WO2010007063A2 - Procédé de diagnostic de la dyslexie - Google Patents

Procédé de diagnostic de la dyslexie Download PDF

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Publication number
WO2010007063A2
WO2010007063A2 PCT/EP2009/058995 EP2009058995W WO2010007063A2 WO 2010007063 A2 WO2010007063 A2 WO 2010007063A2 EP 2009058995 W EP2009058995 W EP 2009058995W WO 2010007063 A2 WO2010007063 A2 WO 2010007063A2
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homozygous
major
dyslexia
minor
human
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PCT/EP2009/058995
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WO2010007063A3 (fr
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Arndt Wilcke
Holger Kirsten
Johannes Boltze
Peter Ahnert
Wilhelm Gerdes
Frank Emmrich
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Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.
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Priority to DE112009001722T priority Critical patent/DE112009001722B4/de
Publication of WO2010007063A2 publication Critical patent/WO2010007063A2/fr
Publication of WO2010007063A3 publication Critical patent/WO2010007063A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to a method of diagnosing dyslexia in a human being by analysing the DNA of said human being in regulatory and/or coding regions of at least one gene selected from a group of specific genes implicated in neuronal migration.
  • the present invention is furthermore concerned with a method of diagnosing dyslexia by determining the genotypes of specific SNPs in the genes RTN4, OTXl, HIFlA, FOXP2, DCDCl, TUBB6 and DYXlCl of said DNA.
  • the present invention is also concerned with the use of such a method for diagnosing dyslexia at an early stage in development of a human being. Furthermore, a method according to the invention may be used to substantiate the suspicion of dyslexia in a human being.
  • Dyslexia may in a very general way be described as a disease affecting the reading and writing abilities of a human being. Otherwise, it seems that an individual suffering from dyslexia shows normal development including normal intellectual development such as e.g. memory or learning skills.
  • dyslexia due to this specific phenotype of the disease, the symptoms of dyslexia usually begin to manifest at a late stage of development only, namely when reading and writing abilities start to be required and/or are taught. Thus, symptoms of dyslexia may be detected during the first years a child spends at school at the age of about 5 to 8 years. Clearly, already during these first years at school, affected children suffer from disadvantages as they are not able to cope with reading and/or writing tasks they are confronted with. Furthermore, this may be accompanied by social exclusion due to said failure.
  • dyslexic persons are very likely to suffer from the symptoms associated with dyslexia and may be handicapped in many tasks of their daily lives.
  • dyslexia The specific molecular events underlying dyslexia are not understood yet. However, it seems that a genetic predisposition plays an important role for developing dyslexia. Several linkage studies led to the identification of genes that seem to be associated with dyslexia. Said genes lie within chromosomal regions that have been mapped in experimental studies. For an overview of the genetic component of dyslexia, reference is made to Paracchini, Scerri and Monaco; Annu. Rev. Genomics Hum. Genet. 2007(8); pages 57 to 79: "The Genetic Lexicon of Dyslexia”.
  • a method of diagnosing dyslexia may preferably be designed such that it can be carried out as early as possible.
  • dyslexia As set out above, some symptoms of dyslexia may also be associated with other diseases such as attention deficit syndrome (ADS) or hyperactivity.
  • ADS attention deficit syndrome
  • a method of diagnosing dyslexia in a human being comprising at least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) analysing said DNA in regulatory and/or coding regions of at least one gene implicated in neuronal migration selected from the group of genes comprising RELN, CDK5, DCX, MDCR, SMPDl, TUBB6, DCDCl, VAPA, SMPDL3B, DCDC2B, DCDC2C, LOC728597, DCAMKL2, DCAMKLl, HIFlA, TBP, SEMA3A, TSNAX, DISCI, SRF, RTN4, OTXl, CNTN4, NRGl, DNER, PTPRF, NRCAM, NDUFV2, GNAL, RHBDL2, NELLl , IMPA2, ELAVL4, PHC2,
  • a method of diagnosing dyslexia in a human being comprising at least the steps of: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) analysing said DNA in regulatory and/or coding regions of at least one gene selected from the group of genes comprising HIFlA, OTXl, RTN4, FOXP2, DCDCl and TUBB6; c) comparing the result of said analysis to the result of a reference analysis of a non-dyslexic human being; d) assigning dyslexia to said human being based on said comparison.
  • a method of diagnosing dyslexia in a human being comprising at least the steps of: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) analysing said DNA in regulatory and/or coding regions of the group of genes consisting of HIFlA, OTXl, RTN4, FOXP2, DCDCl and TUBB6; c) comparing the result of said analysis to the result of a reference analysis of a non-dyslexic human being; d) assigning dyslexia to said human being based on said comparison.
  • the DNA is analysed in at least one further region in step b) of the two above-mentioned embodiments, i.e. said DNA is analysed in regulatory and/or coding regions of at least one further gene of the group of genes comprising RELN, CDK5, DCX, MDCR, SMPDl, VAPA, SMPDL3B, DCDC2B, DCDC2C, LOC728597, DCAMKL2, DCAMKLl, TBP, SEMA3A, TSNAX, DISCI, SRF, CNTN4, NRGl, DNER, PTPRF, NRCAM, NDUFV2, GNAL, RHBDL2, NELLl, IMPA2, ELAVL4, PHC2, VAX2, TRAKl, NTRK3, FGR and CNTN6.
  • RELN regulatory and/or coding regions of at least one further gene of the group of genes comprising RELN, CDK5, DCX, MDCR, SMPDl, VAPA, SMPDL3B, D
  • provision of a sample of the human being may take place outside the human body.
