insAAAT、c.G7899A、c.G7898A、c.7894delC、c.C7894T、c.7891dupC、c.7885_7886del、c.7873delC、c.C7873T、c.7872+1G>C、c.G7864T、c.7861delA、c.7860delC、c.7858dupA、c.A7855T、c.7833dupT、c.C7828A、c.G7822T、c.G7817A、c.C7814G、c.7798_7799insCA、c.C7792T、c.7787delT、c.C7780T、c.7768_7771del、c.7755delG、c.G7755A、c.C7750T、c.7739delA、c.7730_7734del、c.C7720T、c.C7717T、c.7714delA、c.C7711G、c.C7705T、c.7686_7702A、c.C7693T、c.7689delA、c.G7683A、c.G7682A、c.C7672T、c.7669delA、c.7665_7666insGA、c.7661-1G>C、c.7661-1G>A、c.7661-2A>C、c.7661-2A>T、c.7661-2A>G、NC_000023.11(chrX):g.31679597A>G、NC_000023.11(chrX):g.31729627T>-、c.7660+1G>T、c.7660+1G>C、c.C7657T、c.7654delG、c.7543_7641del、c.7615_7616insC、c.7585_7597del、c.7587_7591del、c.G7585T、c.G7582T、c.G7578C、c.C7576T、c.G7571A、c.7565delA、c.C7564T、c.G7561T、c.7559delT、c.G7555A、c.7548_7549insGGCAACA、c.7542+2T>C、c.7542+1G>A、c.7538dupA、c.C7537T、c.7523delA、c.G7510T、c.7497_7506del、c.7476delT、c.C7471T、c.7470_7470delinsAA、c.7467delT、c.G7455A、c.7447_7451TCT、c.7441delG、c.G7437A、c.7431_7434CA、c.7425delC、c.7401_7402AT、c.G7402T、c.7400delT、c.7395delG、c.7360dupA、c.7353dupT、c.7348delG、c.7348dupG、c.7341delA、c.C7339T、c.7329_7330insA、c.7327dupA、c.C7318T、c.7310-1G>T、c.7310-1G>A、NC_000023.11(chrX):g.31819970C>T、NC_000023.11(chrX):g.31819970C>G、NC_000023.11(chrX):g.31819972->AGC、c.7309+1G>A、c.7292_7296del、c.G7288T、c.7279delC、c.7265delC、c.7264dupG、c.G7255T、c.7247delT、c.G7229A、c.7221_7227del、c.7223_7224del、c.7224dupT、c.A7204T、c.7195delG、c.G7183A、c.7179_7180del、c.C7151A、c.7148dupT、c.7128delA、c.C7126T、c.G7105T、c.G7105T、c.6915_7095del、NC_000023.11(chrX):g.31875187C>T、c.7095+1A>C、c.7089dupT、c.C7085A、c.7077_7078T、c.C7075T、c.7060delT、c.G7054T、c.T7031A、c.G7029A、c.A7016G、c.C7006T、c.6993dupA、c.6986delA、c.6986dupA、c.A6974T、c.C6973T、c.6964delG、c.C6955T、c.G6949T、c.G6943T、c.6923_6933del、c.6931dupG、c.6913-1G>A、c.6913-2A>G、NC_000023.11(chrX):g.31879410A>C、c.G6906A、c.G6905A、c.A6880T、c.6878dupA、c.A6868T、c.6826_6866del、c.C6862T、c.G6856T、c.6850dupA、c.6848dupT、c.6836dupT、c.6824dupG、c.6810_6813del、c.6808_6811del、c.T6809G、c.6804_6807del、c.C6805T、c.C6799T、c.6794delG、c.6776_6792del、c.6791delA、c.C6790T、c.6784delC、c.6762+2T>A、c.6762+1G>A、c.6762+1G>T、c.6762+1G>C、c.6751_6754del、c.6754dupC、c.C6754T、c.6746dupA、c.6741delA、c.G6742T、c.A6739T、c.C6730T、c.6720delT、c.G6721T、c.G6678A、c.T6674G、c.6659dupT、c.T6659G、c.C6649T、c.6644_6645insC、c.6643delG、c.C6641A、c.6638delT、c.6615-1G>T、c.6615-2A>T、c.6615-2A>G、NC_000023.11(chrX):g.31965029C>A、c.6440_6614del、c.6581_6614del、c.6614+2T>C、c.6614+1G>A、c.6614+1G>T、c.6613dupA、c.6611dupA、c.A6607T、c.6598_6601del、c.C6592T、c.6574_6578del、c.G6576A、c.6559delA、c.6554dupT、c.A6550T、c.G6547T、c.C6544T、c.6537dupT、c.6499delG、c.6472_6473del、c.C6460T、c.6446dupA、c.C6445T、c.G6439T、c.6439-1G>A、c.6439-2A>G、c.6436_6438del、NC_000023.11(chrX):g.32216911CTTAC>-、c.6438+2T>A、c.6438+1G>T、c.6438+1G>A、c.A6436T、c.T6432A、c.6430dupT、c.G6429A、c.C6423A、c.C6423G、c.G6408A、c.6393_6394del、c.6391_6392del、c.C6391T、c.6385_6388del、c.6380dupT、c.C6373T、c.G6370T、c.6351_6366del、c.G6364T、c.G6357A、c.G6356A、c.6353delA、c.C6352T、c.6348delT、c.6337delA、c.6328delC、c.G6318A、c.G6310T、c.C6292T、c.6291-1G>T、c.6291-1G>A、NC_000023.11(chrX):g.32256575G>A、NC_000023.11(chrX):g.32287524C>-、NC_000023.11(chrX):g.32287524C>T、NC_000023.11(chrX):g.32287524C>G、NC_000023.11(chrX):g.32287524C>A、c.6290+2T>A、c.6290+1G>A、c.6290+1G>T、c.G6290T、c.C6286T、c.C6283T、c.A6277T、c.C6276G、c.6272delT、c.6261delA、c.6261dupA、c.A6259T、c.G6256T、c.G6255A、c.C6250T、c.6244_6246TA、c.6237_6238del、c.C6238T、c.C6223T、c.6201_6203CCCA、c.6200delC、c.C6200T、c.C6190T、c.T6188A、c.6183dupA、c.6182delC、c.C6136T、c.6128_6131del、c.6127delG、c.6118-1G>A、c.6118-2A>T、NC_000023.11(chrX):g.32287704G>T、NC_000023.11(chrX):g.32287716T>C、NC_000023.11(chrX):g.32287762->AT、c.G6117C、c.G6117A、c.G6106T、c.G6103T、c.6100delC、c.G6085T、c.6077_6078insAA、c.6077dupA、c.T6072A、c.6045delA、c.6036_6037insATTA、c.G6037T、c.T6035G、c.6027dupA、c.C6025T、c.C6023A、c.C6023G、c.6006_6007del、c.G6007T、c.5996_5999del、c.T5985G、c.5973_5974insA、c.5958delT、c.G5938T、NC_000023.11(chrX):g.32342095C>G、NC_000023.11(chrX):g.32342096T>A、NC_000023.11(chrX):g.32342097C>G、c.5922+2T>C、c.C5917T、c.5914delG、c.T5911C、c.5906_5907insGACT、c.5903_5904del、c.A5902T、c.C5899T、c.C5899T、c.5893_5894del、c.C5893T、c.A5884C、c.G5878T、c.G5868A、c.G5867A、c.5848_5858del、c.C5851T、c.5845delC、c.5831dupC、c.G5800T、c.5771_5772del、c.G5773T、c.5768_5771del、c.5766_5770del、c.G5770T、c.A5764T、c.A5761T、c.5747_5757del、c.C5758T、c.5756dupT、c.G5752T、c.5740-1G>A、c.5740-2A>G、c.5740-2A>T、NC_000023.11(chrX):g.32342297C>A、c.A5731T、c.G5725T、c.5704_5707del、c.5699_5704G、c.5694_5697del、c.5697delA、c.5697dupA、c.5689delG、c.5662delG、c.5654delA、c.5652delG、c.C5653T、c.A5647T、c.C5646A、c.C5646G、c.C5641T、c.G5637A、c.C5632T、c.5610_5615T、c.5614delG、c.5612delA、c.A5611T、c.A5608T、c.5606delG、c.5602_5605del、c.5602dupA、c.A5602T、c.C5599T、c.5591dupT、NC_000023.11(chrX):g.32343293A>T、NC_000023.11(chrX):g.32345925T>C、c.5582_5583del、c.5574_5575del、c.5570_5571del、c.5571delA、c.5565_5568del、c.5567_5568T、c.C5563T、c.5561delT、c.C5554T、c.5548_5552del、c.5551delC、c.C5551T、c.A5542T、c.G5533T、c.C5530T、c.5525_5526del、c.G5521T、c.5510delG、c.C5503T、c.5487_5488del、c.G5489T、c.A5488T、c.C5485T、c.5476_5477del、c.5475delA、c.G5476T、c.G5461T、c.5451_5454del、c.5449-1G>A、c.5449-1G>C、c.5449-2A>G、NC_000023.11(chrX):g.32346083G>C、c.5447delT、c.5446delA、c.A5444G、c.5434_5437del、c.5413delG、c.5413dupG、c.C5407T、c.C5404T、c.5401_5402del、c.G5398T、c.C5371T、c.5364dupA、c.C5353T、c.G5350T、c.G5344T、c.A5341T、c.5328_5332TCCTTTGAAGGC、NC_000023.11(chrX):g.32348743A>C、NC_000023.11(chrX):g.32361028TCTACCCATTTTTTAATA>-、c.A5314T、c.5307delC、c.A5308T、c.5274_5287del、c.C5287T、c.C5287T、c.5285delA、c.5272_5280CCAA、c.5272_5273del、c.C5266T、c.G5260T、c.5253_5256del、c.T5255G、c.C5247A、c.G5234A、c.5199_5209del、c.C5209T、c.G5167T、c.G5163C、c.T5159A、c.T5159G、NC_000023.11(chrX):g.32362967C>T、c.5154+2T>G、c.5154+2T>C、c.5154+1G>A、c.5151delT、c.5140delG、c.5139_5140T、c.5139delA、c.5139dupA、c.G5140T、c.C5134T、c.5131delC、c.C5131T、c.5124_5127del、c.5118_5119del、c.5101delC、c.5100_5101del、c.5092delG、c.G5082A、c.5071dupA、c.5068_5070del、c.5066delA、c.5052delT、c.G5044T、c.C5032T、c.C5031A、NC_000023.11(chrX):g.32364716T>C、c.5023_5024insGT、c.5017delC、c.T5016A、c.G5009A、c.4996_5004T、c.5000_5002del、c.5001_5002insCA、c.G5002T、c.C4996T、c.4983dupA、c.4980delG、c.4976dupA、c.4960dupA、c.4956dupA、c.A4954T、c.4937delA、c.A4933T、c.4925dupT、c.T4925A、c.4918_4919TG、c.4918delA、c.4898_4899del、c.4888delA、c.4876_4887del、c.4872_4873del、c.4870delC、c.C4870T、c.G4864T、c.4857delA、c.4856_4857del、c.G4858T、c.C4852T、c.4845+2T>C、c.4845+1G>A、c.4845+1G>T、c.4841delG、c.G4838A、c.4807_4808insGGAA、c.C4793A、c.4786_4787del、c.G4777T、c.4771delG、c.4770delA、c.G4758A、c.G4757A、c.4746_4747del、c.A4732T、c.4729delC、c.C4729T、c.4724delA、c.4720dupC、c.A4711T、c.T4697A、c.4693_4694del、c.C4693T、c.C4690T、c.A4687T、c.4681_4682del、c.4679_4680insTAAC、c.4675_4679TATGTTAAAATATT、c.4675-1G>T、c.4675-2A>G、NC_000023.11(chrX):g.32380691T>C、c.4674+1G>A、c.G4666T、c.G4660T、c.T4656A、c.4638delA、c.4630delA、c.G4618T、c.C4613T、c.4611delT、c.G4606T、c.C4604T、c.C4600T、c.C4591T、c.4583delA、c.C4582T、c.4572delG、c.A4570T、c.4565delT、c.4561dupA、c.G4558T、c.4545_4549del、c.4538_4541del、c.4536_4540del、c.G4540T、c.4535_4536del、c.4523_4535del、c.T4527G、c.4519_4523del、c.4519-1G>C、NC_000023.11(chrX):g.32386470G>C、NC_000023.11(chrX):g.32386472T>C、NC_000023.11(chrX):g.32389496C>T、NC_000023.11(chrX):g.32389499AC>-、NC_000023.11(chrX):g.32389498T>A、c.4518+2T>C、c.4518+2T>G、c.4518+1G>A、c.4518+1G>C、c.4518+1G>T、c.G4518A、c.4516delG、c.C4501T、c.C4499A、c.C4495T、c.G4486T、c.C4483T、c.4471_4472del、c.4450delC、c.4443delG、c.C4414T、c.4412_4413insGTCT、c.C4405T、c.C4384T、c.C4375T、c.4368delG、c.4351_4352insA、c.T4352A、c.4350delA、c.4350dupA、c.A4328G、c.C4327T、c.4315dupA、c.G4303T、c.G4296C、c.C4294T、c.4290_4291del、c.A4289G、c.A4285T、c.T4250A、c.C4240T、c.4233+2C>T、c.4231dupC、c.C4231T、c.C4213T、c.4187dupA、c.T4178A、c.C4174T、c.4160delC、c.4156delC、c.4151delA、c.G4150T、c.C4147T、c.T4142G、c.4131delA、c.G4126T、c.4120delG、c.C4117T、c.C4108T、c.4103delG、c.4100delA、c.C4099T、c.4087_4088del、c.A4087T、c.C4084T、c.4072-2A>-、c.4071+2T>A、c.4071+2T>C、c.4071+1G>T、c.4071+1G>A、c.4071+1G>C、c.4069_4070insCATGAAG、c.G4069T、c.G4066T、c.G4057T、c.4033_4045del、c.C4020G、c.4012dupG、c.G4012T、c.G4000T、c.G4000A、c.3988delC、c.C3982T、c.G3971A、c.C3970T、c.3963delT、c.C3964T、c.3959delC、c.G3952C、c.C3947A、c.C3940T、c.C3940T、c.3932delA、c.C3923A、NC_000023.11(chrX):g.32441168T>C、NC_000023.11(chrX):g.32441177->AC、c.3914dupT、c.3908_3909del、c.3909dupT、c.3907dupT、c.3867_3876del、c.A3868T、c.3864delA、c.A3862T、c.G3850T、c.A3848G、c.G3843A、c.3833delC、c.C3822A、c.C3822G、c.C3818A、c.3808dupG、c.G3804A、c.G3803A、c.G3795A、c.3787-1G>T、NC_000023.11(chrX):g.32442157G>T、c.3786+1G>A、c.3779_3785GG、c.3784delG、c.G3784T、c.C3774A、c.C3774G、c.3772dupT、c.3768delG、c.A3769T、c.3766_3767insT、c.3765dupT、c.G3747A、c.3737_3743del、c.C3742T、c.3727_3728del、c.3728delT、c.3728dupT、c.G3715T、c.3713dupA、c.3712_3713insGGCCTTAAAAA、c.A3709T、c.3703_3704del、c.G3700T、c.C3679T、c.3673delA、c.3664_3667del、c.3661_3662del、c.G3655T、c.3630delA、c.G3631T、c.G3631T、c.3627_3628T、c.C3625T、c.C3622T、c.3613delG、c.G3613T、c.3609_3612CTT、c.3604-1G>C、NC_000023.11(chrX):g.32452609C>G、NC_000023.11(chrX):g.32454658->TA、NC_000023.11(chrX):g.32454659->A、NC_000023.11(chrX):g.32454659T>A、c.3603+2T>C、c.3603+2T>G、c.3603+2T>A、c.3603+1G>A、c.3603+1G>T、c.G3603A、c.C3580T、c.T3578A、c.T3578G、c.3569delC、c.3565dupA、c.A3562T、c.G3556T、c.3550_3551del、c.G3544T、c.3539_3540insAGAAGAGTA、c.G3516A、c.G3515A、c.G3511T、c.C3500G、c.3494_3497CCTTCGTGC、c.C3487T、c.3478_3479del、c.3454_3479del、c.3464_3471del、c.A3472T、c.3470delA、c.G3469T、c.G3460T、c.3447_3448TT、c.G3448T、c.A3445T、c.3433_3434del、c.3433_3433GTT、NC_000023.11(chrX):g.32454833CT>AG、NC_000023.11(chrX):g.32454833CT>TC、c.3433-1G>A、c.3433-2A>G、NC_000023.11(chrX):g.32461199T>C、NC_000023.11(chrX):g.32461403T>C、NC_000023.11(chrX):g.32463436T>C、NC_000023.11(chrX):g.32463436T>A、c.3432+2->G、c.3432+2T>C、c.3432+1G>C、c.3432+1G>T、c.3432+1G>A、c.G3432T、c.G3432A、c.C3430T、c.3427dupC、c.C3427T、c.C3426A、c.3420delC、c.G3414A、c.G3413A、c.3408_3409GT、c.C3409T、c.3405delC、c.G3397T、c.G3388T、c.A3376T、c.3373dupT、c.3370_3371del、c.3365_3366del、c.G3358T、c.3356delC、c.G3352T、c.3347_3350del、c.3347delA、c.A3346T、c.A3340T、c.3336delG、c.C3337T、c.3333_3334del、c.G3328T、c.G3328T、c.3326delA、c.3326dupA、c.C3304T、c.C3295T、c.3285_3288del、c.T3281G、c.T3281A、c.3277-1G>C、c.3277-2A>T、c.3276+2T>G、c.3276+1G>A、c.A3274T、c.C3268T、c.3266_3267insC、c.3260delA、c.C3259T、c.3257delA、c.3257dupA、c.A3256T、c.A3253T、c.3247delA、c.3246_3247insTTTCTAAAAA、c.G3244T、c.C3226G、c.G3224A、c.3222delA、c.G3220T、c.G3217T、c.G3217A、c.3205delG、c.3201dupT、c.3188_3200del、c.G3196T、c.G3189A、c.G3188A、c.3183delG、c.3179delT、c.3170_3173del、c.C3172T、c.C3151T、c.3147delA、c.C3136T、c.3132_3133insTA、c.3125delA、c.C3121T、c.3116dupA、c.3097_3098del、c.G3087A、c.G3086A、c.G3079T、c.3075delT、c.G3076T、c.3067delG、c.G3061T、c.T3054G、c.3042_3052del、c.3033delC、c.G3013T、c.3009delG、c.3009_3010insTG、c.T2994A、c.C2991G、c.2954_2979del、c.C2977T、c.C2974T、c.G2971T、c.G2971C、c.C2968T、c.2962delT、c.C2956T、c.2950-1G>A、c.2950-2A>G、c.2949+2T>A、c.2949+1G>T、c.2949+1G>A、c.G2949T、c.C2947T、c.G2941T、c.2933_2934del、c.2929dupC、c.C2929T、c.G2926T、c.2887_2888del、c.2887delT、c.2880_2884del、c.C2873G、c.C2869T、c.A2867C、c.C2866T、c.2864dupT、c.G2862A、c.2853delC、c.2852delT、c.A2842G、c.2836_2838del、c.G2836T、c.2833delC、c.C2833T、c.T2832G、c.T2832A、c.C2827T、c.T2816A、c.2808dupT、c.2804-1G>T、c.2804-1G>A、c.2804-2A>C、c.2804-2A>T、c.2804-2A>G、NC_000023.11(chrX):g.32472312T>C、NC_000023.11(chrX):g.32472316C>T、NC_000023.11(chrX):g.32484911TTAC>-、NC_000023.11(chrX):g.32484914C>G、c.2803+1G>-、c.2803+1G>A、c.2803+1G>T、c.C2797T、c.T2795C、c.G2791T、c.A2788T、c.C2776T、c.2767delT、c.2761delG、c.C2758T、c.2737delG、c.2734dupG、c.2712dupC、c.G2707T、c.C2704T、c.G2701T、c.G2695T、c.C2677T、c.2674delA、c.2673_2674del、c.2673_2674G、c.A2671T、c.T2669G、c.2667dupA、c.2665_2666insA、c.C2665T、c.2636_2654del、c.C2650T、c.A2645G、c.2638delC、c.2623-2A>G、c.2623-2A>C、NC_000023.11(chrX):g.32485102G>C、NC_000023.11(chrX):g.32491272CTTAC>-、c.2622+1G>A、c.2622+1G>T、c.G2622C、c.2614dupA、c.A2612C、c.A2611T、c.T2609G、c.C2605T、c.2601_2602del、c.A2599T、c.2591delC、c.2588delC、c.G2584T、c.C2582G、c.2578_2579insACCC、c.2568_2575del、c.2571delC、c.2559_2560del、c.A2560T、c.T2558A、c.G2556A、c.C2530T、c.2527delG、c.G2527T、c.C2521T、c.C2518T、c.C2512T、c.2496_2496delinsTT、c.2489delA、c.C2485T、c.T2484A、c.G2479T、c.2471_2474del、c.G2475A、c.G2474A、c.T2473G、c.2463_2466del、c.2462dupA、c.C2449T、c.2447_2448AA、c.C2448A、c.2430_2443del、c.G2440T、c.2436dupG、c.G2436A、c.G2435A、c.2423dupT、c.C2419T、c.G2416T、c.C2414G、c.C2407T、c.A2404T、c.2400delC、c.T2391G、c.2388delT、c.2384delG、c.A2381G、NC_000023.11(chrX):g.32491521A>G、NC_000023.11(chrX):g.32501752T>G、c.2380+1G>A、c.2380+1G>T、c.2379dupT、c.G2380T、c.G2380A、c.2327_2378del、c.A2378G、c.2376_2376delinsTT、c.C2368T、c.A2367G、c.G2365T、c.G2365A、c.2359delC、c.C2353T、c.C2348A、c.2293_2339del、c.C2332T、c.T2330C、c.A2317T、c.A2317G、c.G2314T、c.A2308T、c.C2302T、c.2300delA、c.G2299T、c.2293-1G>A、c.2293-1G>T、c.2293-2A>G、NC_000023.11(chrX):g.32501845G>T、c.2292+2T>C、c.2292+2T>G、c.2264_2291del、c.2281_2285del、c.2281_2284del、c.G2281T、c.T2276G、c.C2270G、c.2268delC、c.G2257T、c.2224_2242del、c.2225_2241del、c.G2236T、c.2230_2231del、c.C2227T、c.2217_2225del、c.2222delT、c.2214delA、c.G2215T、c.C2213G、c.2191delC、c.2187_2188del、c.2183_2184del、c.2169_2169TT、NC_000023.11(chrX):g.32518132CTAA>AAAG、c.2169-1G>T、c.2169-1G>A、NC_000023.11(chrX):g.32518134AAGACAGCAAAAAATAA>-、c.2169-2A>G、c.2169-2A>T、c.2168+1G>C、c.2168+1G>T、c.2142dupT、c.C2137T、c.A2128T、c.2125dupC、c.C2125T、c.2111delC、c.G2104T、c.2086_2098del、c.C2098T、c.2095_2095delinsTC、c.2071_2093del、c.A2089T、c.2079dupG、c.C2077T、c.2007_2073del、c.G2074T、c.2069_2070del、c.2061_2067del、c.2054dupT、c.G2047T、c.G2047T、c.2044dupA、c.2034_2037del、c.2034delG、c.2032_2033del、c.C2032T、c.C2017T、c.T2006C、c.2002delG、c.1993_2001del、c.C1997A、c.1980_1992del、NC_000023.11(chrX):g.32565692TATCAC>-、c.1992+2T>G、c.1992+1G>T、c.C1990T、c.1980delG、c.1978_1979del、c.1979delA、c.1974delT、c.A1967G、c.C1966T、c.T1961A、c.1952_1953C、c.G1952A、c.1945delC、c.1940_1941del、c.A1934G、c.G1928A、c.1912delC、c.C1912T、c.1905_1906del、c.C1904G、c.1901dupA、c.1899_1901CTTCTTTCAACACTGG、c.1898dupA、c.C1886G、c.1881delT、c.1872delA、c.C1873T、c.C1865G、c.1860_1861del、c.1859delT、c.1853delG、c.T1850C、c.C1843T、c.1836_1837TT、c.A1837T、c.G1831T、c.1817delT、NC_000023.11(chrX):g.32565884G>T、c.1812delC、c.1812+1G>A、c.C1793G、c.C1793G、c.1760_1791del、c.1784_1788del、c.G1783T、c.C1777T、c.1773delA、c.1758delC、c.A1732T、c.G1729T、c.1726delT、c.C1727A、c.T1724C、c.G1721A、c.1713delT、c.1713dupT、c.C1707A、NC_000023.11(chrX):g.32573642A>C、NC_000023.11(chrX):g.32573645A>G、c.1704+2T>A、c.1704+1G>A、c.1704+1G>C、c.1704+1G>T、c.C1702T、c.G1699T、c.1684dupC、c.C1684T、c.C1684T、c.G1683A、c.G1682A、c.1666delG、c.G1666A、c.C1663T、c.1654_1655insAC、c.G1652A、c.1648dupC、c.G1642T、c.G1638A、c.G1637A、c.A1635G、c.A1633T、c.1627delA、c.G1619A、c.C1615T、c.G1612T、c.G1609T、c.1603_1605CT、c.1603-1G>A、c.1603-1G>T、c.1603-2A>C、c.1603-2A>T、c.1602+1G>-、c.1602+1G>A、c.1602+1G>C、c.1601delA、c.G1602A、c.G1602T、c.1593delA、c.C1594T、c.1590delA、c.1574delC、c.G1564T、c.G1555T、c.1540dupG、c.1533_1536del、c.1527_1530del、c.1529_1530del、c.1519delG、c.1510dupC、c.C1510T、c.C1504T、c.1498delC、c.C1489T、c.1483-1G>C、c.1483-2A>C、NC_000023.11(chrX):g.32595884A>C、c.1482+1G>-、c.1482+2T>A、c.1481_1482del、c.1482+1G>A、c.C1474T、c.C1471T、c.C1465T、c.G1438T、c.G1429T、c.1427_1428insGA、c.G1426T、c.1412delC、c.A1396T、c.1394delC、c.1390delC、c.G1389A、c.G1388A、c.1376_1377del、c.1376delA、c.1376dupA、c.1374delA、c.1373_1374del、c.1374dupA、c.G1375T、c.A1372T、c.1365_1366del、c.C1363T、c.C1357T、c.1350_1351AT、c.G1351T、c.1346delT、c.1346dupT、c.1341_1342del、c.1341_1342T、c.A1339T、c.1336_1337del、c.1336delC、c.A1337G、NC_000023.11(chrX):g.32614462T>C、NC_000023.11(chrX):g.32626362G>C、c.1329_1331del、c.1331+2T>C、c.1331+1G>T、c.1331+1G>A、c.1327dupA、c.1323_1324G、c.1323delA、c.C1324T、c.G1318A、c.1300_1310del、c.C1310G、c.1307_1308insGT、c.1297_1298insAT、c.1294dupG、c.G1292A、c.1289delG、c.C1286A、c.1283delA、c.T1280C、c.T1280G、c.C1267T、c.C1261T、c.G1255T、c.1252_1253insTGAAGAAA、c.1240_1249del、c.G1249T、c.C1238G、c.A1231T、c.1208delG、c.1206_1207AT、c.G1207T、c.1205dupT、c.1201delC、c.1193_1200del、c.C1201T、c.1198_1199insA、c.1188dupT、c.1183_1186TGTCAAATATTGGTAATA、c.1181delG、c.C1177T、c.1152delG、c.1150-2A>-、c.1150-2A>C、c.1150-2A>T、c.1150-2A>G、NC_000023.11(chrX):g.32644316G>C、c.1149+2->G、c.1149+2T>G、c.1149+2T>C、c.1149+1G>A、c.G1149T、c.1147delG、c.1132_1136del、c.1135_1136insCAGT、c.1134delG、c.C1132T、c.G1117T、c.G1099T、c.A1098T、c.G1097A、c.C1093T、c.1083_1090del、c.C1087T、c.1082_1085GAAGAAGTGCTTGCAATG、c.1076delA、c.1067_1070CTCTT、c.G1062A、c.G1061A、c.T1055G、c.1036delA、c.C1033T、c.T1032A、c.G1012T、c.G1006T、c.C998A、c.A994T、c.992delG、c.967dupG、c.966_967insT、c.T965A、c.961-1G>A、NC_000023.11(chrX):g.32650983G>A、NC_000023.11(chrX):g.32651077T>G、c.960+2T>G、c.C956G、c.C907T、c.899_903TCTAG、c.C903A、c.C903G、c.C894G、c.C883T、c.857_858del、c.G853T、c.841_844del、c.A835G、NC_000023.11(chrX):g.32698013T>C、c.831+2T>C、c.831+1G>A、c.831+1G>T、c.G831T、c.C829T、c.C826T、c.A821G、c.C811T、c.A804C、c.C799T、c.783_793del、c.784_786TAG、c.783dupT、c.777delA、c.A775T、c.772_773del、c.773dupC、c.770_773AAATGTTGCAAGTG、c.G754T、c.G748T、c.C745T、c.C724T、c.C721T、c.715_716del、c.709delC、c.C709T、c.T707G、c.C701A、c.C701G、c.697_698insGT、c.C693A、c.T691G、c.T691A、c.689delT、c.688delA、c.T686A、c.676_678del、c.A673T、c.669delA、c.650_657del、c.T653G、NC_000023.11(chrX):g.32738791T>C、NC_000023.11(chrX):g.32738868T>G、NC_000023.11(chrX):g.32809488C>T、c.649+2T>C、c.649+1G>T、c.649+1G>A、c.645delT、c.G640T、c.633dupA、c.625delA、c.620dupT、c.T620G、c.C616T、c.T615A、c.597_614CTAGTTTC、c.C596A、c.593dupA、c.C583T、c.C580T、c.C572G、c.C568T、c.C565T、c.C564A、c.G549A、c.547dupT、c.544dupG、c.531-1G>C、c.531-1G>A、c.531-2A>G、NC_000023.11(chrX):g.32809627A>T、NC_000023.11(chrX):g.32809627A>C、c.530+1G>-、c.530+2T>C、c.530+1G>T、c.530+1G>A、c.522_523del、c.516delC、c.T515A、c.G511C、c.C503A、c.T500C、c.G497T、c.G496T、c.A494T、c.484_493TGGCTTTGAAT、c.G488A、c.G488C、c.486_487insGC、c.T487G、c.482_484del、c.A481C、c.475_476del、c.C474G、c.471delC、c.462dupT、c.457dupC、c.C457T、c.T453A、c.T450G、c.A442C、c.C440A、c.C440G、c.C436T、c.433delC、c.G434A、c.G434C、c.C433T、c.G429A、c.G428A、c.418delC、c.A412T、c.G409T、c.402_405del、c.C394T、c.386delC、c.377delA、c.372delG、c.367_368del、c.366dupT、c.364_365T、c.360dupC、c.A361T、c.358-1G>C、c.358-2A>G、c.358-2A>T、c.357+2T>A、c.357+1G>T、c.357+1G>C、c.C355T、c.G354A、c.G353A、c.T352A、c.T347C、c.G336A、c.G335T、c.321delT、c.312_313del、c.A313T、c.305delG、c.305dupG、c.294delC、c.282dupT、c.280delA、c.T272A、c.265-1G>C、c.265-1G>A、c.265-2A>G、NC_000023.11(chrX):g.32823850T>C、c.264_264del、NC_000023.11(chrX):g.32844778C>G、NC_000023.11(chrX):g.32844778C>A、NC_000023.11(chrX):g.32844778C>T、NC_000023.11(chrX):g.32844780->AC、c.264delT、c.264+1->T、c.264+1G>A、c.264+1G>T、c.C253T、c.251dupT、c.G245C、c.238delG、c.238dupG、c.G238C、c.A227T、c.198dupA、c.G199T、c.A196T、c.193_194del、c.193delG、c.G193T、c.187-1G>C、c.187-2A>G、NC_000023.11(chrX):g.32844866AACAA>-、NC_000023.11(chrX):g.32849721CACATAC>-、c.186+2T>C、c.186+2T>A、c.186+2T>G、c.186+1G>C、c.175_184del、c.183delA、c.183dupA、c.C178T、c.174_175del、c.167delG、c.160_162del、c.G163T、c.T161G、c.157_158GA、c.T158G、c.116_155del、c.151_153del、c.152dupT、c.151dupC、c.T152G、c.T149A、c.G139A、c.A137T、c.134delA、c.C133T、c.130dupC、c.128_129insGA、c.118delC、c.116dupA、c.114_115del、c.T110A、c.C103T、c.A100T、c.96delT、c.94-1G>T、c.94-1G>A、c.94-1G>C、c.94-2A>T、c.94-2A>G、NC_000023.11(chrX):g.32849828->A、NC_000023.11(chrX):g.33014549A>T、c.93+1G>C、c.93+1G>A、c.C82T、c.G79C、c.A77G、c.G72A、c.T70C、c.65dupC、c.58delA、c.53delA、c.G54T、c.C49T、c.40_41del、c.39delA、c.34_38del、c.32-2A>T、NC_000023.11(chrX):g.33174335C>T、NC_000023.11(chrX):g.33211276A>G、NC_000023.11(chrX):g.33211277C>G、NC_000023.11(chrX):g.33211277C>T、c.31+1G>A、c.31+1G>C、c.31+1G>T、c.14_15T、c.G12A、c.G11A、c.G9A、c.A1T、c.-54T>A
进一步的，分类为gene_variants的探针组还包括α-地贫(HBA1、HBA2)临床常见SNV位点379个(转录本：HBA1为NM_000558.4，HBA2为NM_000517.4)，如下：
HBA1相关位点151个：c.-9G>C、c.-4_-3del-、c.A1G、c.T2A、c.T2C、c.G4C、c.G19T、c.A20G、c.A22G、c.A29G、c.C30G、c.C38A、c.G40A、c.T43C、c.G44A、c.G44T、c.G45A、c.G46C、c.G47A、c.A49G、c.A49T、c.51delG、c.A50C、c.A62C、c.C63A、c.A74G、c.T75G、c.G84T、c.G85T、c.G91T、c.95+1G>A、NC_000016.10(chr16):g.176815A>G、NC_000016.10(chr16):g.176849C>T、c.96-2A>G、c.96-1G>A、c.T98A、c.T98C、c.100delT、c.G99A、c.T104G、c.111_113del、c.113_115del、c.114_115insGAA、c.G123C、c.132delC、c.132dupC、c.C133G、c.C133T、c.C136G、c.G142C、c.G142A、c.146_147insGAGCCG、c.149_172del、c.C153G、c.155_167del、c.G154C、c.G154A、c.C158G、c.G166C、c.T167C、c.A170C、c.A176T、c.G178C、c.G179A、c.181_183del、c.183_184TT、c.186delG、c.186_188del、c.189delG、c.T188C、c.192_224del、c.193_194insACGCGCTGACCA、c.G193A、c.G193C、c.A205C、c.A205G、c.C207G、c.G223A、c.G223C、c.A224G、c.G226T、c.C232T、c.C233A、c.A235C、c.237delC、c.C237G、c.247_254TGCA、c.G247A、c.G247C、c.G256C、c.C262G、c.C262T、c.A263C、c.G265T、c.C266T、c.A269T、c.C270G、c.A271G、c.A272G、c.A272C、c.G273C、c.C274T、c.C277T、c.G278T、c.G278A、c.T281C、c.G283A、c.A284C、c.A284G、c.C287A、c.C287G、c.A298T、c.A298G、c.G300T、c.300+1G>A、NC_000016.10(chr16):g.177280C>G、c.301-2A>G、c.301-2A>T、c.301-1G>C、c.C309A、c.C310T、c.312_327del、c.T313A、c.T320C、c.326delC、c.C326A、c.T329C、c.C332A、c.336_337insCACCTCCCCGCCGAG、c.C344A、c.G349A、c.352_353insTCA、c.C358T、c.C362A、c.G370C、c.T373C、c.T377A、c.G379C、c.A382G、c.385delT、c.T389C、c.393dupT、c.T394C、c.396delT、c.396dupT、c.T398G、c.404delC、c.T410G、c.T421C、c.G425T、c.*62_*64delTCC