  • the present invention also refers to a method of data acquisition comprising at least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) analysing said DNA in regulatory and/or coding regions of at least one gene implicated in neuronal migration selected from the group of genes comprising RELN, CDK5, DCX, MDCR, SMPDl, TUBB6, DCDCl, VAPA, SMPDL3B, DCDC2B, DCDC2C, LOC728597, DCAMKL2, DCAMKLl, HIFlA, TBP, SEMA3A, TSNAX, DISCI, SRF, RTN4, OTXl, CNTN4, NRGl, DNER, PTPRF, NRCAM, NDUFV2, GNAL, RHBDL2, NELLl , IMPA2, ELAVL4, PHC2,
  • a method of data acquisition comprising at least the steps of: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) analysing said DNA in regulatory and/or coding regions of at least one gene selected from the group of genes comprising HIFlA, OTXl, RTN4, FOXP2, DCDCl and TUBB6; c) comparing the result of said analysis to the result of a reference analysis of a non-dyslexic human being.
  • a method of data acquisition comprising at least the steps of: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) analysing said DNA in regulatory and/or coding regions of the group of genes consisting of HIFlA, OTXl, RTN4, FOXP2, DCDCl and TUBB6; c) comparing the result of said analysis to the result of a reference analysis of a non-dyslexic human being.
  • the DNA is analysed in at least one further region in step b) of the two above-mentioned embodiments, i.e. said DNA is analysed in regulatory and/or coding regions of at least one further gene of the group of genes comprising RELN, CDK5, DCX, MDCR, SMPDl, VAPA, SMPDL3B, DCDC2B, DCDC2C, LOC728597, DCAMKL2, DCAMKLl, TBP, SEMA3A, TSNAX, DISCI, SRF, CNTN4, NRGl, DNER, PTPRF, NRCAM, NDUFV2, GNAL, RHBDL2, NELLl, IMPA2, ELAVL4, PHC2, VAX2, TRAKl, NTRK3, FGR and CNTN6.
  • RELN regulatory and/or coding regions of at least one further gene of the group of genes comprising RELN, CDK5, DCX, MDCR, SMPDl, VAPA, SMPDL3B, D
  • said regulatory and/or coding regions of said at least one gene selected from the group of genes as listed above are analysed for the presence of point mutations, deletions, insertions and/or translocations leading e.g. to altered gene expression levels, frame-shifts, amino acid substitutions or premature stop-codons and/or any other mutations rendering the gene product inactive.
  • the present invention describes a method of diagnosing dyslexia in a human being comprising at least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) analysing said DNA for the presence of established SNPs and/or deletions and/or insertions in regulatory and/or coding regions of at least one gene implicated in neuronal migration selected from the group of genes comprising RELN, CDK5, DCX, MDCR, SMPDl, TUBB6, DCDCl, VAPA, SMPDL3B, DCDC2B, DCDC2C, LOC728597, DCAMKL2, DCAMKLl, HIFlA, TBP, SEMA3A, TSNAX, DISCI, SRF, RTN4, OTXl, CNTN4, NRGl, DNER,
  • a method of diagnosing dyslexia in a human being comprising at least the steps of: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) analysing said DNA for the presence of established SNPs and/or deletions and/or insertions in regulatory and/or coding regions of at least one gene selected from the group of genes comprising HIFlA, OTXl, RTN4, FOXP2, DCDCl and TUBB6; c) comparing the result of said analysis to the result of a reference analysis of a non-dyslexic human being; d) assigning dyslexia to said human being based on said comparison.
  • a method of diagnosing dyslexia in a human being comprising at least the steps of: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) analysing said DNA for the presence of established SNPs and/or deletions and/or insertions in regulatory and/or coding regions of the group of genes consisting of HIFlA, OTXl, RTN4, FOXP2, DCDCl and TUBB6; c) comparing the result of said analysis to the result of a reference analysis of a non-dyslexic human being; d) assigning dyslexia to said human being based on said comparison.
  • the DNA is analysed in at least one further region in step b) for the presence of established SNPs and/or deletions and/or insertions in regulatory and/or coding regions of at least one further gene of the group of genes comprising RELN, CDK5, DCX, MDCR, SMPDl, VAPA, SMPDL3B, DCDC2B, DCDC2C, LOC728597, DCAMKL2, DCAMKLl, TBP, SEMA3A, TSNAX, DISCI, SRF, CNTN4, NRGl, DNER, PTPRF, NRCAM, NDUFV2, GNAL, RHBDL2, NELLl , IMPA2, ELAVL4, PHC2, VAX2, TRAKl, NTRK3, FGR and CNTN6.
  • said established SNPs and/or deletions and/or insertions in regulatory and/or coding regions of at least one gene selected from the group of genes as mentioned above can be deduced from databases.
  • said SNPs and/or deletions and/or insertions are established polymorphisms in the human DNA.
  • the present invention furthermore describes a method of diagnosing dyslexia in a human being comprising at least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) analysing at least one of the genes RTN4, OTXl, HIFlA, FOXP2, DCDCl and TUBB6 of said DNA for the presence of established SNPs; c) comparing the result of said analysis to the result of a reference analysis of a non-dyslexic human being; d) assigning dyslexia to said human being based on said comparison.
  • said analysis also comprises the analysis of the genotype of the region analysed, i.e. either homozygous for the minor/major allele or heterozygous.
  • the reference analysis mentioned in step c) above represents the result of a large control group of non- dyslexic human beings.
  • dyslexia is assigned to a human being with a probability dependent on the number of differences in the regions analysed, i.e. the higher the number of differences, the higher the probability of dyslexia in said human being.