HBA2相关位点228个：NC_000016.10(chr16):g.172822G>A、NC_000016.10(chr16):g.172854C>T、c.-23C>G、c.-21C>G、c.-4_-3del-、c.-2C>T、c.1delA、c.2delT、c.A1G、c.T2G、c.T2C、c.3_4insGT、c.G3T、c.G3C、c.G4C、c.G4A、c.T5C、c.A22G、c.A22T、c.G24C、c.26delC、c.A28T、c.A29G、c.C30G、c.G37C、c.C38A、c.40_45del、c.T43C、c.G46A、c.G46C、c.A49G、c.G51T、c.G52T、c.55delG、c.G55C、c.G56A、c.60delG、c.C61G、c.C63A、c.G64T、c.G64C、c.69delC、c.C69T、c.G70A、c.G70C、c.G70T、c.A71G、c.A71T、c.T75G、c.T75A、c.G77A、c.G79A、c.C80T、c.A83T、c.G84C、c.90_92del、c.T89C、c.91_92del、c.G91C、c.93_95del、c.A94G、c.A94T、c.A94C、c.A94G、c.G95A、c.95+1G>T、c.95+1G>A、NC_000016.10(chr16):g.173012G>A、NC_000016.10(chr16):g.173120C>A、c.96-2A>G、c.G96C、c.G96A、c.T98G、c.G99A、c.T104C、c.T106C、c.111delC、c.113_115del、c.C112T、c.C113T、c.C113G、c.C116T、c.118_124TACTTC、c.123delG、c.130delT、c.T130A、c.T130C、c.132delC、c.C132G、c.C134T、c.T139G、c.T140C、c.143delA、c.G142C、c.T146G、c.149_150del、c.149_172del、c.A148C、c.C150G、c.C150A、c.C153G、c.G154C、c.C161A、c.C163T、c.C163G、c.167dupT、c.T167C、c.C175T、c.A176T、c.C177G、c.C177A、c.G178C、c.G179A、c.A181G、c.A184T、c.G186C、c.G187A、c.T188G、c.G193A、c.T200C、c.A205C、c.A205G、c.C207A、c.C207G、c.C217G、c.A218G、c.223_225del、c.G223A、c.G226T、c.G226A、c.G226C、c.A227T、c.C233A、c.C237G、c.C237A、c.C241G、c.244delT、c.T244C、c.T251G、c.T251C、c.G256A、c.A257T、c.C262T、c.C264G、c.C266T、c.272_279del、c.A272G、c.G273T、c.C274T、c.T275A、c.278delG、c.T281G、c.G283A、c.G283T、c.G283C、c.C286T、c.C287G、c.C287T、c.T290A、c.C294A、c.A299G、c.300+2T>A、c.301-1G>A、c.A307C、c.C310T、c.A311T、c.A311G、c.T313C、c.G314A、c.323delT、c.C326A、c.T329G、c.C335T、c.338_349del、c.339delC、c.342delC、c.341_342insCC、c.T341G、c.347_357del、c.G349A、c.G349T、c.T352A、c.T353C、c.356delC、c.C356T、c.C358T、c.362_363insGGT、c.C362A、c.A368T、c.369_370GA、c.C369G、c.G370T、c.T377G、c.T377A、c.T377C、c.G379A、c.A380G、c.A382G、c.A382T、c.G384T、c.387delC、c.T389C、c.G391C、c.T394C、c.399_405del、c.T398G、c.C402A、c.C409A、c.T410C、c.C416T、c.418delA、c.A418C、c.A418G、c.C424T、c.T427C、c.T427A、c.T427G、c.A428C、c.A428T、c.A429T、c.*47G>C、c.*74_*89delCCTTCCTGGTCTTTGA、c.*92_*93delAA、c.*92A>G、c.*94A>C、c.*94A>G、c.*104G>T、NC_000016.10(chr16):g.173736A>G
进一步的，分类为gene_variants的探针组还包括β-地贫(HBB)临床常见SNV位点779个(转录本为NM_000518.4)，如下：
NC_000011.10(chr11):g.5225365C>G、c.*132C>A、c.*132C>T、c.*129T>C、c.*118A>G、c.*116_*115delAA、c.*114_*110delTAAAA、c.*113A>G、c.*111_*110delTA、c.*112A>T、c.*112A>G、c.*111A>G、c.*110T>G、c.*110T>A、c.*110T>C、c.*108A>C、c.*108A>G、c.*105_*93delATCTGGATTCTGC、c.*96T>C、c.*74A>G、c.*47C>G、c.*32A>C、c.*6C>G、c.443_444insTA、c.A443C、c.441_442insAC、c.T442C、c.C441G、c.C441A、c.A440C、c.A440T、c.C439G、c.C439T、c.T438A、c.A437G、c.T436C、c.T436A、c.T436G、c.434delA、c.G435T、c.G435C、c.425_433del、c.A434C、c.A434G、c.A433T、c.C432G、c.429_430del、c.430delC、c.A431G、c.A431C、c.C430A、c.C430G、c.C430T、c.C428T、c.C428A、c.424_426del、c.G427C、c.424delC、c.T425G、c.C424G、c.C422A、c.C422T、c.420dupT、c.G421A、c.413_418del、c.A419G、c.A419C、c.415_418T、c.417dupT、c.A418G、c.A418T、c.411_414del、c.G415C、c.412_413TG、c.404_413GCAG、c.G412A、c.G410A、c.408delT、c.397_407del、c.C407T、c.C407A、c.404_405del、c.G406C、c.394_404del、c.T404C、c.T404A、c.T401C、c.G400A、c.G400C、c.A399C、c.A399T、c.A398C、c.380_396del、c.A397C、c.A395G、c.A395C、c.C394A、c.391_392insGCCT、c.A392G、c.A392C、c.T391G、c.C389T、c.G388C、c.383_385del、c.C386T、c.C386A、c.G385C、c.A383G、c.A383C、c.C382G、c.C382A、c.C382T、c.380delT、c.380_381insCCAGT、c.379delG、c.T380A、c.T380G、c.371_378del、c.378delA、c.378_379insCCA、c.375delA、c.C374A、c.C374T、c.C374G、c.370delA、c.C371T、c.T368C、c.364delG、c.A365C、c.A365T、c.363delA、c.363dupA、c.G364T、c.G364C、c.G364A、c.G359C、c.G359A、c.357delT、c.T356C、c.A353C、c.A353G、c.C352T、c.349delC、c.349_350insTGAT、c.A350T、c.A350C、c.348_349G、c.C349T、c.346delG、c.335_346del、c.C347T、c.C347A、c.G346C、c.343_344G、c.T344C、c.340delG、c.T341A、c.T339A、c.T339G、c.326_337del、c.G338T、c.G338A、c.T337C、c.334delG、c.T335C、c.G334T、c.G334C、c.T332G、c.T332C、c.330delG、c.328delG、c.G328T、c.G328C、c.G328A、c.C327G、c.A326T、c.A325G、c.323dupG、c.G323A、c.T320C、c.T320G、c.T320A、c.C319G、c.317_318insAGCT、c.T317C、c.C316T、c.316-1G>C、c.316-1G>A、c.316-1G>T、c.316-2A>G、c.316-2A>C、NC_000011.10(chr11):g.5225729G>T、NC_000011.10(chr11):g.5225729G>C、NC_000011.10(chr11):g.5225733GAGGAA>TAGGAG、NC_000011.10(chr11):g.5225733G>T、NC_000011.10(chr11):g.5225733G>C、NC_000011.10(chr11):g.5225734A>C、NC_000011.10(chr11):g.5225740A>C、NC_000011.10(chr11):g.5225756T>G、NC_000011.10(chr11):g.5225796G>C、NC_000011.10(chr11):g.5225816T>C、NC_000011.10(chr11):g.5225832G>C、NC_000011.10(chr11):g.5225851T>C、NC_000011.10(chr11):g.5225872A>C、NC_000011.10(chr11):g.5225905T>G、NC_000011.10(chr11):g.5225923G>A、NC_000011.10(chr11):g.5225928A>-、NC_000011.10(chr11):g.5225964G>A、NC_000011.10(chr11):g.5225986A>G、NC_000011.10(chr11):g.5226372AGA>GG、NC_000011.10(chr11):g.5226572CT>-、NC_000011.10(chr11):g.5226572C>G、NC_000011.10(chr11):g.5226574CA>TCAGAGAACGT、c.315+2T>-、c.315+1G>-、c.315+2T>A、c.315+2T>G、c.315+2T>C、c.315+1G>C、c.315+1G>A、c.315+1G>T、c.G315C、c.G314C、c.A313T、c.C312G、c.T310G、c.T310A、c.T310C、c.C309A、c.307_308insTC、c.A308G、c.A308C、c.A307C、c.A307T、c.G306C、c.A305G、c.A305C、c.G304C、c.G304A、c.301_302TCTGAGAACT、c.C302T、c.C302G、c.C301G、c.T300A、c.A299G、c.A299T、c.A299C、c.297_298insTG、c.G298A、c.G298T、c.G298C、c.293_295del、c.T296A、c.T296G、c.T296C、c.280_294del、c.294_295insTGTGACAAGCTGCAC、c.G295A、c.C294A、c.C294G、c.A293T、c.A293C、c.C292A、c.C292T、c.T290C、c.C289G、c.287dupA、c.A287T、c.285_286insGAGCTGCACTGTGAC、c.A286T、c.A286G、c.283_284insTG、c.A284G、c.G283A、c.G283C、c.G283T、c.268_281del、c.T282G、c.T280C、c.C279G、c.A278G、c.A278C、c.C277G、c.C277A、c.C277T、c.275delT、c.T275C、c.T275G、c.270_273del、c.C274T、c.G273C、c.270_271del、c.A272C、c.A272G、c.G271C、c.G271T、c.G271A、c.T270A、c.T270G、c.G269A、c.G269C、c.266_267del、c.A268C、c.265_266del、c.266dupT、c.244_265del、c.T266G、c.T266C、c.C265G、c.262delA、c.C263A、c.C263T、c.261delC、c.A262C、c.253_260del、c.259_260AT、c.C260T、c.C260A、c.G259C、c.G259A、c.237_256del、c.T257C、c.T257G、c.T256C、c.C254A、c.251delG、c.G251A、c.A248G、c.A248T、c.A248C、c.A247T、c.A247C、c.A247G、c.244delC、c.T245G、c.T245A、c.C244T、c.232_242TACCTGGACAG、c.240delC、c.G238A、c.G238C、c.235delC、c.235dupC、c.T236C、c.C235G、c.C232G、c.C232T、c.229_230del、c.230delC、c.224_229del、c.C230A、c.G229C、c.221_227CTCGGTGCCA、c.226delC、c.T227G、c.T227C、c.G224A、c.G224T、c.220_221TT、c.217_221T、c.219_220AT、c.G220T、c.G220A、c.T219A、c.217dupA、c.G218C、c.216delT、c.216dupT、c.T215C、c.206_212del、c.C212G、c.C212T、c.C212A、c.210delT、c.G211C、c.209delG、c.G208A、c.T206A、c.T206C、c.203_204del、c.C205T、c.T203G、c.201delA、c.G202A、c.A201T、c.A200T、c.A200C、c.187_198del、c.A199G、c.189_195del、c.193_195del、c.A196C、c.A196G、c.194delG、c.G194C、c.G194A、c.G194T、c.A191C、c.A191G、c.C190T、c.C190A、c.182_187del、c.C188T、c.C188A、c.G187C、c.A185T、c.A184T、c.170_181del、c.T182C、c.T182A、c.179delA、c.G180C、c.A179C、c.165_177del、c.A178T、c.A178G、c.176dupC、c.C176G、c.A173G、c.170delG、c.G170A、c.G169C、c.G169T、c.166delA、c.166dupA、c.T167A、c.165delT、c.163dupG、c.T164A、c.162delT、c.C161T、c.G160A、c.158delA、c.158_159insCTCCTGA、c.A158G、c.G157A、c.155delC、c.C155G、c.153delT、c.A151T、c.C149T、c.146delT、c.146_147insTCT、c.146_147insATCT、c.T146G、c.T146C、c.143dupA、c.142dupG、c.A143T、c.G142T、c.131_139del、c.G140A、c.138delT、c.138_139insA、c.138dupT、c.T137A、c.T137C、c.T137G、c.135delC、c.C134G、c.130dupG、c.126_130A、c.129delT、c.126_129del、c.129dupT、c.G130A、c.G130T、c.G130C、c.T129G、c.T128G、c.T128C、c.126delC、c.T127C、c.T127A、c.T127G、c.125dupT、c.T125G、c.T125A、c.T125C、c.123delG、c.G122C、c.G122A、c.114_120del、c.119delA、c.111_118del、c.118delC、c.117_118del、c.A119G、c.C118T、c.115delA、c.C116T、c.C116G、c.C116A、c.114delG、c.A115C、c.G114T、c.G114C、c.G114A、c.112delT、c.G113C、c.G113A、c.T112C、c.110delC、c.C110A、c.C110G、c.C109T、c.C109A、c.C109G、c.C108G、c.C108A、c.A107G、c.A107T、c.102_104del、c.T104A、c.G103C、c.G103T、c.G103A、c.T98C、c.T98G、c.T98A、c.C97G、c.93_95del、c.94delC、c.33_94del、c.94_95insGGC、c.T95C、c.T95G、c.C94G、NC_000011.10(chr11):g.5226800CTAAGGGTGGGAAAATA>-、c.G93T、c.G93C、c.93-1G>A、c.93-1G>C、c.93-2A>C、c.93-2A>G、NC_000011.10(chr11):g.5226802A>C、NC_000011.10(chr11):g.5226814A>C、NC_000011.10(chr11):g.5226821A>-、NC_000011.10(chr11):g.5226820C>T、NC_000011.10(chr11):g.5226822A>G、c.76_92del、NC_000011.10(chr11):g.5226923T>C、NC_000011.10(chr11):g.5226924A>G、NC_000011.10(chr11):g.5226925C>G、NC_000011.10(chr11):g.5226925C>T、NC_000011.10(chr11):g.5226925C>A、c.92+2T>G、c.92+2T>C、c.92+2T>A、c.92+1G>C、c.92+1G>T、c.92+1G>A、c.91delA、c.G92A、c.G92C、c.A91C、c.A91G、c.89delG、c.C90T、c.G89A、c.G88A、c.85delC、c.85dupC、c.T86C、c.T86A、c.T86G、c.C85A、c.81_83CG、c.C83A、c.C83G、c.G82T、c.G82T、c.69_80del、c.77_79del、c.79_80insT、c.A80C、c.78dupT、c.G79A、c.G79T、c.G79A、c.G77A、c.68_75del、c.74delG、c.68_74del、c.T75A、c.71_73del、c.G74A、c.73_73delinsCAC、c.T71C、c.T71A、c.T71G、c.G70T、c.G70A、c.67_68CC、c.64_67del、c.A68T、c.A68G、c.A68C、c.G67A、c.G67C、c.G67T、c.64dupG、c.A65T、c.A65G、c.G64T、c.G64A、c.G64C、c.T62C、c.T62A、c.T62G、c.G61A、c.54_59del、c.C60A、c.A59G、c.T56G、c.G55A、c.53dupA、c.A53T、c.51delC、c.A52T、c.50delG、c.50dupG、c.C51T、c.G50A、c.G49C、c.G48A、c.46delT、c.G47A、c.20_45del、c.45dupG、c.T46A、c.G45A、c.44delT、c.44dupT、c.T44C、c.T44G、c.43delC、c.34_42del、c.C41T、c.C41A、c.36delT、c.A37C、c.22_34del、c.T35A、c.33delC、c.G34A、c.G34T、c.C33A、c.C33A、HBB:NM_000518:wholegene、c.C32A、c.C32T、c.30dupT、c.28_29insTA、c.C29A、c.C29G、c.27delG、c.27dupG、c.25_26del、c.26_27insAGAA、c.G27C、c.A26C、c.A26G、c.22_24del、c.24dupG、c.23delA、c.G24T、c.A23T、c.A23G、c.G22T、c.G22C、c.20delA、c.18_19del、c.19delG、c.A20C、c.A20T、c.15_19ATCTT、c.17_18del、c.G19T、c.G19C、c.G19A、c.C17T、c.C17G、c.10_16TCTGACT、c.C16G、c.C16T、c.C14A、c.T11A、c.9delT、c.C10G、c.C10A、c.8delA、c.T9G、c.A8G、c.A8C、c.5_6del、c.C7T、c.4delG、c.T5C、c.G4A、c.G4C、c.G4T、c.G3A、c.G3T、c.G3C、c.T2C、c.T2G、c.T2A、c.A1C、c.A1G、c.-7_-10delAACA、c.-6G>C、c.-12C>T、c.-18C>G、c.-21T>A、c.-28delT、c.-29G>T、c.-29G>A、c.-31delC、c.-31C>T、c.-41delT、c.-43C>T、c.-48A>T、c.-50A>G、c.-50A>T、c.-50A>C、NC_000011.10(chr11):g.5227082T>G、NC_000011.10(chr11):g.5227082T>C、NC_000011.10(chr11):g.5227097TT>-、NC_000011.10(chr11):g.5227096C>G、NC_000011.10(chr11):g.5227096C>A、NC_000011.10(chr11):g.5227097T>G、NC_000011.10(chr11):g.5227098T>C、NC_000011.10(chr11):g.5227098T>A、NC_000011.10(chr11):g.5227099T>G、NC_000011.10(chr11):g.5227099T>C、NC_000011.10(chr11):g.5227101A>-、NC_000011.10(chr11):g.5227100T>C、NC_000011.10(chr11):g.5227101A>T、NC_000011.10(chr11):g.5227101A>G、NC_000011.10(chr11):g.5227102T>G、NC_000011.10(chr11):g.5227102T>C、NC_000011.10(chr11):g.5227103G>A、NC_000011.10(chr11):g.5227103G>T、NC_000011.10(chr11):g.5227109C>-、NC_000011.10(chr11):g.5227110C>G、NC_000011.10(chr11):g.5227112T>G、NC_000011.10(chr11):g.5227113G>C、NC_000011.10(chr11):g.5227121C>T、NC_000011.10(chr11):g.5227123C>A、NC_000011.10(chr11):g.5227125C>-、NC_000011.10(chr11):g.5227125CCC>TTA、NC_000011.10(chr11):g.5227126C>A、NC_000011.10(chr11):g.5227127C>G、NC_000011.10(chr11):g.5227142G>A、NC_000011.10(chr11):g.5227143A>T、NC_000011.10(chr11):g.5227144T>A、NC_000011.10(chr11):g.5227147G>T、NC_000011.10(chr11):g.5227148C>G、NC_000011.10(chr11):g.5227154C>T、NC_000011.10(chr11):g.5227157G>A、NC_000011.10(chr11):g.5227157G>T、NC_000011.10(chr11):g.5227157G>C、NC_000011.10(chr11):g.5227158G>C、NC_000011.10(chr11):g.5227158G>A、NC_000011.10(chr11):g.5227158G>T、NC_000011.10(chr11):g.5227159G>A、NC_000011.10(chr11):g.5227159G>T、NC_000011.10(chr11):g.5227161G>C、NC_000011.10(chr11):g.5227161G>A、NC_000011.10(chr11):g.5227163G>A、NC_000011.10(chr11):g.5227164G>C、NC_000011.10(chr11):g.5227169A>T、NC_000011.10(chr11):g.5227172G>C、NC_000011.10(chr11):g.5227172G>A、NC_000011.10(chr11):g.5227173G>T、NC_000011.10(chr11):g.5227261C>T、NC_000011.10(chr11):g.5227294A>G