  • a method of diagnosing dyslexia in a human being comprises at least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) determining the genotype of at least one SNP present in said DNA selected from the group of SNPs comprising rsl0210840, rsl2469804, rsl2713284, rsl3387751, rs2255112, rs2580765, rs2580772, rs2588517, rs2588518, rs2588521, rs2860453, rs2919129, rs2972097, rs6545466, rs6760429, rs7340476, rs7562292, rs7597198 in RTN4; rs2075375 in OTXl; rs2057482, rs2301113 in HIFlA; rslO15511,
  • homozygous major i.e. C
  • heterozygous i.e. C/T
  • G at rs7597198, homozygous major (i.e. A) at rs2075375, homozygous major (i.e. G) and heterozygous (i.e. A/G) at rs2057482, homozygous minor (i.e. C) at rs2301113, homozygous major (i.e. G) at rslO15511, homozygous major (i.e. G) at rs 10228494, homozygous major (i.e. A) at rsl0249234, homozygous major (i.e. A) at rsl0262103, homozygous major (i.e.
  • G at rsl0262462, homozygous major (i.e. T) at rsl0266297, homozygous major (i.e. G) at rsl0280045, homozygous major (i.e. G) at rsl2533005, homozygous major (i.e. G) at rsl989903, homozygous major (i.e. C) at rs2040658, homozygous major (i.e. A) at rs2189010, homozygous major (i.e. G) at rs2189015, homozygous major (i.e. A) at rs2396753, homozygous major (i.e.
  • a method of diagnosing dyslexia in a human being comprises at least the steps of: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) determining the genotype of at least one SNP present in said DNA selected from the group of SNPs comprising rs2057482; rs2075375; rs2255112; rs2301113; rs2588517; rs4255730; rs4727799; rs7121949; rs7597198; rsl2324434; rsl2533005 and rs 12960267; c) comparing the genotype of said at least one SNP to genotypes associated with dyslexia wherein the genotypes homozygous major (i.e.
  • G and heterozygous (i.e. A/G) at rs2057482; homozygous major (i.e. A) at rs2075375; homozygous minor (i.e. G) at rs2255112; homozygous minor (i.e. C) at rs2301113; homozygous major (i.e. C) at rs2588517; homozygous minor (i.e. A) at rs4255730; homozygous major (i.e. A) at rs4727799; heterozygous (i.e. T/G) at rs7121949; homozygous minor (i.e.
  • G at rs7597198; homozygous major (i.e. A) at rsl2324434; homozygous major (i.e. G) at rsl2533005 and homozygous minor (i.e. C) at rsl2960267 are associated with dyslexia; d) assigning dyslexia to said human being based on said comparison.
  • a method of diagnosing dyslexia in a human being comprising at least the steps of: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) determining the genotypes of SNPs present in said DNA selected from the group of SNPs consisting of rs2057482; rs2075375; rs2255112; rs2301113; rs2588517; rs4255730; rs4727799; rs7121949; rs7597198; rsl2324434; rsl2533005 and rs 12960267; c) comparing the genotype of said at least one SNP to genotypes associated with dyslexia wherein the genotypes homozygous major (i.e.
  • G and heterozygous (i.e. A/G) at rs2057482; homozygous major (i.e. A) at rs2075375; homozygous minor (i.e. G) at rs2255112; homozygous minor (i.e. C) at rs2301113; homozygous major (i.e. C) at rs2588517; homozygous minor (i.e. A) at rs4255730; homozygous major (i.e. A) at rs4727799; heterozygous (i.e. T/G) at rs7121949; homozygous minor (i.e.
  • G at rs7597198; homozygous major (i.e. A) at rsl2324434; homozygous major (i.e. G) at rsl2533005 and homozygous minor (i.e. C) at rsl2960267 are associated with dyslexia; d) assigning dyslexia to said human being based on said comparison.
  • the genotype of at least one further SNP present in said DNA is determined in step b), wherein said at least one further SNP is selected from the group of SNPs comprising rs 10210840, rsl2469804, rsl2713284, rsl3387751, rs2580765, rs2580772, rs2588518, rs2588521, rs2860453, rs2919129, rs2972097, rs6545466, rs6760429, rs7340476, rs7562292, rslO15511, rsl0228494, rsl0249234, rsl0262103, rsl0262462, rsl0266297, rsl0280045, rsl989903, rs2040658, rs2189010, rs2189015, rs239675
  • G at rs 10210840, homozygous major (i.e. C) and heterozygous (i.e. C/T) at rsl2469804, homozygous minor (i.e. G) at rsl2713284, homozygous minor (i.e. C) at rsl3387751, homozygous minor (i.e. C) at rs2580765, homozygous minor (i.e. T) at rs2580772, homozygous minor (i.e. T) at rs2588518, homozygous minor (i.e. G) at rs2588521, homozygous minor (i.e.
  • G at rs2860453, homozygous minor (i.e. A) at rs2919129, homozygous minor (i.e. C) at rs2972097, homozygous minor (i.e. C) at rs6545466, homozygous minor (i.e. C) at rs6760429, homozygous minor (i.e. G) at rs7340476, homozygous minor (i.e. C) at rs7562292, homozygous major (i.e. G) at rslO15511, homozygous major (i.e. G) at rs 10228494, homozygous major (i.e.
  • the method refers to the provision of a sample of said human being outside the human body.
  • the present invention also refers to a method of data acquisition comprising at least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) determining the genotype of at least one SNP present in said DNA selected from the group of SNPs comprising rsl0210840, rsl2469804, rsl2713284, rsl3387751, rs2255112, rs2580765, rs2580772, rs2588517, rs2588518, rs2588521, rs2860453, rs2919129, rs2972097, rs6545466, rs6760429, rs7340476, rs7562292, rs7597198 in RTN4; rs2075375 in OTXl; rs
  • G at rs 10210840, homozygous major (i.e. C) and heterozygous (i.e. C/T) at rsl2469804, homozygous minor (i.e. G) at rsl2713284, homozygous minor (i.e. C) at rsl3387751, homozygous minor (i.e. G) at rs2255112, homozygous minor (i.e. C) at rs2580765, homozygous minor (i.e. T) at rs2580772, homozygous major (i.e. C) at rs2588517, homozygous minor (i.e.
  • G at rs7597198, homozygous major (i.e. A) at rs2075375, homozygous major (i.e. G) and heterozygous (i.e. A/G) at rs2057482, homozygous minor (i.e. C) at rs2301113, homozygous major (i.e. G) at rslO15511, homozygous major (i.e. G) at rs 10228494, homozygous major (i.e. A) at rsl0249234, homozygous major (i.e. A) at rsl0262103, homozygous major (i.e.
  • G at rsl0262462, homozygous major (i.e. T) at rsl0266297, homozygous major (i.e. G) at rsl0280045, homozygous major (i.e. G) at rsl2533005, homozygous major (i.e. G) at rsl989903, homozygous major (i.e. C) at rs2040658, homozygous major (i.e. A) at rs2189010, homozygous major (i.e. G) at rs2189015, homozygous major (i.e. A) at rs2396753, homozygous major (i.e.
  • a method of data acquisition comprises at least the steps of: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) determining the genotype of at least one SNP present in said DNA selected from the group of SNPs comprising rs2057482; rs2075375; rs2255112; rs2301113; rs2588517; rs4255730; rs4727799; rs7121949; rs7597198; rsl2324434; rsl2533005 and rs 12960267; c) comparing the genotype of said at least one SNP to genotypes associated with dyslexia wherein the genotypes homozygous major (i.e.
  • G and heterozygous (i.e. A/G) at rs2057482; homozygous major (i.e. A) at rs2075375; homozygous minor (i.e. G) at rs2255112; homozygous minor (i.e. C) at rs2301113; homozygous major (i.e. C) at rs2588517; homozygous minor (i.e. A) at rs4255730; homozygous major (i.e. A) at rs4727799; heterozygous (i.e. T/G) at rs7121949; homozygous minor (i.e.
  • homozygous major i.e. A
  • homozygous major i.e. G
  • homozygous minor i.e. C
  • a method of data acquisition comprising at least the steps of: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) determining the genotypes of SNPs present in said DNA selected from the group of SNPs consisting of rs2057482; rs2075375; rs2255112; rs2301113; rs2588517; rs4255730; rs4727799; rs7121949; rs7597198; rsl2324434; rsl2533005 and rs 12960267; c) comparing the genotype of said at least one SNP to genotypes associated with dyslexia wherein the genotypes homozygous major (i.e.
  • G and heterozygous (i.e. A/G) at rs2057482; homozygous major (i.e. A) at rs2075375; homozygous minor (i.e. G) at rs2255112; homozygous minor (i.e. C) at rs2301113; homozygous major (i.e. C) at rs2588517; homozygous minor (i.e. A) at rs4255730; homozygous major (i.e. A) at rs4727799; heterozygous (i.e. T/G) at rs7121949; homozygous minor (i.e.
  • homozygous major i.e. A
  • homozygous major i.e. G
  • homozygous minor i.e. C
  • the genotype of at least one further SNP present in said DNA is determined in step b), wherein said at least one further SNP is selected from the group of SNPs comprising rs 10210840, rsl2469804, rsl2713284, rsl3387751, rs2580765, rs2580772, rs2588518, rs2588521, rs2860453, rs2919129, rs2972097, rs6545466, rs6760429, rs7340476, rs7562292, rslO15511, rsl0228494, rsl0249234, rsl0262103, rsl0262462, rsl0266297, rsl0280045, rsl989903, rs2040658, rs2189010, rs2189015, rs239675
  • G at rs 10210840, homozygous major (i.e. C) and heterozygous (i.e. C/T) at rsl2469804, homozygous minor (i.e. G) at rsl2713284, homozygous minor (i.e. C) at rsl3387751, homozygous minor (i.e. C) at rs2580765, homozygous minor (i.e. T) at rs2580772, homozygous minor (i.e. T) at rs2588518, homozygous minor (i.e. G) at rs2588521, homozygous minor (i.e.
  • G at rs2860453, homozygous minor (i.e. A) at rs2919129, homozygous minor (i.e. C) at rs2972097, homozygous minor (i.e. C) at rs6545466, homozygous minor (i.e. C) at rs6760429, homozygous minor (i.e. G) at rs7340476, homozygous minor (i.e. C) at rs7562292, homozygous major (i.e. G) at rslO15511, homozygous major (i.e. G) at rs 10228494, homozygous major (i.e.
  • the method of diagnosing dyslexia in a human being comprises at least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) determining the genotype of at least one SNP present in said DNA selected from the group of SNPs comprising rs2255112, rs2588518 and rs7597198 in RTN4; rs2075375 in OTXl; rs2057482 and rs2301113 in HIFlA; rsl2533005 and rs4727799 in FOXP2, rs7121949 in DCDCl; rs 12960267 in TUBB6; c) comparing the genotype of said at least one SNP to genotypes associated with dyslexia wherein the genotypes homozygous minor (i.e.
  • a method of diagnosing dyslexia in a human being comprises at least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) determining the genotype of at least one SNP present in said DNA selected from the group of SNPs comprising rsl0210840, rsl2469804, rsl2713284, rsl3387751, rs2255112, rs2580765, rs2580772, rs2588517, rs2588518, rs2588521, rs2860453, rs2919129, rs2972097, rs6545466, rs6760429, rs7340476, rs7562292, rs7597198 in RTN4; rs2075375 in OTXl; rs2057482, rs2301113 in HIFlA; rslO15511,
  • G at rs2860453, homozygous minor (i.e. A) at rs2919129, homozygous minor (i.e. C) at rs2972097, homozygous minor (i.e. C) at rs6545466, homozygous minor (i.e. C) at rs6760429, homozygous minor (i.e. G) at rs7340476, homozygous minor (i.e. C) at rs7562292, homozygous minor (i.e. G) at rs7597198, homozygous major (i.e. A) at rs2075375, homozygous major (i.e.