进一步的，分类为gene_variants的探针组还包括脊髓性肌萎缩症临床常见SNV位点92个(SMN1转录本为NM_000344.3，SMN2转录本为NM_017411.3)，位点如下：
SMN1相关位点91个：c.-39A>G、c.-7_9delGTTTGCTATGGCGATG、c.5C>T、c.5C>G、c.22dupA、c.40G>T、c.43C>T、c.48_55dupGGATTCCG、c.56delT、c.77G>A、c.81+1dupG、c.84C>T、c.88G>A、c.91dupT、c.100delT、c.109dupA、c.131A>T、c.198_214delAAAAACCACACCTAAAA、c.208_209insGTGT、c.275G>C、c.281T>G、c.286delG、c.283G>C、c.305G>A、c.312dupA、c.314_317dupACGG、c.326A>G、c.332C>G、c.346A>T、c.389A>G、c.399_402delAGAG、c.400G>A、c.406C>G、c.411delT、c.429_435delCCCAATC、c.431delC、c.439_443delGAAGT、c.469C>T、c.510_511delTG、c.524delC、c.549delC、c.558delA、c.562G>T、c.570G>A、c.585dupT、c.628-140A>G、c.662C>T、c.683T>A、c.684dupA、c.689C>T、c.722delC、c.734dupC、c.731C>T、c.734C>T、c.740dupC、c.744delC、c.770_780dupCTGATGCTTTG、c.779T>C、c.784A>G、c.785G>T、c.788T>C、c.788T>G、c.796T>C、c.811_814dupGGCT、c.815A>G、c.818A>G、c.819dupT、c.821C>T、c.823G>A、c.824G>C、c.826T>C、c.830A>G、c.834+2T>G、c.835-18_835-12delCCTTTAT、c.835-5T>G、c.835-3C>T、c.835-2A>G、c.835-2A>T、c.835-1G>A、c.835G>T、c.836G>T、c.836G>A、c.844C>T、c.861_862insT、c.863G>T、c.*3+1G>C、c.*3+4_*3+7delAGTC、c.*3+6T>G
SMN2相关位点1个：c.835-44A>G
进一步的，分类为gene_variants的探针组还包括耳聋GJB2相关SNV位点423个(转录本为NM_004004.6)：
c.*84T>C、c.T677G、c.T677A、c.C674T、c.A670C、c.G653A、c.647_650del、c.A650G、c.645delT、c.T641C、c.T638A、c.T638C、c.632_633del、c.T633A、c.G632A、c.A622C、c.A617G、c.A617C、c.A616C、c.T614C、c.C613G、c.608_609AA、c.T608C、c.G605T、c.T604C、c.592_600CAGTGTTCATGACATTC、c.G599C、c.G598T、c.G598A、c.C596T、c.594_595insCAGTG、c.G592A、c.G589T、c.G585C、c.T584C、c.A583G、c.T578A、c.576delA、c.575_576del、c.572delT、c.T571C、c.T569A、c.564_565del、c.A563G、c.559561del、c.C557T、c.C557A、c.G551A、c.G551C、c.C550T、c.C550G、c.C548T、c.G535A、c.G535C、c.516_532del、c.T533C、c.G532A、c.A526G、c.C524A、c.509_522del、c.C523A、c.G521C、c.G521A、c.T520C、c.C518G、c.C517T、c.G516A、c.G516C、c.T514A、c.511_512del、c.512_513insAACG、c.502_511del、c.511_512insAACG、c.G511A、c.G511T、c.509dupA、c.A509C、c.G506A、c.504_505insAAGG、c.T505C、c.A503G、c.G499A、c.C493T、c.T488C、c.486_487insT、c.A487G、c.A487C、c.T482C、c.G478A、c.G478C、c.475_476insTCTTCTATGTCATGTACG、c.A476T、c.G475A、c.G475T、c.A473G、c.464_465del、c.T465A、c.T458C、c.G457A、c.C456A、c.C456G、c.T452G、c.431_450del、c.G445A、c.G439T、c.G439A、c.C438T、c.435_436del、c.G428A、c.G428T、c.424_426del、c.C427T、c.C426G、c.T424C、c.T424A、c.T419G、c.G416A、c.A415T、c.G413A、c.A412G、c.409dupA、c.407dupA、c.C408A、c.A407G、c.405delC、c.402delG、c.G402A、c.G401A、c.390_399del、c.T400C、c.G399A、c.G398A、c.T397G、c.C394G、c.G389C、c.G389T、c.G389A、c.G385A、c.G385T、c.383_384insTCCGCAT、c.C384G、c.G380T、c.G380A、c.C379T、c.377_378insATGCGGA、c.C370T、c.367delA、c.C368A、c.A365T、c.363delC、c.355_363del、c.T362A、c.360delG、c.358_360del、c.G358A、c.356_357insTCGA、c.G355A、c.G355T、c.345dupT、c.T344G、c.A341G、c.G340T、c.G340A、c.T339G、c.334_335del、c.G336T、c.A335T、c.A331G、c.329delA、c.328delG、c.327_328del、c.327_328A、c.314_327del、c.G328A、c.313_326del、c.G326T、c.G326A、c.310_323del、c.A319G、c.C318A、c.303_316del、c.T317A、c.313_314del、c.314delA、c.A314G、c.A307T、c.301_303del、c.A302G、c.299_300del、c.T300A、c.298_299insCGGAGAC、c.A299T、c.A299C、c.296_297del、c.C298T、c.290_295CCCG、c.G293C、c.G293A、c.C292T、c.290dupA、c.284_285insCACGT、c.G283A、c.G279A、c.T278C、c.A277G、c.269delT、c.269dupT、c.T269G、c.T269C、c.C268G、c.T266C、c.C263G、c.C263T、c.C263A、c.G262T、c.G262C、c.258_260del、c.C257G、c.C257T、c.C254A、c.T253C、c.T251C、c.247_249del、c.G250A、c.G250T、c.G250C、c.C249G、c.T247A、c.C246G、c.T245A、c.A244G、c.C241G、c.G240C、c.236_239AGATCCG、c.A239C、c.A239G、c.A239T、c.C238T、c.C238A、c.235delC、c.T236C、c.C235G、c.232dupG、c.G232A、c.G232T、c.G231A、c.G230A、c.T229C、c.T227C、c.G224A、c.C223T、c.A218G、c.C217T、c.C215G、c.T212C、c.T212A、c.C209T、c.C209G、c.C208G、c.C208T、c.T205C、c.C204G、c.A203G、c.A200G、c.C199A、c.G196A、c.G196C、c.C195A、c.C195G、c.A194G、c.T193C、c.176_191del、c.C192A、c.G191A、c.187delG、c.T188C、c.G187T、c.G187A、c.184_185insT、c.A181C、c.G179A、c.T178G、c.176delG、c.G176C、c.G176T、c.G175C、c.G175A、c.C173G、c.171_172TT、c.C172G、c.C169T、c.167delT、c.T167C、c.C164A、c.A163C、c.A163G、c.C162A、c.A161T、c.A161G、c.A160C、c.155_158del、c.T157C、c.153delT、c.G154C、c.A149C、c.147delC、c.G148A、c.G148T、c.C146T、c.138_143del、c.G139A、c.G139C、c.G139T、c.T138G、c.G136A、c.G134A、c.G133A、c.G132C、c.G132A、c.G131C、c.G131A、c.G131T、c.129delG、c.T130G、c.125_127del、c.127delG、c.T128G、c.G127A、c.G127T、c.G127C、c.G126T、c.G124A、c.A121G、c.C119A、c.C119T、c.C119G、c.G118T、c.T113C、c.T110C、c.G109A、c.G109C、c.T107C、c.T104G、c.G102A、c.T101G、c.T101C、c.99delT、c.A100T、c.A100G、c.T98C、c.T98A、c.G95A、c.G95T、c.93delT、c.C94T、c.C94A、c.C94G、c.T91A、c.88delA、c.T89A、c.85_87del、c.A88G、c.A88C、c.C82A、c.G79A、c.G71T、c.G71A、c.31_68del、c.G66T、c.51_62A、c.G62A、c.G61A、c.T60G、c.T59C、c.A58C、c.G56C、c.A55G、c.A55C、c.C53T、c.C50T、c.C50A、c.A47G、c.31_44del、c.A44C、c.C42G、c.A40T、c.A40G、c.G37A、c.35delG、c.35dupG、c.G35T、c.G35A、c.G34C、c.G34T、c.G32A、c.28_29TG、c.28delC、c.T29C、c.23_24insA、c.G24A、c.C23T、c.A20C、c.C19T、c.T17C、c.A13G、c.11delG、c.G11A、c.G9A、c.7dupT、c.T7C、c.G3T、c.A1G、c.-1G>A、c.-15C>T、c.-3202G>T、GJB2:NC_000013.11(chr13):g.20189605T>G、GJB2:NC_000013.11(chr13):g.20189609A>G、GJB2:NC_000013.11(chr13):g.20189615G>A、GJB2:NC_000013.11(chr13):g.20191991G>A、GJB2:NC_000013.11(chr13):g.20192751C>T、GJB2:NC_000013.11(chr13):g.20192781A>T、GJB2:NC_000013.11(chr13):g.20192782C>T、GJB2:NC_000013.11(chr13):g.20193019G>A
进一步的，分类为gene_variants的探针组还包括耳聋GJB3相关SNV位点39个(转录本为NM_024009.3)：
c.G34A、c.G34C、c.G35A、c.G79A、c.G88A、c.C94T、c.T101C、c.C124T、c.G125C、c.G131C、c.G134A、c.G141C、c.143_145del、c.A166C、c.194_196del、c.G250A、c.T256A、c.G298A、c.G302A、c.G317A、c.C403G、c.T409C、c.C411A、c.C411G、c.421_423del、c.A421G、c.T437C、c.G459T、c.G474A、c.A497G、c.G520A、c.T529G、c.C538T、c.G547A、c.G580A、c.C605A、c.C625T、c.C667A、c.G766A
进一步的，分类为gene_variants的探针组还包括耳聋SLC26A4相关SNV位点585个(转录本为NM_000441.2)：
c.-103T>C、NC_000007.14(chr7):g.107660799A>G、NC_000007.14(chr7):g.107660856G>C、NC_000007.14(chr7):g.107661637A>G、c.T2C、c.T2G、c.G3C、c.C15A、c.G17T、c.C23A、c.C28A、c.39delC、c.43dupG、c.55delA、c.T58C、c.65dupT、c.C68A、c.C70G、c.G71T、c.G71A、c.C73T、c.C73A、c.T79A、c.C81A、c.A82C、c.A82G、c.C84A、c.G85C、c.A86G、c.G87C、c.G109T、c.119delT、c.129dupC、c.G128A、c.139dupC、c.C147G、c.T149G、c.T149C、c.A154T、c.164delG、c.164+1G>C、NC_000007.14(chr7):g.107661807TAGC>GAGG、c.164+2T>C、NC_000007.14(chr7):g.107663283T>G、NC_000007.14(chr7):g.107663291G>A、c.165-2A>G、c.165-1G>A、c.C170A、c.C170G、c.C200G、c.T203C、c.C209T、c.218delA、c.G222T、c.C225G、c.C226T、c.C227T、c.A230T、c.T232C、c.234delC、c.A233G、c.C235T、c.G236A、c.A241G、c.G249A、c.G259T、c.G262A、c.C269T、c.279delT、c.T279A、c.C281T、c.G284C、c.T290A、c.C296G、c.T299C、c.G304A、c.304+2T>C、c.305-2A>G、c.C311T、c.A314G、c.C317A、c.C317T、c.322delC、c.G328A、c.C334T、c.336dupT、c.G340A、c.T343G、c.G346A、c.G347T、c.G347A、c.349delC、c.C349T、c.360dupT、c.C367T、c.382_384AA、c.387delC、c.G391A、c.G392T、c.C395T、c.T397A、c.C398A、c.C398T、c.A400G、c.C403T、c.A404G、c.406_410del、c.T409C、c.C410T、c.413delT、c.G412C、c.G412T、c.T413A、c.415+2T>C、NC_000007.14(chr7):g.107672252A>G、NC_000007.14(chr7):g.107672255A>G、c.416-1G>A、c.G416T、c.G416C、c.C419A、c.T421C、c.T422C、c.C425G、c.C425T、c.A439G、c.T440C、c.G441A、c.G445A、c.451delG、c.454delG、c.T481A、c.G487C、c.G487A、c.A493C、c.496delA、c.G497A、c.504delA、c.A532C、c.G542C、c.G554C、c.G556T、c.T563C、c.G565T、c.572delC、c.C578T、c.T587A、c.G589A、c.T596C、c.600+1G>T、c.600+2T>A、c.601-1G>A、c.G611T、c.624_632ACTTGGC、c.G626A、c.G626T、c.A641G、c.T644C、c.661dupG、c.G664A、c.G665T、c.G665C、c.G665A、c.T668C、c.T678C、c.G679C、c.681_697del、c.C683A、c.G691A、c.G691C、c.T692A、c.T695G、c.G697C、c.A704G、c.C706G、c.708delA、c.T707C、c.T716A、c.733delA、c.A736C、c.750_753del、c.T749C、c.T754C、c.A757G、c.A760G、c.765+1G>A、NC_000007.14(chr7):g.107675112A>T、NC_000007.14(chr7):g.107675112A>C、NC_000007.14(chr7):g.107675113A>C、c.768delG、c.T770C、c.774_778del、c.779dupT、c.G796A、c.G811C、c.A812G、c.G841A、c.G845A、c.G849C、c.862dupT、c.879_880del、c.888delC、c.C890A、c.A898C、c.C902T、c.G907C、c.T911A、c.916dupG、c.917delT、c.T917G、c.G918A、c.918+1G>A、c.918+2T>C、NC_000007.14(chr7):g.107683398ACA>-、NC_000007.14(chr7):g.107683437T>G、c.919-2A>G、c.919_936CCCCA、c.A919G、c.C920T、c.C920A、c.923_929del、c.C929T、c.C941A、c.C941T、c.G946T、c.959dupA、c.A964G、c.A970T、c.974_977TTAAATTA、c.T983G、c.G1000T、c.G1001T、c.G1001C、c.G1001T、c.1001+1G>T、c.1001+1G>A、c.1001+2T>C、NC_000007.14(chr7):g.107683541A>G、NC_000007.14(chr7):g.107683542G>T、NC_000007.14(chr7):g.107683542G>C、NC_000007.14(chr7):g.107683567A>G、NC_000007.14(chr7):g.107689044A>C、NC_000007.14(chr7):g.107689044A>G、NC_000007.14(chr7):g.107689045C>G、NC_000007.14(chr7):g.107689049C>G、c.1002-1G>T、c.T1003C、c.T1003G、c.T1004C、c.1019delT、c.1021dupC、c.T1061C、c.C1079T、c.1086dupT、c.A1087G、c.G1102T、c.G1102A、c.A1105T、c.A1105G、c.C1115T、c.A1124G、c.1131_1133del、c.G1138A、c.1146delC、c.C1146G、c.C1147G、c.1149+1G>A、NC_000007.14(chr7):g.107689203A>G、NC_000007.14(chr7):g.107690089TTTGTAGG>-、c.1150-1G>A、c.A1151G、c.C1160T、c.G1165C、c.G1165A、c.G1172A、c.C1173A、c.A1174T、c.A1175G、c.1178_1180del、c.G1187A、c.T1195C、c.1197delT、c.1197dupT、c.G1204A、c.C1211T、c.1217_1218del、c.G1216A、c.C1225T、c.G1226C、c.G1226T、c.G1226A、c.C1229A、c.C1229T、c.G1231C、c.G1231A、c.G1234A、c.1238delA、c.A1238C、c.A1238G、c.1240_1243AAAG、c.G1240A、c.A1243G、c.C1245A、c.A1246C、c.G1252A、c.C1259T、c.C1261A、c.A1262G、c.A1262T、c.A1262C、c.1263+1G>A、c.1263+2T>C、NC_000007.14(chr7):g.107694391T>A、NC_000007.14(chr7):g.107694400C>G、c.1264-1G>C、c.G1264A、c.T1265A、c.G1271A、c.T1277A、c.1280_1282del、c.C1286A、c.1299dupC、c.G1300A、c.C1301A、c.G1315A、c.G1317C、c.A1318T、c.T1322C、c.G1327C、c.1334_1335insAGTC、c.T1334G、c.C1336T、c.A1337G、c.1339delA、c.1341delG、c.1341+1G>C、NC_000007.14(chr7):g.107694483A>C、NC_000007.14(chr7):g.107694617->CAGT、c.1342-2A>C、c.1342_1343insCGGTCTTGGCAG、c.C1343T、c.C1343A、c.A1363T、c.C1367A、c.A1369G、c.A1369T、c.A1370T、c.C1371A、c.T1373C、c.1392delG、c.G1397A、c.C1405T、c.G1409A、c.1412delT、c.G1415A、c.1423delA、c.1437+1G>A、NC_000007.14(chr7):g.107695919->T、c.T1439A、c.T1448A、c.C1454G、c.C1454T、c.1458dupT、c.1468_1469GC、c.A1468C、c.T1472C、c.G1477T、c.G1483A、c.G1489C、c.G1489A、c.T1511C、c.T1517G、c.1519delT、c.A1522G、c.C1523A、c.T1529A、c.1533_1534del、c.C1540T、c.C1540A、c.A1541G、c.T1544G、c.T1544C、NC_000007.14(chr7):g.107696044G>A、NC_000007.14(chr7):g.107696045T>C、NC_000007.14(chr7):g.107696048C>G、NC_000007.14(chr7):g.107696048C>T、NC_000007.14(chr7):g.107698037T>G、c.1545-2A>G、c.1546dupC、c.C1546T、c.1549_1550insCTTGGAATGGC、c.1555_1556del、c.G1554A、c.C1574T、c.A1579C、c.1586delT、c.T1586G、c.T1588C、c.A1589C、c.C1590G、c.1594_1595T、c.A1594C、c.G