  • G and heterozygous (i.e. A/G) at rs2057482, homozygous minor (i.e. C) at rs2301113, homozygous major (i.e. G) at rslO15511, homozygous major (i.e. G) at rsl0228494, homozygous major (i.e. A) at rsl0249234, homozygous major (i.e. A) at rsl0262103, homozygous major (i.e. G) at rsl0262462, homozygous major (i.e. T) at rsl0266297, homozygous major (i.e.
  • G at rsl0280045, homozygous major (i.e. G) at rsl2533005, homozygous major (i.e. G) at rsl989903, homozygous major (i.e. C) at rs2040658, homozygous major (i.e. A) at rs2189010, homozygous major (i.e. G) at rs2189015, homozygous major (i.e. A) at rs2396753, homozygous major (i.e. C) at rs2894699, homozygous major (i.e. A) at rs4727799, homozygous major (i.e.
  • the method refers to the provision of a sample of said human being outside the human body.
  • the present invention also refers to a method of data acquisition comprising at least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) determining the genotype of at least one SNP present in said DNA selected from the group of SNPs comprising rsl0210840, rsl2469804, rsl2713284, rsl3387751, rs2255112, rs2580765, rs2580772, rs2588517, rs2588518, rs2588521, rs2860453, rs2919129, rs2972097, rs6545466, rs6760429, rs7340476, rs7562292, rs7597198 in RTN4; rs2075375 in OTXl; rs2057482, rs2301113 in HIFlA; rslO15511, rs 10228494,
  • G at rs 10210840, homozygous major (i.e. C) and heterozygous (i.e. C/T) at rsl2469804, homozygous minor (i.e. G) at rsl2713284, homozygous minor (i.e. C) at rsl3387751, homozygous minor (i.e. G) at rs2255112, homozygous minor (i.e. C) at rs2580765, homozygous minor (i.e. T) at rs2580772, homozygous major (i.e. C) at rs2588517, homozygous minor (i.e.
  • G at rs7597198, homozygous major (i.e. A) at rs2075375, homozygous major (i.e. G) and heterozygous (i.e. A/G) at rs2057482, homozygous minor (i.e. C) at rs2301113, homozygous major (i.e. G) at rslO15511, homozygous major (i.e. G) at rs 10228494, homozygous major (i.e. A) at rsl0249234, homozygous major (i.e. A) at rsl0262103, homozygous major (i.e.
  • G at rsl0262462, homozygous major (i.e. T) at rsl0266297, homozygous major (i.e. G) at rsl0280045, homozygous major (i.e. G) at rsl2533005, homozygous major (i.e. G) at rsl989903, homozygous major (i.e. C) at rs2040658, homozygous major (i.e. A) at rs2189010, homozygous major (i.e. G) at rs2189015, homozygous major (i.e. A) at rs2396753, homozygous major (i.e.
  • the method of diagnosing dyslexia in a human being comprises at least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) determining the genotype of at least one SNP present in said DNA selected from the group of SNPs comprising rs2255112, rs2588518 and rs7597198 in RTN4; rs2075375 in OTXl; rs2057482 and rs2301113 in HIFlA; rsl2533005 and rs4727799 in FOXP2, rs7121949 in DCDCl; rs 12960267 in TUBB6; rs 12324434, rs4255730 in DYXlCl; c) comparing the genotype of said at least one SNP to genotypes associated with dyslexia wherein the genotypes homozygous minor (i.e.
  • G at rs2255112, homozygous minor (i.e. T) at rs2588518, homozygous minor (i.e. G) at rs7597198, homozygous major (i.e. A) at rs2075375, homozygous major (i.e. G) and heterozygous (i.e. A/G) at rs2057482, homozygous minor (i.e. C) at rs2301113, homozygous major (i.e. G) at rsl2533005, homozygous major (i.e. A) at rs4727799, heterozygous (i.e. T/G) at rs7121949, homozygous minor
  • dyslexia is assigned to a human being with a probability dependent on the number of consensuses between the genotypes of the SNPs analysed and the SNPs associated with dyslexia, i.e. the higher the number of consensuses between said SNPs the higher the probability of dyslexia in said human being.
  • the human being, the sample comprising DNA is obtained from is a Caucasian human being.
  • Said Caucasian may furthermore in one embodiment preferably belong to an Indo-Germanic-speaking population; however, said Caucasian may also belong to a west-Germanic-speaking, High German or a German-speaking population.
  • the sample comprising DNA is obtained from a tissue sample such as blood, skin or saliva of the human being or a sample comprising cells of the individual to be tested.
  • the DNA comprised in the sample of the human being is first purified and then preferably amplified outside the human body.
  • a method of the present invention it is furthermore preferred to do the analysis such that it is performed using at least one technique selected from the group of techniques comprising DNA-sequencing, DNA-microarray, real-time PCR and mass- spectrometry.
  • any other method suited for the analysis of DNA and/or determination of a genotype of a SNP may be used.
  • Yet another aspect of the present invention relates to the use of the methods as described above.
  • a method as described above may be used in a medical check of a human being at a stage of development too early for the occurrence of manifested symptoms of dyslexia.
  • the medical check may be a routine medical check for children at the age of twelve months.
  • the method as disclosed above may be used in order to obtain an early diagnosis and let children diagnosed with dyslexia have special medical and/or educational treatment.
  • a method as described above may be used for substantiating the diagnosis of dyslexia in a human being, already tested by conventional methods such as reading and/or writing tests.
  • a DNA-microarray device comprises at least: a) a chamber suitable for containing a liquid sample wherein said liquid sample comprises DNA of the individual to be tested for dyslexia; b) one or more different probe nucleotides which are positioned on different locations on a surface of the chamber wherein the probe nucleotides comprise probe nucleotides specifically detecting at least one of the SNPs comprising SNP rs2255112, rs2588517, rs7597198, rs2075375, rs2057482, rs2301113, rsl2533005, rs4727799, rs7121949, rsl2960267, rsl2324434 and rs4255730.
  • said microarray comprises a) a chamber suitable for containing a liquid sample wherein said liquid sample comprises DNA of the individual to be tested for dyslexia; b) one or more different probe nucleotides which are positioned on different locations on a surface of the chamber wherein the probe nucleotides comprise at least probe nucleotides specifically detecting the group of SNPs consisting of rs2057482; rs2075375; rs2255112; rs2301113; rs2588517; rs4255730; rs4727799; rs7121949; rs7597198; rsl2324434; rsl2533005 and rs 12960267.
  • the inventors have found that it is possible to diagnose dyslexia in a human being based on the analysis of DNA of said human being in regulatory and/or coding regions of at least one gene implicated in neuronal migration selected from the group of genes as listed in Table 1. After comparing said results to the results of a reference analysis, it is possible to assign dyslexia to a human being.
  • said diagnosis can be based on the determination of at least one genotype of a SNP as listed in Table 2 and the comparison of said genotype to the corresponding genotype associated with dyslexia.
  • Said method may be used in order to diagnose dyslexia, for example, when applied during a routine medical check for children.
  • a genetic component for the susceptibility of an individual to a disease has been shown, there may be several advantages to base a diagnosis on said genetic component.
  • the term “about” and “approximately” denote an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question.
  • the term “typically” indicates a deviation from the indicated numerical value of ⁇ 10% and preferably ⁇ 5%. It is to be understood that the term “comprising” is not limiting.
  • the term “consisting of” is considered to be a preferred embodiment of the term “comprising of. If, hereinafter, a group is defined as comprising at least a certain number of embodiments, this is also meant to encompass a group that preferably consists of these embodiments only.
  • the present invention relates to a method of diagnosing dyslexia in a human being.
  • Said method comprises at the least the steps of: a) providing a sample of said human being wherein said sample comprises DNA; b) analysing said DNA in regulatory and/or coding regions of at least one gene implicated in neuronal migration selected from the group of genes as depicted in Table 1 ; c) comparing the result of said analysis to the result of a reference analysis of a non-dyslexic human being; d) assigning dyslexia to said human being based on said comparison.
  • the present invention also relates to a method of diagnosing dyslexia in a human being comprising at least the following steps: a) providing a sample of said human being wherein said sample comprises
  • dyslexia is used as known and defined in the medical field.
  • dyslexia is meant to describe a complex disorder characterised by unexpected difficulties in learning to read and/or to write and/or understand words/texts and/or to spell by otherwise normal intelligence.
  • the disease may manifest in different forms of severity, all of which are meant to be encompassed by the term “dyslexia” as used herein. It may be preferred to associate the term “dyslexia” as used herein with reading disability (RD). The term “dyslexia” as used herein may, however, also be associated with any disabilities and/or problems to write.
  • the method of the present invention is concerned with the analysis of genetic material, it is in a first step necessary to provide genetic material of the individual to be tested.
  • said individual may be a child at the age of 12 months or even younger.
  • a tissue sample of the corresponding individual as sample comprising DNA, such as e.g. blood, skin or saliva of said individual. Any other sample may also be used; however, said sample has to contain genetic material, i.e. DNA of the individual.
  • Any method for collecting and providing said sample known to the person skilled in the art may be used.
  • a blood sample may for example be taken using a sterile needle connected to a sterile tube from a vein of an individual's arm.
  • a saliva sample may for example be taken by using a sterile cotton bud and collecting saliva out of the mouth and throat area of an individual or by flushing said area and collecting said flushing solution.
  • a saliva sample may, however, also comprise saliva, which has been spit by the individual and collected.
  • Said first step of the method according to the invention may comprise direct contact with the body of the suspected individual. However, as e.g. in case of collection of the spitted saliva, said first step does not necessarily involve contact with the body of the individual. In any case, all further steps may be executed outside the human body.
  • the DNA of an individual is present in a suitable buffer at a suitable concentration and a level of purity sufficient for any further analysis.
  • any impurity due to proteins still present in the solution may be defined by measuring at a wavelength of 280 nanometres, whereas the purity and the concentration of the DNA may be analysed by employing 260 nanometres followed by the analysis of the corresponding peaks.
  • any standard protocol may be used for purification of the DNA with the final goal of providing a DNA-sample appropriate for the analysis method employed. As different methods as discussed below may be employed, the purification may also vary according to the method used in later steps.
  • primers located upstream and downstream of a DNA-region of interest one hybridising to the Watson-strand, one hybridising to the Crick-strand
  • suitable enzymes such as polymerases and employing several temperature cycles comprising denaturing, annealing and reaction temperatures, the region of interest may be amplified.
  • any detection methods based on hybridisation may be used in later steps, it may be preferred to include labelled primers and/or labelled nucleotides in the amplification reaction in order to label the DNA regions of interest already in this initial step for easier and more convenient detection of said regions in the corresponding following assays, such as DNA-microarrays.