1595T、c.A1607G、c.C1614T、c.1614+1G>A、c.1614+1G>T、c.1614+1G>C、NC_000007.14(chr7):g.107698118A>G、NC_000007.14(chr7):g.107700076A>G、c.1615-2A>G、c.1615-1G>A、c.1615-1G>C、c.A1615G、c.C1625G、c.T1634A、c.T1634C、c.A1639G、c.1645dupA、c.1648dupT、c.T1649A、c.G1655T、c.T1656G、c.C1658A、c.T1666C、c.A1667G、c.T1668A、c.G1670A、c.A1673T、c.A1673G、c.T1674G、c.G1678A、c.1687delA、c.1687dupA、c.1693_1694insA、c.T1693C、c.T1693G、c.G1694A、c.A1699T、c.1707+1G>A、NC_000007.14(chr7):g.107700180G>A、NC_000007.14(chr7):g.107701069CATTTTAAGTAACTTGA>-、NC_000007.14(chr7):g.107701083T>A、c.1708-2A>T、c.1708-1G>A、c.G1708C、c.T1714C、c.T1714G、c.T1716A、c.G1717T、c.G1720A、c.A1723G、c.T1730C、c.1733_1735del、c.1738_1739del、c.G1742T、c.G1743C、c.1746delG、c.1755_1756insAGGAAAATA、c.A1768T、c.G1784A、c.C1786T、c.T1790C、c.C1796T、c.G1803C、c.G1803A、c.1803+2T>C、NC_000007.14(chr7):g.107701821G>A、c.1825delG、c.T1826G、c.C1829A、c.1833delA、c.1862delT、c.G1864A、c.C1870G、c.G1873T、c.T1880G、c.1898delA、c.G1897A、c.G1905A、c.G1919A、c.G1920A、c.G1927T、c.T1949A、c.C1952T、c.T1958C、c.T1964A、c.A1969T、c.G1970A、c.G1970T、c.G1975C、c.T1976G、c.T1979G、c.G1981T、c.A1982G、c.C1983A、c.G1985A、c.G1987A、c.G1988A、c.G1990A、c.C1991T、c.A1993G、c.C1997T、c.T1999C、c.T2000C、c.T2000G、c.T2003C、c.G2005A、c.A2006T、c.C2007A、c.C2007G、c.T2009C、c.G2014A、c.G2015A、c.2027dupT、c.T2027A、c.G2030C、c.G2034A、c.2035-1G>A、c.G2044T、c.T2048C、c.G2054T、c.G2059T、c.T2069C、c.T2074C、c.T2080C、c.2082delA、c.C2086T、c.G2089C、c.2089+1G>A、NC_000007.14(chr7):g.107709995AAAC>-、c.2090-1G>A、c.A2090C、c.A2090G、c.G2095A、c.2106delG、c.2105_2106insGCTGG、c.C2107G、c.T2108C、c.G2110A、c.G2110C、c.C2118A、c.2124delC、c.2125delT、c.A2134T、c.A2135T、c.2137delA、c.A2137G、c.T2139G、c.G2141A、c.G2145T、c.A2147G、c.A2149C、c.T2153C、c.G2160C、c.C2162T、c.C2167G、c.C2167T、c.A2168G、c.G2170A、c.A2171G、c.A2171T、c.2173_2174insCTAT、c.G2173C、c.A2176G、c.C2179T、c.2182dupT、c.2182_2183insG、c.T2182C、c.T2186C、c.G2190T、c.T2205G、c.G2211C、c.G2218A、c.G2219T、c.T2228A、c.C2234T、c.2235+2T>C、NC_000007.14(chr7):g.107712514T>A、c.A2283G、c.2320-2A>G、c.T2324C、c.C2326T、c.C2326G、c.A2343G、c.*69C>A
进一步的，分类为gene_variants的探针组还包括耳聋PRPS1相关SNV位点39个(转录本为NM_002764.3)：
c.T46C、c.C47T、c.A129C、c.G154C、c.G193A、c.A202T、c.A217G、c.G244C、c.G259A、c.A319G、c.G334C、c.G337T、c.A341G、c.A343G、c.T344C、c.C362G、c.C367G、c.C385A、c.A398C、c.G424C、c.T455C、c.G520A、c.G521T、c.G547C、c.C569T、c.G573C、c.A578T、c.C579G、c.C586T、c.C640T、c.G641C、c.T824C、c.C826T、c.A830C、c.T869C、c.G916A、c.G917A、c.G925T、c.935_936insATTC
进一步的，分类为gene_variants的探针组还包括耳聋MYO15A相关SNV位点311个(转录本为NM_016239.3)：
c.C263T、c.283dupA、c.373_374del、c.414delA、c.G442A、c.C514T、c.G535T、c.G554A、c.T613C、c.G625T、c.A671G、c.G700T、c.C742G、c.C843A、c.855dupT、c.C867G、c.C1047A、c.C1128A、c.1133delT、c.1134delC、c.1170_1171insGCCATCT、c.1179dupC、c.G1210T、c.C1223T、c.A1387G、c.T1454C、c.C1634T、c.G1651A、c.1656delC、c.G1721C、c.G1783A、c.T2152G、c.2279delC、c.C2336A、c.C2456A、c.2515delC、c.G2759A、c.C3026A、c.3306dupG、c.G3313T、c.3334delG、c.C3385T、c.C3505T、c.3524dupA、c.C3685T、c.C3742T、c.C3753G、c.3756+1G>T、c.3756+1G>A、c.3756+1G>C、NC_000017.11(chr17):g.18126313AGCCACGACGCTGAGGCCACCGTCTGCCCAGC>-、c.3757-2A>G、c.C3758T、c.A3833C、c.A3836G、c.C3844T、c.3862dupC、c.3866+1G>A、c.3867-1G>A、c.C3871T、c.G3892A、c.T3932C、c.G3944A、c.C3956G、c.C3971A、c.4010dupA、c.G4072A、c.C4101A、c.C4108T、c.A4139G、c.4142+1G>T、c.G4156A、c.C4176A、c.G4193A、c.G4198A、c.G4216A、c.G4240A、c.G4252A、c.C4273T、c.A4310G、c.T4313C、c.4320+1G>A、c.G4322T、c.G4351A、c.C4369T、c.T4441C、c.G4457T、c.C4528T、c.4537_4544del、c.C4549T、c.C4570T、c.4596+1->T、c.4596+1G>A、c.4597-2A>G、c.G4642A、c.C4643T、c.C4652A、c.4655+1G>A、c.G4660A、c.G4666A、c.A4669G、c.C4744G、c.T4747C、c.T4760C、c.4761_4762insGTTTCTAT、c.G4777A、c.G4780C、c.C4821A、c.C4823A、c.G4828A、c.C4888G、c.T4898C、c.4907_4909del、c.C4952T、c.C4998A、c.C5005T、c.5007+1G>C、c.5054dupC、c.5087dupT、c.5117_5118TT、c.G5117T、c.5133+1G>A、c.A5141T、c.T5183C、c.T5189C、c.C5203T、c.5212-2A>G、c.5285_5286del、c.C5287T、c.A5305G、c.5334delC、c.T5336C、c.T5417C、c.5419delT、c.5421_5437del、c.C5443A、c.G5492T、c.G5504A、c.T5507C、c.G5603A、c.5650-1G>A、c.C5692T、c.5805_5811del、c.C5809T、c.G5810A、c.T5835G、c.C5866T、c.5910+1G>T、c.G5925A、NC_000017.11(chr17):g.18143622G>A、c.C5977T、c.G5978A、c.6046+1G>A、c.C6061T、c.C6146A、c.6177+1G>T、c.6178-2A>G、c.T6194A、c.C6217T、c.C6218T、c.6273+1G>A、c.G6281A、c.6307dupG、c.A6331T、c.A6337T、c.G6340A、c.T6341G、c.G6371A、c.C6436T、c.G6437A、c.T6442A、c.6457delG、c.G6461A、c.C6479T、c.6486delG、c.T6550G、c.C6580T、c.C6589T、c.C6614T、c.G6634A、c.G6692C、c.T6703C、c.G6731A、c.6764+2T>A、c.G6787A、c.G6796A、c.A6845G、c.C6892T、c.G6893A、c.6941delG、c.6956+1G>A、NC_000017.11(chr17):g.18148961C>G、c.7003dupC、c.7045delG、c.7121_7124del、c.G7207T、c.7225delC、c.7296_7297insACCCCCAGGAG、c.7395+1G>A、NC_000017.11(chr17):g.18150768G>C、NC_000017.11(chr17):g.18150768G>A、c.7396-1G>A、c.C7550G、c.C7636T、c.G7679A、c.7708_7709insCA、c.C7720T、c.A7730T、NC_000017.11(chr17):g.18151531A>G、c.A7801T、c.G7822A、c.7893+1G>A、c.G7894C、c.G7894T、c.7966+2T>C、c.C7982A、c.7986dupG、c.C7990A、c.8033_8056del、c.T8050C、c.T8065C、c.8076delC、c.T8090C、c.8097delC、c.G8148T、c.8149-1G>A、c.G8158C、c.G8158A、c.C8182T、c.C8182G、c.G8183A、c.A8198C、c.T8222C、NC_000017.11(chr17):g.18154758A>G、c.A8300G、c.8307_8309del、c.G8324A、c.G8340A、c.T8375C、c.T8396A、c.8429_8447del、c.8431delG、c.G8450A、c.C8457G、c.G8467A、c.T8474C、c.C8552T、c.8601+2T>G、c.8602-1G>C、c.8634_8637del、c.C8707T、c.G8725A、c.C8767T、c.G8771A、c.8791delT、c.8797delT、c.G8812A、c.8820_8821insGT、c.8902_8931del、c.8968-1G>C、c.8968-1G>T、c.A9041G、NC_000017.11(chr17):g.18158644T>A、c.T9221C、c.9229+1G>A、c.9229+2T>C、c.9315dupC、c.G9319T、c.C9400T、c.G9408C、c.T9413A、c.A9437C、c.C9478T、c.C9514T、c.G9517A、c.9517+2T>C、c.9518-2->G、c.9518-2A>G、c.C9534G、c.C9571G、c.C9571T、c.G9572A、c.C9584G、c.9610_9612del、c.G9620A、c.9690+1G>A、c.A9781T、c.C9790T、c.G9876T、c.A9908G、c.G9948A、c.9956_9959del、c.9994_9995insGCCGGCCC、c.C10111T、c.C10181T、c.G10202A、c.10208_10209CCACCAGGCCCGTGCAGCTC、c.10245_10247del、c.10251_10253del、c.C10263G、c.G10266C、c.10361delT、c.G10394A、c.A10420G、c.C10425A、c.C10474T、NC_000017.11(chr17):g.18178766->A、c.T10502A、c.10567dupC、c.10573delA、c.A10573G
进一步的，分类为gene_variants的探针组还包括耳聋MYO7A相关SNV位点582个(转录本为NM_000260.4)：
c.-2147A>G、c.G3A、c.4_5insTGAT、c.18+2T>A、c.19-2->G、c.19-2A>G、c.19-1G>A、c.G20T、c.T29C、c.T47A、c.C52T、c.73_80del、c.G73A、c.C77A、c.C93A、c.132+2T>G、NC_000011.10(chr11):g.77142827G>A、c.133-2A>G、c.G141A、c.180delC、c.198_199insA、c.G199A、c.219delG、c.T218C、c.224dupA、c.G223C、c.C247A、c.C252G、c.C262T、c.G269C、c.A284G、c.285+2T>G、c.C287T、c.C318A、c.C324A、c.334_335insCCATCTACTCG、c.360delC、c.391delC、c.391dupC、c.C392T、c.C395T、c.C397G、c.C397T、c.C397A、c.399dupC、c.A398C、c.T401A、c.C448T、c.G458A、c.C462A、c.G470A、c.470+1G>A、c.471-2A>G、c.471-1G>A、c.G472A、c.C479G、c.G487A、c.G487C、c.A490T、c.A491G、c.A493G、c.495delG、c.C494T、c.C562G、c.578_579del、c.A577C、c.C578T、c.G592A、c.592+1G>T、c.592+1G>A、c.A610G、c.C616T、c.G617A、c.A620G、c.C629G、c.A631G、c.C634T、c.G635A、c.G640A、c.647_652del、c.653_658del、c.G652A、c.C687T、c.C689T、c.C700T、c.T703G、c.T707A、c.T710G、c.C721T、c.C721G、c.C721A、c.G722A、c.G722C、c.G724T、c.C730T、c.G731C、c.G735A、NC_000011.10(chr11):g.77157276C>T、c.G745T、c.A755G、c.797_799del、c.A803G、c.C834A、c.T848C、c.G849A、c.849+2T>C、NC_000011.10(chr11):g.77157397G>A、c.881_882insCAGCC、c.G905A、c.938delC、c.G940T、c.T977A、c.T977C、c.984dupG、c.G986A、c.T999G、c.1003+1G>A、c.G1007A、c.1061delC、c.1066_1067insATCTCTGC、c.G1093A、c.T1097C、c.C1117T、c.C1132A、c.1134_1135insGGGGAGACGGTGT、c.G1135A、c.G1138A、c.C1142T、c.1157_1158del、c.C1172T、c.C1183T、c.G1184A、c.G1189A、c.C1190A、c.G1200T、c.G1200T、c.1217_1224del、c.A1244G、c.A1258T、c.G1300C、c.1302delC、c.T1304A、c.T1307C、c.G1309A、c.A1325G、c.G1326C、c.1342_1343del、c.1343+1G>A、c.1344-2A>G、c.G1348C、c.T1355C、c.A1363C、c.C1370T、c.A1373T、c.C1384T、c.T1391G、c.1400_1401insGCA、c.A1403G、c.G1426T、c.T1436G、c.1454delT、c.A1459G、c.C1477T、c.A1478C、c.C1508T、NC_000011.10(chr11):g.77162845C>G、c.1555-1G>C、c.G1556A、c.G1556T、c.1563delC、c.A1580G、c.C1591T、c.1595delA、c.1617dupC、c.C1622T、c.G1667T、c.A1679C、c.G1690A、c.1690+1G>A、NC_000011.10(chr11):g.77166052G>A、c.1691-1G>A、c.T1697C、c.C1708T、c.1715delC、c.T1747C、c.G1797A、NC_000011.10(chr11):g.77172745C>G、c.1798-1G>-、c.1798-1G>A、c.C1820A、c.1833_1838del、c.C1837T、c.A1838G、c.1845delG、c.C1846T、c.T1849C、c.G1868A、c.C1884A、c.C1900T、c.G1901A、c.T1903C、c.C1913A、c.1923_1931del、c.1930_1931insCCAT、c.G1935A、c.1935+1G>A、NC_000011.10(chr11):g.77172889A>T、c.C1945T、c.1952_1953insAG、c.T1952C、c.1954delT、c.T1954C、c.G1955A、c.1959delG、c.C1969T、c.1977delA、c.C1976A、c.G1978A、c.A1993G、c.C1996T、c.G1997A、c.C2002T、c.G2003A、c.C2005T、c.G2011A、c.C2023T、c.C2028G、c.2036dupT、c.G2035A、c.C2055A、c.G2074A、c.C2115A、c.C2116T、c.G2164C、c.2171delC、c.2179dupT、c.T2183C、NC_000011.10(chr11):g.77175466TGAGCAC>-、c.2187+1G>T、c.2187+1G>A、c.2188-1G>T、c.A2210G、c.G2215T、c.G2236A、c.2239_2240del、c.C2254T、c.C2266T、c.G2269T、c.2283-1G>T、c.2283-1G>A、c.A2302T、c.2307delC、c.G2311T、c.C2323T、c.2336delG、c.C2361A、c.2367+1G>A、c.2367+1G>C、c.2425delC、c.C2461T、c.G2463C、c.G2476A、c.G2489A、c.2499delC、c.G2513A、c.C2557T、c.G2558A、c.C2617T、c.2656_2664del、c.2662dupA、NC_000011.10(chr11):g.77181371A>G、c.C2724G、c.2766_2779del、c.2795delC、c.T2837G、c.G2863A、c.2868_2872del、c.G2878T、c.G2904T、c.G2904C、c.2905-1G>A、c.C2914T、c.G2947T、c.3040_3043TACTTCCAGGGGACA、c.T3049G、c.T3080C、c.3108+1G>A、NC_000011.10(chr11):g.77182403G>A、c.3109-2A>G、c.3135dupC、c.T3134C、c.C3171G、c.A3238T、c.3260_3264CGCA、c.T3260C、c.C3262T、c.3264delG、c.C3289T、c.C3364A、c.3376-1G>A、c.G3397A、c.G3437A、c.T3461C、c.T3470A、c.G3476T、c.T3500A、c.C3502T、c.G3503C、c.G3503A、NC_000011.10(chr11):g.77184727G>A、c.3504-1G>C、c.G3508A、c.3520_3531del、c.G3527A、c.C3546A、c.C3547A、c.G3560T、c.3564_3570del、c.G3576A、c.3586_3587del、c.T3590C、c.C3594A、c.3596dupT、c.G3602C、c.C3610A、c.A3628T、NC_000011.10(chr11):g.77190017C>G、c.3631delT、c.3631-1G>A、c.G3652A、c.3657dupC、c.C3659T、c.G3670A、c.C3671A、c.C3674T、c.G3689A、c.3695_3705del、c.3701delC、c.C3701G、c.C3702G、c.C3718T、c.G3719A、c.C3728T、c.C3728G、c.C3731G、c.G3742A、c.3747delG、c.3750+2T>A、c.G3751C、c.3763delA、c.A3797G、c.C3827A、c.3847_3848insTCTG、c.G3862C、c.3872_3873del、c.G3892A、c.3904delT、c.3906_3907insATTG、c.G3924A、c.3924+1G>C、c.T3935C、c.C3978A、c.G3979A、c.C3987A、c.3998delA、c.4008delG、c.4012delC、c.G4018C、c.G4018A、c.G4029C、c.4031_4033del、c.4034_4048del、c.C4039A、c.G4045A、c.4065delC、c.4073delC、c.G4107T、c.C4108T、c.T4115G、c.C4117T、c.G4120A、c.4129dupT、c.G4152C、c.4153-2A>G、c.4159dupG、c.G4159A、c.4166delC、c.4184dupA、c.C4248A、c.4251delC、c.C4268T、c.C4280T、c.G4293A、c.4295delC、c.4323+2T>C、c.4323+2T>G、c.C4354T、c.G4360A、c.G4398A、c.C4400T、c.T4411C、c.T4418C、c.G4441C、c.G4441T、c.4442-2A>C、c.C4450T、c.C4475T、c.4482_4483insTG、c.G4485A、c.C4487A、c.C4487T、c.G4489C、c.4500_4501del、c.A4505G、c.C4510T、c.G4513T、c.4544_4551CA、c.C4589T、c.C4697T、c.C4740A、c.4769dupT、c.G4798C、c.G4805A、c.C4814T、c.C4814A、c.4816delA、c.4818delG、c.4838delA、c.G4882T、c.4910_4911del、c.4909_4910insAT、c.4917delG、c.C4916T、c.G4921A、c.G4944A、c.4996_4997del、c.A4996T、c.T5