  • the first steps of the method of detecting dyslexia in a human being comprises obtaining a sample comprising the individual's DNA, preferably purifying said DNA out of the sample as well as preferably amplifying regions of interest of said DNA prior to the following steps in the analysis. All these steps and methods mentioned so far are routine methods to the person skilled in the art and any known method suited for the corresponding purpose may be used.
  • the optionally purified and amplified DNA may now be analysed in certain DNA-regions by a method as set out further below after discussing the genomic regions of interest.
  • any disruption of the process of neuronal migration may play a role in the development of dyslexia.
  • the inventors set out to identify genes that are known or suspected to play a role in neuronal migration and to link such genes to chromosomal regions being potentially involved in dyslexia.
  • Genes implicated in neuronal migration were selected using the PANTHER classification system (www.pantherdb.org). Thus, the inventors have found that the 40 genes as listed in Table 1 seem to be implicated in the susceptibility to dyslexia.
  • a so-called mecanic wild-type” state may be defined for said gene.
  • Said state may comprise the regulation of expression of said gene and the gene product itself as defined in detail below.
  • a "mutant” state may also be defined. Said state refers to a situation differing from the wild-type situation.
  • said gene is present in two alleles in each individual.
  • the two alleles of said gene one commonly refers to the genotype of said allele.
  • the terms "allele” and "genotype of said allele” or simply “genotype” are used in the present invention as known to the skilled person.
  • two alleles of a gene are present in each individual and said two alleles may be identical, e.g. in the wild-type state; in this case, the genotype is referred to as being "homozygous wildtype” for said allele.
  • the genotype is referred to as being "heterozygous" for said region of said allele.
  • a wild-type state of a gene may comprise the regulation and expression of a gene.
  • the terms “regulation” and “expression” of a gene will be addressed.
  • regulatory regions usually differ from the coding regions of a gene, i.e. they may for example be located at a region far away from the coding region itself. Binding of proteins to DNA usually depends on a certain sequence of nucleotides in said regulatory DNA-region; thus, a defined sequence may create docking sites for transcription factors. On these docking or binding sites, protein complexes regulating the "expression of the gene” may then assemble. Thus, certain regulatory sequences such as promoters may play an important role for the expression level of a gene. In the context of the present invention, any sequence not coding for the gene product but being part of said gene may be referred to as "regulatory region”; thus, also up- or downstream regulatory regions as well as introns are referred to as "regulatory regions”.
  • RNA is encoded by the gene
  • mRNA is referred to as mRNA.
  • the mRNA can be further processed (e.g. spliced) and, in a second step, the mRNA is translated into protein.
  • Proteins may thus be the final products of gene expression.
  • the amount of a protein as final product may correlate with the level of gene expression.
  • RNA-molecules may be the final products of gene expression, such as microRNAs.
  • Said RNAs may also be subject of processing and modification in a second step.
  • proteins as final gene products may be preferred and are discussed in the following.
  • other final gene products also comprising splice- variants and the like are also encompassed by the present invention.
  • the coding region of a gene determines a defined sequence of amino acids according to the genetic code. Said amino acid sequence itself seems to define and determinate the overall structure of the final protein.
  • the coding sequence of a gene does not necessarily have to be continuous; there may be non-coding stretches, which may have regulatory functions, in between.
  • said introns may have regulatory functions.
  • both types of regions are part of a gene.
  • coding region or "coding sequence” is meant to encompass a DNA-sequence, which starts at the 5 '-end with the Start-codon, i.e. ATG. This triplet codes for the first amino acid, a methionine, of the corresponding protein when translation of the mRNA is initiated. Accordingly, the coding region ends at the 3 '-end with a Stop-codon, e.g. TAG, in order to terminate protein translation. Translation of the mRNA results in one protein, which may be, comprised of different domains/ polypeptides/ parts.
  • DNA-sequence of a gene comprised of regulatory and coding regions. This may lead to a defined and regulated expression of said gene with the gene product being e.g. a protein of a defined amino acid sequence and function. This may be referred to as the wild-type state of said gene.
  • Said gene may, however, not be in the wild-type state but rather in a mutant state, e.g. in terms of expression or structure of the gene product.
  • Mutations in the regulatory regions of a gene may lead to misregulation of gene- expression; mutations in promoter sequences may disturb the binding sites for transcription factors important in gene regulation or affect binding affinities leading either to a higher expression level or may result in a decreased expression level.
  • the final products of gene expression e.g. a protein
  • the misregulation may lead to a diseased state.
  • oncogenes in various cancers which are permanently turned on instead of being regulated for example during the cell cycle.
  • a protein may thus differ from the wild-type protein by one or more amino acids.
  • amino acid important for the overall structure of a protein is affected and replaced by an amino acid not able to cope with the structural requirements, the overall structure may be disturbed and the protein may be non- functional.
  • binding affinities of a protein may be disturbed due to different surfaces present in the mutant protein.
  • a protein may be also rendered inactive by being truncated to various extents or by integration of a new domain and/or part of a different protein.
  • the basis for a non- functional protein may be mutations in the DNA coding for said protein.
  • one nucleotide in the coding sequence is missing or one nucleotide is additionally introduced, the genetic code being comprised of triplets of nucleotides is shifted and, thus, coding for a nonsense amino acid sequence in most cases. This is usually referred to as frame shift.
  • other mutations such as point mutations, may lead to amino acid substitutions or the generation of stop codons, which in turn lead to truncated proteins.
  • Additional mutations on the DNA level may comprise deletions, insertions and translocations, all of which result in a new sequence as compared to the wild type situation. Such effects may of course be responsible for massive losses of function in the products of gene expression.
  • point mutations, insertions, deletions and/or translocations present in the coding region of a gene may lead to a non- functional gene expression product; the presence of said mutations in regulatory regions of a gene may lead to misregulation.