000A、c.C5004G、c.G5065A、c.C5068T、c.5069_5070insC、c.C5074T、c.C5095T、c.C5101T、c.C5122A、c.C5132A、c.5142_5144del、c.G5146T、c.A5156G、c.G5168C、c.5168+1G>A、NC_000011.10(chr11):g.77203057C>G、c.5169-2A>G、c.C5177T、c.5207dupC、c.C5215T、c.C5227T、c.T5233G、c.C5309A、c.T5320C、c.T5320G、NC_000011.10(chr11):g.77203220A>G、NC_000011.10(chr11):g.77204062T>G、c.G5345C、c.5360_5361del、c.C5392T、c.5411delT、c.G5421T、c.A5428T、c.G5434A、c.G5434C、c.A5464C、c.C5472G、c.5480+1G>A、c.5481-1G>T、c.G5502A、c.T5507C、c.T5510C、c.T5510A、c.T5516C、c.C5522G、c.C5537A、c.5561dupT、c.G5560A、c.5567delG、c.T5573C、c.C5581T、c.C5617T、c.G5618A、c.C5623T、c.5630delC、c.5636+1G>T、NC_000011.10(chr11):g.77206094C>G、c.5637-1G>A、c.C5647T、c.G5648A、c.C5660T、c.C5662T、c.C5686T、c.T5730A、c.5746delT、c.G5749T、c.T5753A、c.C5759A、c.C5785T、c.C5803A、c.5806_5808del、c.T5810C、c.G5824A、c.G5824T、c.5834_5837del、c.5836delT、c.G5856A、c.5856+1G>C、c.5856+1G>A、NC_000011.10(chr11):g.77207407G>C、NC_000011.10(chr11):g.77208403->TTGAG、c.G5866A、c.5879_5880del、c.5880_5882del、c.5884_5887del、c.5887_5889del、c.C5899T、c.G5916A、c.C5929T、c.G5944A、c.5945-1G>A、c.G5945A、c.5958dupA、c.C5968T、c.G5994A、c.6024delG、c.G6025A、c.G6028A、c.G6028T、c.A6041G、c.T6043C、c.6046_6047insACCA、c.C6049T、c.6051+1G>A、c.A6062G、c.C6070T、c.6077_6079del、c.G6092A、c.G6115C、c.G6115C、c.T6122A、c.6193delC、c.C6196T、c.6204_6205del、c.C6211T、c.C6220T、c.6230dupG、c.T6229A、c.A6232T、c.C6235T、c.A6316T、c.6321_6336del、c.G6321A、c.C6335G、c.G6337C、c.G6354C、c.6354+1G>A、c.6355-2A>G、c.6375delC、c.T6408G、c.G6409A、c.G6410A、c.G6424A、NC_000011.10(chr11):g.77213040G>C、c.6439-2A>G、c.6439-1G>A、c.T6470C、c.T6478G、c.G6487A、c.T6542C、c.C6551T、c.T6557C、c.G6560A、c.C6577T、c.G6610C
进一步的，分类为gene_variants的探针组还包括耳聋COCH相关SNV位点31个(转录本为NM_004086.3)：
c.G113A、c.T116A、c.C151T、c.T197G、c.G226A、c.G259T、c.G260T、c.G263A、c.C266A、c.T275A、c.C292T、c.309_311del、c.T326A、c.T326C、c.T341C、c.T349C、c.G355A、c.T362C、c.T368A、c.G485A、c.T1115C、c.1195_1212del、c.A1303G、c.G1459C、c.A1529G、c.T1535C、c.T1580G、c.A1621T、c.T1624C、c.G1625T、c.G1625A
进一步的，分类为gene_variants的探针组还耳聋DIABLO相关SNV位点2个(转录本为NM_019887.6)：
c.A641T、c.C377T
进一步的，分类为gene_variants的探针组还包括耳聋TMC1相关SNV位点108个(转录本为NM_138691.3)：
c.-32234A>C、c.16+1G>T、c.64+2T>C、c.64+2T>A、c.C100T、c.150delT、c.236+1G>A、c.236+1G>C、NC_000009.12(chr9):g.72700512T>G、c.237_239del、c.G247T、c.G256T、c.295delA、NC_000009.12(chr9):g.72700661A>G、c.G453A、c.453+2T>C、c.G458A、c.A534C、c.535+1G>C、c.535+1G>A、NC_000009.12(chr9):g.72751842T>A、c.536-1G>A、c.G545A、c.G582A、c.G589A、c.A596T、c.C604G、c.A616T、c.C624A、c.626_628del、c.645delC、c.A662G、c.741+1G>A、c.766delT、c.G773A、c.A776G、c.C790T、c.T797C、c.G800A、c.G804A、c.C821T、c.A830G、c.884+1G>A、c.G945A、c.C960A、c.1080_1084del、c.C1107A、c.G1114A、c.T1127C、c.T1141A、c.C1143G、c.C1165T、c.G1166A、c.C1171T、c.G1209C、c.G1209A、c.T1210C、c.1224+1G>T、c.1224+2T>C、c.T1247G、c.G1249A、c.G1250A、c.T1253A、c.G1259A、c.C1283A、c.G1312A、c.G1330A、c.C1333T、c.G1334A、c.T1363C、c.1396_1398del、c.1404+1G>T、c.T1444C、c.C1534T、c.C1541T、c.T1543C、c.1566+1G>A、c.1586_1587del、c.G1627A、c.G1676A、c.1696-1G>A、c.A1703G、c.G1714A、c.G1714C、c.T1718A、c.C1728G、NC_000009.12(chr9):g.72816213A>G、c.G1764A、c.A1765G、c.C1788A、c.T1808A、c.C1810T、c.C1810G、c.T1814C、c.T1939C、c.C1959G、c.A1960G、c.C1979T、c.T2004G、c.T2027A、c.T2030C、c.G2035A、c.G2050A、c.G2050C、NC_000009.12(chr9):g.72826999G>A、c.2130-1G>-、c.2210_2211insCT、c.2260+2T>A
进一步的，分类为gene_variants的探针组还包括包括耳聋DSPP相关SNV位点58个(转录本为NM_014208.3)：
c.T16G、c.C44T、c.C49A、c.C49T、c.C50T、NC_000004.12(chr4):g.87612080ATAGCCAGTATTTTCTACTTGGC>-、NC_000004.12(chr4):g.87612099T>G、NC_000004.12(chr4):g.87612102C>G、NC_000004.12(chr4):g.87612102C>A、c.52-2A>G、c.52-1G>A、c.G52T、c.T53A、c.C133T、c.G135T、c.135+1G>A、c.135+1G>T、c.135+2T>C、NC_000004.12(chr4):g.87612191A>G、c.A202T、c.G727A、c.1686delT、c.1830delC、c.1868_1871del、c.1871_1874del、c.1912_1915del、c.1916_1919del、c.1919_1922del、c.2040delC、c.2063delA、c.2134delA、c.2272delA、c.2349delT、c.2525delG、c.2593delA、c.A2615C、c.2666delG、c.2684delG、c.2688delT、c.3153delC、c.3179delG、c.3264_3265insCGATAGCAA、c.A3274G、c.3438delC、c.3456_3457insTAGCAGCGATAGCAGCGA、c.3480delT、c.3479_3480insTCTGC、c.3502_3503insGCAGC、c.3508_3520del、c.3533_3534insTA、c.3546_3550G、c.3560delG、c.3582_3591del、c.3625_3700del、c.3660_3661insATCT、c.3676delA、c.3682_3686del、c.3734_3742del
进一步的，分类为gene_variants的探针组还包括包括耳聋12S rRNA相关SNV位点8个(转录本为NC_012920.1)：
MT-CO1:m.7444G>A、MT-RNR1:m.1494C>T、MT-RNR1:m.1555A>G、MT-TH:m.12201T>C、MT-TL1:m.3243A>G、MT-TS1:m.7445A>G、MT-TS1:m.7505T>C、MT-TS1:m.7511T>C
进一步的，分类为gene_variants的探针组还包括先天性肾上腺皮质增生症基因CYP21A2相关SNV位点284个(转录本为NM_000500.9)：
NC_000006.12(chr6):g.32038115G>C、NC_000006.12(chr6):g.32038139A>G、NC_000006.12(chr6):g.32038350C>T、c.A1G、c.A1C、c.T2C、c.G3A、c.22_31del、c.29_30del、c.G46A、c.C49T、c.G59A、c.G60A、c.G65A、c.67dupT、c.G68A、c.G69A、c.80_92del、c.84dupC、c.C92T、c.C92A、c.A116T、c.C124T、c.127delC、c.135dupC、c.C137T、c.144delT、c.A143G、c.A163T、c.G169A、c.T178A、c.A188T、c.G194A、c.203-2A>G、c.203_204insTGTGGTGGT、c.A217C、c.A223T、c.T233C、c.257_258insGGCAGACTTTGCT、c.G258A、c.C269T、c.G272T、c.A274G、c.C286T、c.292dupT、c.292+1G>A、NC_000006.12(chr6):g.32038816G>A、NC_000006.12(chr6):g.32039015G>A、NC_000006.12(chr6):g.32039081C>G、NC_000006.12(chr6):g.32039087C>G、c.293-2A>G、c.C294A、c.A295G、c.304_305AA、c.C317T、c.T323G、c.332_339del、c.C339G、c.C341T、c.C346T、c.A359G、c.A364C、c.T368C、c.C371T、c.C373T、c.G374A、c.C377G、c.T389C、c.G392A、c.A394G、c.C397T、c.T419A、c.G421A、c.C424T、c.T428C、c.A434C、c.T439C、c.T442C、c.447+1G>A、c.C448T、c.G449C、c.T452G、c.C460T、c.C479T、c.481dupA、c.T482C、c.G484T、c.491delA、c.T494C、c.T496C、c.T500C、c.T503C、c.C506A、c.508_509A、c.T508C、c.511dupA、c.C510A、c.G512A、c.T515A、c.T515G、c.T518A、c.G535A、c.G536C、c.549+1G>A、c.549+1G>C、c.550-1G>A、c.552delC、c.G564A、c.T571A、c.T574C、c.T584A、c.587_589del、c.T596G、c.A597T、c.T604C、c.A607G、c.G634A、c.G634C、c.638dupT、c.T638C、NC_000006.12(chr6):g.32039741T>A、c.652-2A>G、c.661delA、c.C673T、c.682dupA、c.C685T、c.T692C、c.A700G、c.G701A、c.705_713CCACAACGA、c.709_716del、c.T713A、c.T719A、c.T725C、c.740delA、c.T749C、c.786dupC、c.T785C、c.C787T、c.C797T、c.C803T、c.G806C、c.838delG、c.G838A、c.G844T、c.G844C、c.T845G、c.C847A、c.A850T、c.A850G、c.G874C、c.G874A、c.G874T、c.G878A、c.C887A、c.C901T、c.C905A、c.T907C、c.G908C、c.G909A、c.G913A、c.T914A、c.917delT、c.917dupT、c.T919G、c.C925T、c.939+1G>C、c.939+2T>G、c.C946T、c.C949T、c.G950A、c.C952A、c.C952G、c.956_958del、c.C955T、c.G961A、c.T965C、c.A968G、c.989_998del、c.G988A、c.1001delG、c.C1011G、c.G1019A、c.C1024T、c.G1025C、c.1030delC、c.T1037C、c.G1054A、c.A1055T、c.T1061G、c.C1063T、c.G1064A、c.C1069T、c.G1070A、c.G1070C、c.G1075A、c.C1088T、c.T1091G、c.1093delC、c.C1096T、c.C1096A、c.C1099T、c.G1100A、c.C1108T、c.G1109A、c.A1114G、c.1118+1G>T、c.1118+1G>A、c.1119-2A>G、c.G1126A、c.C1128G、c.C1131A、c.G1132T、c.G1143C、c.G1145A、c.C1160G、c.1164_1172del、c.A1163T、c.C1164G、c.T1166G、c.G1174A、c.1178_1179insCCTGGATGAGACGGTC、c.C1179G、c.C1204T、c.C1205T、c.1209dupT、c.T1213C、c.T1214C、c.G1217A、c.G1222A、c.1222+1G>T、c.1222+1G>C、NC_000006.12(chr6):g.32040860C>A、c.1223-1G>A、c.C1225T、c.G1226A、c.G1226T、c.T1232G、c.1270_1274del、c.G1273A、c.C1279T、c.G1280A、c.G1280C、c.T1285C、c.C1287A、c.1290_1291del、c.G1294A、c.C1298T、c.C1304T、c.C1304A、c.C1306T、c.G1312A、c.C1331A、c.C1333T、c.T1340C、c.T1348C、c.A1351C、c.C1352T、c.G1356A、c.C1360T、c.1373_1390del、c.1372_1373insCCCTGCCCTCCCTGCAGC、c.C1378T、c.C1379A、c.C1379T、c.T1385C、c.1390delC、c.C1391T、c.1416_1431del、c.1428delT、c.G1439T、c.C1444T、c.A1445C、c.1447dupC、c.C1447T、c.1451_1452del、c.1451delG、c.C1450T、c.1451_1452C、c.G1451A、c.G1451C、c.G1474A、c.G1481A、c.*13G>A
进一步的，分类为gene_variants的探针组还包括先天性肾上腺皮质增生症基因CYP11B1相关SNV位点133个(转录本为NM_000497.3)：
c.T1466C、c.1449_1451del、c.T1451A、c.1440_1447TAAAAG、c.1438delG、c.A1415C、c.T1412G、NC_000008.11(chr8):g.142874952C>G、NC_000008.11(chr8):g.142874953T>C、c.1398+2T>A、c.1393_1394insTGCTGC、c.1393_1394insTGC、c.A1394T、c.T1382C、c.G1361A、c.1359dupG、c.C1360T、c.G1358A、c.C1357T、c.G1343C、c.G1343A、c.C1342T、c.G1337T、c.G1336A、c.G1331A、c.C1325T、c.T1322G、c.1313_1315del、c.G1280A、c.T1269G、c.G1231T、c.T1229G、c.C1219T、c.1210dupC、NC_000008.11(chr8):g.142875163G>T、NC_000008.11(chr8):g.142875230T>C、c.1200+1G>A、c.C1185A、c.1181delA、c.1180_1181insGA、c.C1157A、c.C1157T、c.G1151A、c.C1150T、c.C1150G、c.T1145G、c.1138_1139del、c.G1136T、NC_000008.11(chr8):g.142875707C>A、NC_000008.11(chr8):g.142875707C>T、c.1094_1120del、c.G1121A、c.C1120A、c.A1112G、c.C1103A、c.G1099T、c.C1066T、c.C1021A、c.T1019C、c.C1012T、c.G995A、c.C994G、c.C992T、c.T961G、c.C956T、c.954+2T>G、c.954+1G>C、c.954+1G>A、c.G954A、c.G954C、c.G954A、c.C953A、c.C953T、c.C953G、c.A952C、c.G946A、c.G940C、c.G928A、c.C917T、c.T896C、c.C890T、c.841_842insACAGTACACCA、c.G800A、NC_000008.11(chr8):g.142876677C>G、c.G799C、c.G799A、c.C793T、c.G780A、c.760_777del、c.C776A、c.G740A、c.652dupT、c.G650T、c.G617T、c.C610G、NC_000008.11(chr8):g.142877007C>A、NC_000008.11(chr8):g.142877011C>T、c.G595C、c.A593G、c.A586G、c.T583C、c.566_567insTCCA、c.G562A、c.C556G、c.A520T、c.A517T、c.C494A、c.482_484del、c.C476T、c.T473C、c.C463T、c.C449T、c.T443G、c.A441T、c.T435C、c.G428C、c.C427T、c.G422A、c.C421T、c.T415C、c.C412T、c.C403T、c.A397C、c.396-1G>A、NC_000008.11(chr8):g.142879029T>C、c.G385A、c.A374G、c.372delG、c.C367G、c.363_364insGACAA、c.G348C、c.G347A、c.T346G、c.317_344del、c.C304T、c.C281T、c.273_274insTG、c.G264A、c.G260C、c.T248C、c.T235A、c.A206C、c.199delG、c.G187C、c.G168A、c.G153C、c.G128A、c.C125T、c.C124T、c.96delC、c.G85A、c.C55T、c.53dupT、NC_000008.11(chr8):g.142881671C>T、NC_000008.11(chr8):g.142881701A>C
进一步的，分类为gene_variants的探针组还包括先天性肾上腺皮质增生症基因STAR相关SNV位点83个(转录本为NM_000349.3)：
c.834_844del、c.T824C、c.821_822insA、c.814_816del、c.815delG、c.G815A、c.C814T、c.T800C、c.A791G、c.C790T、c.T779C、c.C772T、c.G749A、c.744+1G>A、c.734dupT、c.719delC、c.714delA、c.707_708CTT、c.695delG、c.T674C、c.G662A、c.G661A、c.C653T、c.G652A、c.G650C、c.C634T、c.629_630del、c.C608A、c.C577T、c.C574T、c.G563A、c.C562T、c.G559A、c.551_552insA、c.G545A、c.G545T、c.C544T、c.524delC、c.517_518insT、c.T509C、c.A506G、c.G505A、c.T498G、c.C491A、c.476_478del、c.T470C、c.467_468del、c.466-1G>A、NC_000008.11(chr8):g.38146158A>T、c.465+2T>A、c.440_452del、c.C444A、c.G441A、c.T439C、c.T431G、c.422_423insTT、c.G419C、c.407delA、c.385_386insTC、c.A383G、c.G367A、c.314_327del、c.306+1G>A、c.G288T、c.238_268del、c.G235T、c.C229T、NC_000008.11(chr8):g.38148638->A、c.178+1G>C、c.135delT、c.125dupG、c.C76T、c.C73T、c.65-2A>G、c.64+1G>-、c.64+2T>G、c.64+1G>T、c.64+1G>A、c.37_38insA、c.T37C、c.33delG、c.5_11del、NC_000008.11(chr8):g.38150990G>A
进一步的，分类为gene_variants的探针组还包括先天性肾上腺皮质增生症基因HSD3B2相关SNV位点70个(转录本为NM_000198.4)：
c.C15A、c.C16T、c.G28A、c.C29A、c.C29T、c.G32A、c.G35A、c.G44A、c.G73T、c.142+1G>A、c.142+1G>T、c.G244C、c.G244A、c.A299G、NC_000001.11(chr1):g.119421803G>A、c.T323G、c.T380A、c.G385A、c.G403T、c.G424A、c.C464T、c.G481C、c.C500T、c.503delC、c.G512A、c.T518G、c.C540A、c.556dupC、c.C557T、c.A569G、c.T614C、c.A637G、c.G638C、c.A646G、c.T652C、c.C664A、c.C665A、c.684_710del、c.T707C、c.G733C、c.742_746AACT、c.C745T、c.G749T、c.T757A、c.T760G、c.C776G、c.C776T、c.796delA、c.T809C、c.817_818del、c.T836A、c.C852G、c.870delG、c.G881T、c.T911C、c.C924G、c.C931T、c.C946T、c.951delC、c.956delT、c.A967G、c.C978G、c.A995C、c.C1000T、c.C1003T、c.A1016G、c.C1022T、c.T1063C、c.G1064A、c.A1119C
进一步的，分类为gene_variants的探针组还包括先天性肾上腺皮质增生症基因CYP17A1相关SNV位点133个(转录本为NM_000102.4)：
NC_000010.11(chr10):g.102821531A>C、c.1480_1487CT、c.G1487A、c.C1486T、c.1459_1467del、c.1466delT、c.1438_1439insATCC、c.T1394C、c.G1386T、c.C1381T、c.T1358C、c.C1345T、c.T1324C、c.T1321C、c.G1319A、c.C1318T、c.1313delG、c.G1306A、c.T1304C、c.C1301T、c.C1283T、c.C1270T、c.G1263A、c.T1250G、c.G1247A、c.C1246T、NC_000010.11(chr10):g.102830988G>T、NC_000010.11(chr10):g.102831503C>T、c.1228delG、c.C1226G、c.C1226T、c.G1217T、c.T1216C、c.C1193T、c.C1169G、c.A1162T、c.1148delA、c.T1142C、c.A1118T、c.C1117G、c.C1117A、c.C1117T、c.G1096A、c.G1085A、c.C1084T、c.1080_1081A、c.G1073A、c.C1072T、c.G1063A、c.1053_1055del、c.G1040A、c.C1039T、c.C1024A、c.1010delG、c.T995C、c.991_993del、c.987delC、c.985_987AA、c.986dupA、c.C987G、c.C987A、c.985delT、c.T985G、c.979_981del、c.972dupG、c.932_939del、c.G938A、c.A916G、c.A914G、c.G904C、c.900_901del、c.T896A、c.C863A、c.C796G、c.775_776del、c.753+1G>A、c.741delT、c.728delT、c.G716A、c.C715T、c.T707G、c.C683T、NC_000010.11(chr10):g.102834132AAAA>-、c.G646C、c.T626C、c.T601A、c.G580T、c.G548A、c.T533A、c.A529G、c.C521A、c.503_505del、c.G484A、c.437-2A>C、NC_000010.11(chr10):g.102835249C>A、c.431_433del、c.393delC、c.G374A、c.C373T、c.G362A、c.T361C、c.359_360insGCGCACA、c.350_351del、c.A347T、c.T340G、c.336_337insATC、c.G331A、c.327dupT、c.A328T、c.T316C、c.302delC、c.298-1G>A、c.297+2T>C、c.G287A、c.C286T、c.T278G、c.G269A、c.C245A、c.C238T、c.198delT、c.A191C、c.186delC、c.177dupA、c.160_162del、c.107delT、c.C103A、c.C81A、c.G62A、c.G51A、c.G3C、c.T2C、c.-34T>C、NC_000010.11(chr10):g.102837961G>T
进一步的，分类为gene_variants的探针组还包括先天性肾上腺皮质增生症基因NR5A1相关SNV位点224个(转录本为NM_004959.5)：
c.*1400T>C、c.*82C>T、c.A1379T、c.A1379G、c.G1333T、c.1309_1315del、c.T1310A、c.G1289T、c.C1279T、c.1277dupT、c.1271_1273del、c.1273delG、c.1267delC、c.T1256A、c.1250delA、c.C1236A、c.C1233T、c.C1227A、c.C1227G、c.1222dupC、c.C1212A、c.C1212G、c.T1210G、c.1187delA、c.1183_1185del、c.A1181C、c.A1171T、c.1151delT、c.1150delC、c.1139-1G>T、c.1138+1G>T、c.1138+1G>A、c.G1138T、c.C1126T、c.1114_1116del、c.G1109A、c.A1100G、c.G1094C、c.C1093T、c.1089_1090insCTTGCGCTGCAGCTG、c.G1090T、c.1083delG、c.T1082C、c.1074dupG、c.T1073C、c.1058_1065del、c.G1063A、c.C1052T、c.C1052A、c.G1020A、c.C1019T、c.991-1G>C、c.984_985del、c.G983T、c.G982A、c.G982T、c.T968C、c.C946T、c.G938A、c.G938T、c.C937T、c.C928G、c.G910A、c.G906C、c.G905A、c.896_897insT、c.T893C、c.G877A、c.871-1G>C、NC_000009.12(chr9):g.124500079GAGA>-、NC_000009.12(chr9):g.124500084ACTC>-、c.C849A、c.G848T、c.T847C、c.G842C、c.G836A、c.T835A、c.A814C、c.G808A、c.G800A、c.744_791del、c.C779T、c.C776T、c.768delC、c.G769A、c.763_764insCACCAAAG、c.G764T、c.C763T、c.C756A、c.C741A、c.T734G、c.G712A、c.G709A、c.C704T、c.691_699del、c.699_700insCTGCAGCTG、c.T689G、c.666delC、c.645dupG、c.630_637del、c.630_636del、c.G634A、c.629_633AGTAA、c.C633G、c.A632G、c.630delG、c.C628T、c.624delG、c.613_614del、c.614dupC、c.614_615insG、c.T603A、c.C598T、c.G594A、c.C593T、c.C571T、c.C549A、c.536delC、c.G532A、c.G517A、c.C503A、c.G493C、c.C486T、c.G460A、c.442delG、c.G437C、c.427_428insCCCA、c.C414A、c.C392T、c.390delG、c.389delC、c.C386T、c.374dupC、c.G375A、c.362_369del、c.369delG、c.G368C、c.C351G、c.G341A、c.C340T、c.C319T、c.305_310del、c.G308A、c.C307G、c.288_304del、c.C289A、c.G275A、c.C274T、c.G272A、c.G271A、c.G268C、c.G268T、c.265delA、c.C259T、c.253_254del、c.G251A、c.C250T、c.G247A、c.245-2A>T、NC_000009.12(chr9):g.124502999C>T、c.244+1G>A、c.238delC、c.G234A、c.A232T、c.G230A、c.G225C、c.G206A、c.C205G、c.G194A、c.A187C、c.G185T、c.C184T、c.C184A、c.140_163del、c.G164A、c.G164C、c.C162A、c.151delG、c.G151T、c.G146A、c.144_145insCACG、c.A140G、c.132_134del、c.T122G、c.C119G、c.A118C、c.G116C、c.C115T、c.A112T、c.T106C、c.104_105AA、c.G104A、c.G104T、c.103-2A>G、NC_000009.12(chr9):g.124503223G>T、c.C99A、c.G98C、c.G95A、c.T90G、c.C86G、c.C86T、c.C86A、c.76_77del、c.G77C、c.G77A、c.G76A、c.A74G、c.70delC、c.C70T、c.C69A、c.51_65del、c.C62T、c.G58C、c.C48A、c.G43A、c.T37C、c.G31T、c.18delC、c.G19T、c.T13G、c.C11A、c.T9A、c.G3A、c.A1G
进一步的，分类为gene_variants的探针组还包括先天性肾上腺皮质增生症基因SRY相关SNV位点108个(转录本为NM_003140.3)：
c.C535T、c.T488A、c.474delA、c.474dupA、c.A427T、c.A427G、c.407_415GT、c.C397G、c.C397T、c.C394G、c.C392G、c.G389C、c.C388T、c.T387A、c.T387G、c.T385A、c.A383G、c.T381A、c.379delT、c.A380T、c.A380G、c.T379C、c.C374T、c.364_367del、c.G352C、c.T347C、c.C338T、c.G337A、c.G334A、c.T326C、c.324delA、c.T325C、c.C323G、c.C322T、c.G320A、c.318dupA、c.A317T、c.T302A、c.C301G、c.G294C、c.G294A、c.T292C、c.C289T、c.A287G、c.G284A、c.G283C、c.280delC、c.T281C、c.C277T、c.A275T、c.A274T、c.A271G、c.C270G、c.A266C、c.A266T、c.264dupA、c.G265A、c.A259T、c.C256T、c.T254C、c.245delA、c.243_244insT、c.T237C、c.T233C、c.230dupA、c.228dupC、c.G227C、c.G227T、c.C226A、c.224_225AT、c.G224A、c.G224T、c.G222C、c.C220T、c.C214G、c.G209T、c.G209A、c.T203C、c.T199C、c.T199G、c.G196A、c.A193C、c.A193G、c.G192A、c.T191G、c.C184G、c.T179C、c.G178C、c.A175G、c.T174G、c.A170G、c.161delG、c.126dupT、c.A113G、c.G89T、c.71delA、c.T72A、c.G53A、c.38dupA、c.T26A、c.12delT、c.T12A、c.C8T、c.6delA、c.C4T、c.-75G>A、NC_000024.10(chrY):g.2787734CCT>-、NC_000024.10(chrY):g.2787733C>G
优选地，所述exon_cnv探针组的核苷酸序列包括如SEQ ID No.1～SEQ ID No.150所示的探针序列，但该部分序列仅为小部分示例。
优选地，所述gene_variants探针组的核苷酸序列包括如SEQ ID No.151～SEQ IDNo.635所示的探针序列，但该部分序列仅为小部分示例。
优选地，exon_cnv探针组均通过与含有相应SNP位点的DNA片段以碱基互补配对原则进行杂交发挥作用；
gene_variants探针组均通过与含有SNV位点的DNA片段以碱基互补配对原则进行杂交发挥作用。
优选地，所述exon_cnv探针组针对所述杜氏肌营养不良和所述地中海贫血相关基因的缺失/重复，计算每个探针拷贝数CN；常染色体和女性X染色体所述正常SNP的所述探针拷贝数CN1为2，计算出现的所述探针拷贝数CN1变异情况为2种，其中所述探针拷贝数CN1为0或1属于缺失，为3或4属于重复；男性X和Y染色体的所述正常SNP的所述探针拷贝数CN2为1，计算出现的所述探针拷贝数CN2变异情况为2种，其中所述探针拷贝数CN2为0属于缺失，为2属于重复；
计算拷贝数度量值是log2 Ratio，其中Ratio＝每个探针拷贝数的观测值÷每个探针拷贝数的参考值，每个探针拷贝数的参考值是来自于正常人群的一组数据：
当log2 Ratio≈-1.5±0.05时，CN＝0；
当log2 Ratio≈-1±0.05时，CN＝1；
当log2 Ratio≈0±0.05时，CN＝2；
当log2 Ratio≈0.58±0.05时，CN＝3；
当log2 Ratio≈1±0.05时，CN＝4。
优选地，所述exon_cnv探针组针对所述脊髓性肌萎缩症的主效基因SMN1和高度同源的基因SMN2的差别SNP位点设计重复探针，计算所有探针的所述拷贝数CN，从而计算出所述主效基因SMN1的拷贝数SMN1_CN以及SMN2的拷贝数SMN2_CN，计算公式分别为：
SMN1_CN＝探针的拷贝数观测值÷探针的拷贝数参考值；
SMN2_CN＝探针的拷贝数观测值÷探针的拷贝数参考值；
探针拷贝数的参考值是来自于正常人群的一组数据，通过SMN1_CN和SMN2_CN的值来区分样本是脊髓性肌萎缩的患者、无表型患者、携带者或者正常人群。
当0≤SMN1_CN≤0.5且SMN2_CN＜5时，可判读为所述脊髓性肌萎缩症的患者；当0≤SMN1_CN≤0.5且SMN2_CN≥5时，可判读为所述脊髓性肌萎缩症的无表型患者；当0.5<SMN1_CN≤1.5时，可判读为所述脊髓性肌萎缩症相关基因的携带者；当SMN1_CN>1.5时，可判读为所述脊髓性肌萎缩症相关基因无缺失突变。
所述exon_cnv探针组针对SMN1和CYP21A2的部分差异SNP位点的重复探针数大于4个，这些重复的探针不仅能显著区分SMN1的假基因SMN2和CYP21A2的假基因CYP21P，还能增加CNV区域的探针密度，提高CNV的阳性检出率。
所述gene_variants的探针组包含的上述疾病临床常见SNV中，每个设计1～2个探针，正义链和反义链方向均可设计。SNV的判读基于该部分探针的检测值来实现的，所用的方法为基因分型和聚类，基因分型结果包括三种，AA、AB和BB，其中AA和BB代表纯和类型，一个代表野生型，一个代表纯合子，需根据实际情况判读属于野生型或纯合子，AB代表杂合子。通过聚类后的样本数目判断检测结果属于阳性还是阴性。一般来说，三种分型聚类结果均包含大量样本，说明该位点人群频率较高，考虑为SNP，一般无临床意义；三种分型聚类结果中包含极少量样本，说明该位点人群频率较低，考虑为阳性的单核苷酸变异SNV；全部聚类为AA或BB中的一种结果，考虑该位点为野生型。优选地，所述试剂盒还包括变性混合液、扩增混合液、片段化混合液、沉淀混合液和杂交混合液。
所述变性混合液由10×变性液用纯水稀释10倍而成。
所述扩增混合液由1体积的扩增酶加45体积的扩增液混合制备而成。
所述片段化混合液由1体积的片段化酶、10.3体积的片段化稀释液加45.7体积的10×片段化缓冲液混合制备所得。
所述沉淀混合液由1体积的沉淀溶液2加119体积的沉淀溶液1混合制备所得。
所述杂交混合液由1体积的杂交液1、18体积的杂交液2和140体积的杂交缓冲液混合制备所得。
优选地，所述试剂盒在
Figure BDA0003340080970000541
微阵列芯片扫描仪中进行检测使用，所用
Figure BDA0003340080970000542
微阵列芯片扫描仪的NMPA医疗器械注册证为苏械注准20212220966。
所述
Figure BDA0003340080970000543
微阵列芯片扫描仪配套试剂包括染料混合物A、染料混合物B、稳定混合物、连接混合物A和连接混合物B。
所述染料混合物A由1体积的染色液1-A、1体积的染色液1-B、2体积的染色缓冲液和96体积的洗液A混合制备所得。
所述染料混合物B由1体积的染色液2-A、1体积的染色液2-B、2体积的染色缓冲液和96体积的洗液A混合制备所得。
所述稳定混合物由1体积的稳定液、8体积的固定稀释液用纯水稀释7.9倍而成。
所述连接混合物A由1体积的连接液1、0.4体积的连接液2和5体积的连接缓冲液混合制备所得。
所述连接混合物B由1体积的连接酶、6.6体积的探针混合液1、6.6体积的探针混合液2和52体积的连接混合物A混合制备所得。
本发明的另一个目的是提供一种一体化全面检测杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症的方法，
所述方法包括以下步骤，
S1、采集样品；
S2、样品制备与质控；
S3、检测反应：
S31、DNA扩增：100ng DNA样本(5ng/μL)中加入20μl变性混合液，室温孵育10min；加入130μl中和液，震荡混匀加入230μl扩增混合液，震荡混匀1000rpm离心1min；37℃孵育箱中孵育23±1h；65℃孵育箱中孵育20min；37℃孵育箱中继续孵育45min；
S32、DNA片段化和沉淀：对步骤S31孵育的样本加入57μl片段化混合液，混匀、简短离心；37℃孵育30min，室温环境下加入19μl终止液，进行震荡混匀离心；室温环境下加入240μl沉淀混合液和600μl异丙醇，充分混匀；-20℃环境放置16～24h；
S33、干燥、重悬及质控：对步骤S32处理后的样本进行4℃3200rpm离心40min，去除废液，置于37℃杂交炉中20min晾干，加入35μl重悬缓冲液进行振荡混匀，震荡仪中震荡10min，加入80μl杂交混合液，进行震荡混匀离心，产生115μl变性杂交液；
质控使用10μl的所述变性杂交液，包括用Nanodrop测量吸光度和凝胶电泳，其中胶上样染料为InvitrogenTMTrackIt Cyan/Orange Loading Buffer；25bp InvitrogenLadder；凝胶电泳系统为Invitrogen E-GelTM48agarose gels 4％，G8008-04；
S34、变性和杂交：将步骤S33产生的所述变性杂交液放于杂交板，将所述杂交板放置于PCR仪中进行变性程序：95℃变性10min；48℃变性3min；冷却；使用移液器转移105μl变性杂交液至杂交盘，载入
Figure BDA0003340080970000561
微阵列芯片处理仪，持续杂交23.5h～24h；
S35、芯片扫描仪检测：对步骤S34产生的混合物进行染料盘对应分装：其中染料混合物A的染料盘2个，每孔105μl；染料混合物B的染料盘1个，每孔105μl；稳定混合物的染料盘1个，每孔105μl；连接混合物B的染料盘1个，每孔105μl；将分装后的所述染料盘载入芯片扫描仪，同时向所述染料盘每孔加入150μl固定缓冲液后盖住，放置于工作台顶部进行检测；
S4、数据质控和分析；
S5、结果分析与注释。
本发明提供的一种一体化全面检测杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症的试剂盒，能够同时特异性杂交捕获杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症五种复杂疾病单外显子水平的常见已知致病性变异类型，实现高效、精准、全面的一体化检测。
本发明提供的一种一体化全面检测杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症的方法，采用全染色体基因分型芯片，能够显著提升临床对复杂疾病临床检测的标准化程度，是一种一体化、高时效性、高准确率和高操作性的分子诊断方法，能够显著提升此类疾病的诊断、治疗、预后及遗传咨询水平；
附图说明
图1为本发明的方法检测流程图；
图2-1为本发明的杜氏肌营养不良相关基因缺失结果图；
图2-2为本发明的杜氏肌营养不良相关基因重复结果图；
图3为本发明的地中海贫血相关基因缺失结果图；
图4为本发明的脊髓性肌萎缩症相关基因缺失结果图；
图5为本发明的遗传性耳聋的相关基因SNV阳性结果图；
图6为本发明的先天性肾上腺皮质增生症的相关基因SNV阳性结果图；
图7-1为本发明的SNV阳性结果图；
图7-2为本发明的SNV阴性结果图。
具体实施方式
下面结合具体实施例，进一步阐述本发明设计、阳性样本验证和结果分析。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
本实施例的一种一体化全面检测杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症的试剂盒，该试剂盒包括exon_cnv和gene_variants两套探针组。
其中，exon_cnv探针组设计为：精确定位DMD、HBA1、HBA2和HBB基因5’端侧翼区域、3’端侧翼区域、各个外显子区域和部分内含子区域的起始位置和终止位置，挑选位于每个起始位置和终止位置的SNP位点设计的一组探针，覆盖密度为平均25个SNP位点/100kb。SNP位点挑选原则，收录于千人基因组计划数据库，最小等位基因频率大于0.1，去除多聚核苷酸，去除上下游50bp序列种GC含量>70％的SNP，去除在人类基因组中具有同源性的SNP位点。同时针对脊髓性肌萎缩症基因SMN1及其高度同源基因SMN2，探针设计时SNP位点避开了高同源区，以保证序列的区分效率。同时对差异SNP位点序列增加了探针密度，特别的7号和8号外显子缺失断裂点前后，均显著增加了探针密度，不仅能保证探针捕获的唯一性，区分同源位点的信号干扰，还能保证检测结果有足够的数据支持，确保检测的有效性，exon_cnv探针组序列如下表3中SEQ ID No.1～SEQ ID No.150所示，但该部分序列仅为小部分示例；
表3 SEQ ID No.1～SEQ ID No.150探针序列
Figure BDA0003340080970000571
Figure BDA0003340080970000581
Figure BDA0003340080970000591
Figure BDA0003340080970000601
Figure BDA0003340080970000611
Figure BDA0003340080970000621
Figure BDA0003340080970000631
Figure BDA0003340080970000641
Figure BDA0003340080970000651
Figure BDA0003340080970000661
Figure BDA0003340080970000671
Figure BDA0003340080970000681
Figure BDA0003340080970000691
Figure BDA0003340080970000701
Figure BDA0003340080970000711
Figure BDA0003340080970000721
Figure BDA0003340080970000731
Figure BDA0003340080970000741
上述的试剂盒中，优选地，gene_variants探针组结合临床实验室的文献报道，针对杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症，依据五病的临床诊疗指南，结合ClinVar、HGMD和gnomAD等数据库对这些基因相关位点进行人群频率的统计和筛选，确认了每个基因的中国人群单外显子水平拷贝数变异遗传特征高发SNV位点，并将这些位点合成相应探针并制成芯片，每个SNV位点至少1个探针。部分位点是2个重复探针，还有的位点可达到6个重复探针，这是为了在芯片不同位置放置相同的探针，从而增加对应基因位点的结果准确度和阳性检出率，筛选原则如下：
(1)三病临床指南收录的中国人群高发位点；
(2)ClinVar数据库评级为致病或可能致病，证据强度为二星及以上；
(3)HGMD数据库评级为DM或DM？，并有明确的文献报道；
(4)gnomAD数据库东亚人群频率<1％，纯合子数量>1。
gene_variants探针组的序列如下表4中SEQ ID No.151～SEQ ID No.635所示；
表4 SEQ ID No.151～SEQ ID No.635探针序列
Figure BDA0003340080970000742
Figure BDA0003340080970000751
Figure BDA0003340080970000761
Figure BDA0003340080970000771
Figure BDA0003340080970000781
Figure BDA0003340080970000791
Figure BDA0003340080970000801
Figure BDA0003340080970000811
Figure BDA0003340080970000821
Figure BDA0003340080970000831
Figure BDA0003340080970000841
Figure BDA0003340080970000851
Figure BDA0003340080970000861
Figure BDA0003340080970000871
Figure BDA0003340080970000881
Figure BDA0003340080970000891
Figure BDA0003340080970000901
Figure BDA0003340080970000911
Figure BDA0003340080970000921
Figure BDA0003340080970000931
Figure BDA0003340080970000941
Figure BDA0003340080970000951
Figure BDA0003340080970000961
Figure BDA0003340080970000971
Figure BDA0003340080970000981
Figure BDA0003340080970000991
Figure BDA0003340080970001001
Figure BDA0003340080970001011
Figure BDA0003340080970001021
Figure BDA0003340080970001031
Figure BDA0003340080970001041
Figure BDA0003340080970001051
Figure BDA0003340080970001061
Figure BDA0003340080970001071
Figure BDA0003340080970001081
gene_variants探针组还包括针对杜氏肌营养不良的相关基因DMD设计的探针，覆盖了常见的致病和可能致病位点，共计2128个，转录本为NM_004006.2；
gene_variants探针组还包括针对地中海贫血的相关基因HBA1、HBA2、HBB设计的探针，覆盖了相关基因HBA1临床常见SNV位点151个、HBA2临床常见SNV位点228个、HBB临床常见SNV位点779个；HBA1转录本为NM_000558.4，HBA2转录本为NM_000517.4，HBB转录本为NM_000518.4；
gene_variants探针组还包括针对脊髓性肌萎缩症的主效基因SMN1、高度同源的基因SMN2设计的探针，覆盖了主效基因SMN1临床常见SNV位点91个、高度同源基因SMN2临床常见SNV位点1个；SMN1转录本为NM_000344.3，SMN2转录本为NM_017411.3；
gene_variants探针组还包括针对耳聋的相关基因GJB2、GJB3、SLC26A4、PRPS1、MYO15A、MYO7A、COCH、DIABLO、TMC1、DSPP、12SrRNA设计的探针，覆盖了GJB2相关SNV位点423个，转录本为NM_004004.6；GJB3相关SNV位点39个，转录本为NM_024009.3；SLC26A4相关SNV位点585个，转录本为NM_000441.2；PRPS1相关SNV位点39个，转录本为NM_002764.3；MYO15A相关SNV位点311个，转录本为NM_016239.3；MYO7A相关SNV位点582个，转录本为NM_000260.4；COCH相关SNV位点31个，转录本为NM_004086.3；DIABLO相关SNV位点2个，转录本为NM_019887.6；TMC1相关SNV位点108个，转录本为NM_138691.3；DSPP相关SNV位点58个，转录本为NM_014208.3；12SrRNA相关SNV位点8个，转录本为NC_012920.1；
gene_variants探针组还包括针对先天性肾上腺皮质增生症的相关基因CYP21A2、CYP11B1、STAR、HSD3B2、CYP17A1、NR5A1、SRY设计的探针，覆盖了CYP21A2相关SNV位点284个，转录本为NM_000500.9；CYP11B1相关SNV位点133个，转录本为NM_000497.3；STAR相关SNV位点83个，转录本为NM_000349.3；HSD3B2相关SNV位点70个，转录本为NM_000198.4；CYP17A1相关SNV位点133个，转录本为NM_000102.4；NR5A1相关SNV位点224个，转录本为NM_004959.5；SRY相关SNV位点108个，转录本为NM_003140.3。
exon_cnv探针组均通过与含有相应SNP位点的DNA片段以碱基互补配对原则进行杂交发挥作用；
gene_variants探针组均通过与含有SNV位点的DNA片段以碱基互补配对原则进行杂交发挥作用。
exon_cnv探针组针对杜氏肌营养不良和地中海贫血相关基因的缺失/重复，计算每个探针拷贝数CN；常染色体和女性X染色体正常SNP的探针拷贝数CN1为2，计算出现的探针拷贝数CN1变异情况为2种，其中探针拷贝数CN1为0或1属于缺失，为3或4属于重复；男性X和Y染色体的正常SNP的探针拷贝数CN2为1，计算出现的探针拷贝数CN2变异情况为2种，其中探针拷贝数CN2为0属于缺失，为2属于重复；
计算拷贝数度量值是log2 Ratio，其中Ratio＝每个探针拷贝数的观测值÷每个探针拷贝数的参考值，每个探针拷贝数的参考值是来自于正常人群的一组数据：
当log2 Ratio≈-1.5±0.05时，CN＝0；
当log2 Ratio≈-1±0.05时，CN＝1；
当log2 Ratio≈0±0.05时，CN＝2；
当log2 Ratio≈0.58±0.05时，CN＝3；
当log2 Ratio≈1±0.05时，CN＝4。
exon_cnv探针组针对脊髓性肌萎缩症的主效基因SMN1和高度同源的基因SMN2的差别SNP位点设计重复探针，计算所有探针的拷贝数CN，从而计算出主效基因SMN1的拷贝数SMN1_CN以及SMN2的拷贝数SMN2_CN，计算公式分别为：
SMN1_CN＝探针的拷贝数观测值÷探针的拷贝数参考值；
SMN2_CN＝探针的拷贝数观测值÷探针的拷贝数参考值；
探针拷贝数的参考值是来自于正常人群的一组数据，通过SMN1_CN和SMN2_CN的值来判读样本是脊髓性肌萎缩的患者、无表型患者、携带者或者正常人群。
如图4所示，当0≤SMN1_CN≤0.5且SMN2_CN＜5时，可判读为所述脊髓性肌萎缩症的患者；当0≤SMN1_CN≤0.5且SMN2_CN≥5时，可判读为所述脊髓性肌萎缩症的无表型患者；当0.5<SMN1_CN≤1.5时，可判读为所述脊髓性肌萎缩症相关基因的携带者；当SMN1_CN>1.5时，可判读为所述脊髓性肌萎缩症相关基因无缺失突变。
exon_cnv探针组针对SMN1和CYP21A2的部分差异SNP位点的探针数大于4个，这些重复的探针不仅能显著区分SMN1的同源基因SMN2和CYP21A2的假基因CYP21P，还能增加CNV区域的探针密度，提高CNV的阳性检出率。
gene_variants探针组包含的五种疾病的临床常见SNV中，每个设计1～2个探针，正义链和反义链方向均可设计。SNV的判读基于该部分探针的检测值来实现的，所用的方法为基因分型和聚类，基因分型结果包括三种，AA、AB和BB，其中AA和BB代表纯和类型，一个代表野生型，一个代表纯合子，需根据实际情况判读哪个是野生型，哪个为纯合子，AB代表杂合子。通过聚类后的样本数目判断检测结果属于阳性还是阴性。一般来说，三种分型聚类结果均包含大量样本，说明该位点人群频率较高，考虑为SNP，一般无临床意义；三种分型聚类结果中包含极少量样本，说明该位点人群频率较低，考虑为阳性的SNV，如图7-1所示；全部聚类为AA或BB中的一种结果，考虑该位点为野生型，如图7-2所示。试剂盒的组分还包括变性混合液、扩增混合液、片段化混合液、沉淀混合液和杂交混合液。
变性混合液由10×变性液用纯水稀释10倍而成。
扩增混合液由1体积的扩增酶加45体积的扩增液混合制备而成。
片段化混合液由1体积的片段化酶、10.3体积的片段化稀释液加45.7体积的10×片段化缓冲液混合制备所得。
沉淀混合液由1体积的沉淀溶液2加119体积的沉淀溶液1混合制备所得。
杂交混合液由1体积的杂交液1、18体积的杂交液2和140体积的杂交缓冲液混合制备所得。
试剂盒在
Figure BDA0003340080970001101
微阵列芯片扫描仪中进行检测使用，所用
Figure BDA0003340080970001102
微阵列芯片扫描仪的NMPA医疗器械注册证为苏械注准20212220966，
Figure BDA0003340080970001103
微阵列芯片扫描仪配套试剂包括染料混合物A、染料混合物B、稳定混合物、连接混合物A和连接混合物B。
染料混合物A由1体积的染色液1-A、1体积的染色液1-B、2体积的染色缓冲液和96体积的洗液A混合制备所得。
染料混合物B由1体积的染色液2-A、1体积的染色液2-B、2体积的染色缓冲液和96体积的洗液A混合制备所得。
稳定混合物由1体积的稳定液、8体积的固定稀释液用纯水稀释7.9倍而成。
连接混合物A由1体积的连接液1、0.4体积的连接液2和5体积的连接缓冲液混合制备所得。
连接混合物B由1体积的连接酶、6.6体积的探针混合液1、6.6体积的探针混合液2和52体积的连接混合物A混合制备所得。
试剂盒中所用试剂可以选自由江苏源隆医疗科技有限公司生产的试剂盒，试剂盒中所用试剂如下表5所示：
表5试剂名称及货号
Figure BDA0003340080970001111
Figure BDA0003340080970001121
实施例2
如图1所示，本实施例中例中的一体化全面检测杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症的方法包括以下步骤：
S1：采集样品：共计117例样本，男性66例，女性51例，全部经其他技术验证过突变结果。其中杜氏肌营养不良患者35例(男23例，女12例)，包括10例为SNV的患者和25例外显子CNV患者；α-地中海贫血患者20例(男12例，女8例)，全部为缺失型突变；脊髓性肌萎缩症患者41例(男22例，女19例)，40例外显子水平CNV患者，1例SNV患者；遗传性耳聋患者11例(男6例，女5例)，全部为SNV突变；先天性肾上腺皮质增生症患者10例(男3例，女7例)，全部为SNV突变，作为发明的阳性验证样品。
S2：样品制备与质控，光密度(Optical Density,OD)260/280nm比值介于1.8至2.0之间，OD 260/230nm比值大于1.5，不满足任一条件的样品需进行纯化等处理：
S3：检测反应：
S31：DNA扩增：100ng DNA样本(5ng/μL)中加入20μl变性混合液，室温孵育10min；加入130μl中和液，震荡混匀后沿管壁缓慢加入230μl扩增混合液，震荡混匀1000rpm离心1min；在37℃孵育箱中孵育23±1h；65℃孵育箱中孵育20min；37℃孵育箱中继续孵育45min；
S32：DNA片段化和沉淀：对步骤S31孵育的样本加入57μl片段化混合液，混匀、简短离心后37℃孵育30min，而后在室温环境下加入19μl终止液，进行震荡混匀离心；室温环境下加入240μl沉淀混合液和600μl异丙醇，用移液器上下充分混匀；转移至-20℃环境中放置16～24h；
S33：干燥、重悬及质控：对步骤S32处理后的样本进行4℃3200rpm离心40min，去除废液，置于37℃杂交炉中20min晾干，加入35μl重悬缓冲液进行振荡混匀，震荡仪中震荡10min，加入80μl杂交混合液，进行震荡混匀离心，产生115μl变性杂交液；
质控使用10μl的变性杂交液，包括用Nanodrop测量吸光度和凝胶电泳，其中胶上样染料为InvitrogenTMTrackIt Cyan/Orange Loading Buffer(Invitrogen P/N10482-028)；25bp Invitrogen Ladder(Invitrogen P/N 10488-022)；凝胶电泳系统为Invitrogen E-GelTM48agarose gels 4％，G8008-04；
S34：变性和杂交：将步骤S33产生的变性杂交液放于杂交板，将杂交板放置于PCR仪中进行变性程序：95℃变性10min；48℃变性3min；冷却；使用移液器转移105μl变性杂交液至杂交盘，载入
Figure BDA0003340080970001132
微阵列芯片处理仪，持续杂交23.5h～24h；采用
Figure BDA0003340080970001133
微阵列芯片扫描仪和自动分析软件，可以实现一次实验同时处理96个样本的检测通量，显著提高结果的可靠性。
S35：芯片扫描仪检测：对步骤S34产生的混合物进行染料盘对应分装：其中染料混合物A的染料盘2个，每孔105μl；染料混合物B的染料盘1个，每孔105μl；稳定混合物的染料盘1个，每孔105μl；连接混合物B的染料盘1个，每孔105μl；将分装后的染料盘载入芯片扫描仪，同时向染料盘每孔加入150μl固定缓冲液后避免接触扫描盘底部。将盖子的切口角对准扫描盘的切口边缘后盖住扫描，放置于工作台顶部进行检测；
S4：数据质控和分析：成像完成后会得到每块杂交板的原始荧光信号数据，利用自动分析软件对其进行质控和分析，即可得到相应样品的变异位点信息结果文件。
S5：结果分析与注释：结果包含每个样品检测到的基因突变位点和拷贝数变异信息，这些信息再经过进一步的注释分析，包括突变评级和医学解读，最终得到的明确的真实的位点信息。本次验证样品位点信息如下表6所示；检测结果如下表7所示。
表6验证样品位点信息
Figure BDA0003340080970001131
Figure BDA0003340080970001141
Figure BDA0003340080970001151
Figure BDA0003340080970001161
表7检测结果
Figure BDA0003340080970001162
Figure BDA0003340080970001171
Figure BDA0003340080970001181
Figure BDA0003340080970001191
注：NA以及NoCall表示无解读结果；Failed表示QC未通过；Affected表示检测到突变，且有影响；Carrier表示携带突变无明显影响，Gain表示拷贝数增加。SMN1_CN表示SMN1基因的拷贝数，SMN1_CN<0.5表示纯合缺失，SMN1_CN在0.5-1.5表示杂合缺失，SMN1_CN>1.5表示正常2拷贝。对于α-地中海贫血患者的缺失型突变，其基因包括HBA1和HBA2，因此得到的结果CN＝(1，1)表示HBA1的CN＝1，HBA2的CN＝1。
如图2-1至图6所示，本发明对117个阳性样本进行检测，其中杜氏肌营养不良患者35例(男23例，女12例)，包括10例SNV的患者和25例外显子CNV患者；α-地中海贫血患者20例(男12例，女8例)，全部为缺失型突变；脊髓性肌萎缩症患者41例(男22例，女19例)，40例外显子CNV患者，1例SNV患者；遗传性耳聋患者11例(男6例，女5例)，全部为SNV突变；先天性肾上腺皮质增生症患者10例(男3例，女7例)，全部为SNV突变。其中只有DMD-10和DMD-24检出失败，如图2-1、图2-2所示，检出率为98.3％。进一步分析可发现，DMD-05样本QC未通过(可能是实验或者样品本身的问题)，但对应的结果可在结果中看到，如图3所示。
此外，部分结果与阳性样本结果不符：
(1)DMD-21样本为E54-55外显子缺失，解读结果为E54-55外显子重复(Gain)；
(2)DMD-22样本为E46外显子缺失，解读结果为E46拷贝数正常(Normal)；
(3)SMA-34样本为Exon7杂合缺失，解读结果为拷贝数正常(Normal)；
从分析结果的准确性角度，上述三个样本通过本发明试剂盒检测的结果可认为是验证失败的，因此本试剂盒的阳性验证率为95.7％。
综上，本发明产品对117例阳性样本进行验证，检出率为98.3％、阳性验证率为95.7％。说明本发明产品所设计的探针具有以下特点：
(1)一体化全面检测：有效覆盖五种疾病基因相关所有的高发变异热点，仅需一次实验，即可对杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症分子水平的所有变异类型和热点进行；
(2)高通量：本发明依托于
Figure BDA0003340080970001201
微阵列芯片扫描仪及分析平台，一次实验可以对96个样本进行同时检测；
(3)临床实用性：通过一体化全面检测和高样本检测通量，操作简单，诊断高效，且仅需一次临床费用支出，适合临床遗传检测广泛使用。
(4)创造性：单外显子水平的拷贝数缺失/重复的高通量检测是传统技术检测难点，本发明通过对几个疾病单基因内部外显子及上下游区域设计多探针覆盖，同时对同源序列的差异位点设计高密度探针，有效的实现单外显子水平缺失/重复检测和区分同源真假基因。
以上对本发明优选的具体实施方式和实施例作了详细说明，但是本发明并不限于上述实施方式和实施例，在本领域技术人员所具备的知识范围内，还可以在不脱离本发明构思的前提下作出各种变化。

Claims (10)

1.一种一体化全面检测五种复杂遗传病的试剂盒，所述五种复杂遗传病为杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症，其特征在于：
所述试剂盒包括exon_cnv和gene_variants两套探针组；
所述exon_cnv探针组包括针对所述杜氏肌营养不良相关基因DMD的一个外显子及以上的缺失/重复设计的探针、所述地中海贫血的相关基因HBA1、HBA2、HBB的外显子缺失设计的探针；以及针对所述脊髓性肌萎缩症的主效基因SMN1内部7号外显子和8号外显子缺失设计的探针；
所述gene_variants探针组包括针对所述杜氏肌营养不良的相关基因DMD设计的探针，覆盖了杜氏肌营养不良相关SNV位点2128个，转录本为NM_004006.2；
针对所述地中海贫血的相关基因HBA1、HBA2、HBB设计的探针，覆盖了所述HBA1相关SNV位点151个，转录本为NM_000558.4；HBA2相关SNV位点228个，转录本为NM_000517.4；HBB相关SNV位点779个，转录本为NM_000518.4；
针对所述脊髓性肌萎缩症的主效基因SMN1、高度同源基因SMN2设计的探针，覆盖了所述主效基因SMN1相关SNV位点91个，转录本为NM_000344.3；高度同源基因SMN2相关SNV位点1个，转录本为NM_017411.3；
针对所述遗传性耳聋的相关基因GJB2、GJB3、SLC26A4、PRPS1、MYO15A、MYO7A、COCH、DIABLO、TMC1、DSPP、12SrRNA设计的探针，覆盖了所述GJB2相关SNV位点423个，转录本为NM_004004.6；GJB3相关SNV位点39个，转录本为NM_024009.3；SLC26A4相关SNV位点585个，转录本为NM_000441.2；PRPS1相关SNV位点39个，转录本为NM_002764.3；MYO15A相关SNV位点311个，转录本为NM_016239.3；MYO7A相关SNV位点582个，转录本为NM_000260.4；COCH相关SNV位点31个，转录本为NM_004086.3；DIABLO相关SNV位点2个，转录本为NM_019887.6；TMC1相关SNV位点108个，转录本为NM_138691.3；DSPP相关SNV位点58个，转录本为NM_014208.3；12SrRNA相关SNV位点8个，转录本为NC_012920.1；
针对所述先天性肾上腺皮质增生症的相关基因CYP21A2、CYP11B1、STAR、HSD3B2、CYP17A1、NR5A1、SRY设计的探针，覆盖了所述CYP21A2相关SNV位点284个，转录本为NM_000500.9；CYP11B1相关SNV位点133个，转录本为NM_000497.3；STAR相关SNV位点83个，转录本为NM_000349.3；HSD3B2相关SNV位点70个，转录本为NM_000198.4；CYP17A1相关SNV位点133个，转录本为NM_000102.4；NR5A1相关SNV位点224个，转录本为NM_004959.5；SRY相关SNV位点108个，转录本为NM_003140.3。
2.根据权利要求1所述的试剂盒，其特征在于：
所述exon_cnv探针组的核苷酸序列包括如SEQ ID No.1～SEQ ID No.150所示的探针序列。
3.根据权利要求1所述的试剂盒，其特征在于：
所述gene_variants探针组的核苷酸序列包括如SEQ ID No.151～SEQ ID No.635所示的探针序列。
4.根据权利要求1所述的试剂盒，其特征在于：
所述exon_cnv探针组均通过与含有相应SNP位点的DNA片段以碱基互补配对原则进行杂交发挥作用。
5.根据权利要求1所述的试剂盒，其特征在于：
所述gene_variants探针组均通过与含有单核苷酸变异位点的DNA片段以碱基互补配对原则进行杂交发挥作用。SNV的判读基于该部分探针的检测值来实现的，所用的方法为基因分型和聚类。
6.根据权利要求1所述的试剂盒，其特征在于：
所述exon_cnv探针组针对所述杜氏肌营养不良和所述地中海贫血相关基因的缺失/重复，计算每个探针拷贝数CN；常染色体和女性X染色体所述正常SNP的所述探针拷贝数CN1为2，计算出现的所述探针拷贝数CN1变异情况为2种，其中所述探针拷贝数CN1为0或1属于缺失，为3或4属于重复；男性X和Y染色体的所述正常SNP的所述探针拷贝数CN2为1，计算出现的所述探针拷贝数CN2变异情况为2种，其中所述探针拷贝数CN2为0属于缺失，为2属于重复；
计算拷贝数度量值是log2 Ratio，其中Ratio＝每个探针拷贝数的观测值÷每个探针拷贝数的参考值，每个探针拷贝数的参考值是来自于正常人群的一组数据：
当log2 Ratio≈-1.5±0.05时，CN＝0；
当log2 Ratio≈-1±0.05时，CN＝1；
当log2 Ratio≈0±0.05时，CN＝2；
当log2 Ratio≈0.58±0.05时，CN＝3；
当log2 Ratio≈1±0.05时，CN＝4。
7.根据权利要求1所述的试剂盒，其特征在于：
所述exon_cnv探针组针对所述脊髓性肌萎缩症的主效基因SMN1和高度同源基因SMN2的差别SNP位点设计重复探针，计算所有探针的所述拷贝数CN，从而计算出所述主效基因SMN1的拷贝数SMN1_CN以及SMN2的拷贝数SMN2_CN，计算公式分别为：
SMN1_CN＝探针的拷贝数观测值÷探针的拷贝数参考值；
SMN2_CN＝探针的拷贝数观测值÷探针的拷贝数参考值；
当0≤SMN1_CN≤0.5且SMN2_CN＜5时，可判读为所述脊髓性肌萎缩症的患者；当0≤SMN1_CN≤0.5且SMN2_CN≥5时，可判读为所述脊髓性肌萎缩症的无表型患者；当0.5<SMN1_CN≤1.5时，可判读为所述脊髓性肌萎缩症相关基因的携带者；当SMN1_CN>1.5时，可判读为所述脊髓性肌萎缩症相关基因无缺失突变。
8.根据权利要求1所述的试剂盒，其特征在于：
所述试剂盒还包括变性混合液、扩增混合液、片段化混合液、沉淀混合液和杂交混合液。
9.根据权利要求1所述的试剂盒，其特征在于：
所述试剂盒在
Figure FDA0003340080960000031
微阵列芯片扫描仪中进行检测使用。
10.一种一体化全面检测五种复杂遗传病的方法，所述五种复杂遗传病为杜氏肌营养不良、地中海贫血、脊髓性肌萎缩症、遗传性耳聋和先天性肾上腺皮质增生症，其特征在于：
所述方法包括以下步骤，
S1、采集样品；
S2、样品制备与质控；
S3、应用权利要求检1所述试剂盒的检测反应：
S31、DNA扩增；
S32、DNA片段化和沉淀；
S33、干燥、重悬及质控；
S34、变性和杂交；
S35、芯片扫描仪检测；
S4、数据质控和分析；
S5、结果分析与注释。
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