  • a mutant state of said gene may be directly linked to a disease resulting from the misregulation and/or misfunction of said gene.
  • the mutation may not drastically alter the state of the gene.
  • the mutation may be compensated by a second mutation in said gene.
  • Other genes may, furthermore, take over the function of said gene, and so on.
  • two alleles of a gene are present in an individual; thus, in some cases one allele in the wild-type state may be able to compensate for the mutant allele.
  • association of a gene with a disease thus seems to strongly depend on its function; if a gene is implicated and seems to be essential in a certain cellular process, the inactivation of either one or both alleles of said gene may directly lead to a disease due to the disruption of said cellular process. Furthermore, the association of a mutant state gene with a disease seems to depend on mutations present in other genes, e.g. in genes of the same pathway. Said genes may be parallel factors in a pathway or essential up- or downstream factors of one cellular pathway; Thus, if either one of two parallel genes may be nonfunctional, this may not lead to a diseased state; however, mutations in both genes in one individual may lead to said disease. The situation is, furthermore, influenced by the allelic state of said genes, i.e. whether the genotype is homozygous for the mutation or heterozygous.
  • a specific genotype of a gene may be associated with a disease. If a certain set of genes is implicated in a cellular process, the disruption of which seems to account for a specific disease, one may thus find specific genotypes of said genes associated with said disease by comparing the genotypes found in the individual to be tested with the situation in an individual not suffering from the disease. Of course, one may not only refer to one single reference individual not afflicted with the disease, but rather to a large population of healthy reference individuals. In doing so, information on said set of genes and their corresponding genotypes in said reference population may be averaged and then compared to the specific situation in an individual to be tested.
  • At least one essential gene of the set of genes shows more mutant genotypes compared to said averaged population, the individual may be categorised as likely suffering from said disease. However, it is important to note that in general also wild-type genotypes may be associated with a disease.
  • genotype of said alleles i.e. either homozygous or heterozygous for said mutation.
  • a reference analysis i.e. to a sample of at least one individual not affected with said particular disease
  • At least one of said 40 genes may be analysed in regulatory and/or coding regions.
  • all 40 genes may be analysed in regulatory and/or coding regions.
  • RTN4, OTXl, HIFlA, FOXP2, DCDCl and TUBB6 are selected for the analysis.
  • genes not only implicated in neuronal migration but also known to interact with the cytoskeleton for the analysis may be essential for a specific process implicated in normal reading and/or writing skills. Thus, disturbance of said process may be implicated in the susceptibility to dyslexia.
  • genes may be classified as not only being implicated in the general process of neuronal migration but also as known to interact with the cytoskeleton: RELN, CDK5, DCX, MDCR, SMPDl, TUBB6, DCDCl, VAPA, SMPDL3B, DCDC2B, DCDC2C, LOC728597, DCAMKL2 and DCAMKLl.
  • all of said 14 genes may be analysed in regulatory and/or coding regions. It may furthermore be preferred to analyse at least 13, at least 12, at least 11, at least 10, at least 9, at least 8, at least 7, at least 6, at least 5, at least 4, at least 3 or at least 2 genes from the list of genes 1 to 14 in Table 1. It may furthermore be possible to use only one gene in the case of a very strong association of said gene with dyslexia. However, preferred is the use of 1 to 10 and preferably 5 to 8 genes of said 14 genes for the analysis of said genes in regulatory and/or coding regions.
  • genes TUBB6 and DCDCl are included in the analysis if genes not only implicated in neuronal migration but also in the interaction with the cytoskeleton are chosen for the analysis.
  • genes not only implicated in neuronal migration but also being classified as so-called semaphorins Said genes and/or the products of said genes seem to play diverse roles in axon guidance and epithelial morphogenetic cell movements.
  • the integrity of said genes may be essential for a specific process implicated in normal reading and/or writing skills. Thus, disturbance of said process may be implicated in the susceptibility to dyslexia.
  • genes may be classified as not only being implicated in the general process of neuronal migration but also as classified as semaphorins: HIFlA, TBP, SEMA3A, TSNAX, DISCI and SRF. In a preferred embodiment of the invention, all of said 6 genes may be analysed in regulatory and/or coding regions.
  • gene HIFlA into the analysis if genes not only implicated in neuronal migration but also classified as semaphorins are chosen for the analysis.
  • genes not only implicated in neuronal migration but also in the growth of nerv fibers may be used.
  • the integrity of said genes may be essential for a specific process implicated in normal reading and/or writing skills.
  • disturbance of said process may be implicated in the susceptibility to dyslexia.
  • genes may be classified as not only being implicated in the general process of neuronal migration but also in the growth of nerv fibers: RTN4, OTXl, CNTN4, NRG 1 , DNER, PTPRF and NRCAM.
  • all of said 7 genes may be analysed in regulatory and/or coding regions. It may furthermore be preferred to analyse at least 6, at least 5, at least 4, at least 3 or at least 2 genes from the list of genes 21 to 27 in Table 1. It may furthermore be possible to use only one gene in the case of a very strong association of said gene with dyslexia. However, preferred is the use of 1 to 6 and preferably 5 genes of said 7 genes for the analysis of said genes in regulatory and/or coding regions.
  • genes RTN4 and OTXl are included in the analysis if genes not only implicated in neuronal migration but also in the growth of nerv fibers are chosen for the analysis.
  • genes not only implicated in neuronal migration but also possessing membrane activity may be used.
  • the integrity of said genes may be essential for a specific process implicated in normal reading and/or writing skills.
  • disturbance of said process may be implicated in the susceptibility to dyslexia.
  • genes may be classified as not only being implicated in the general process of neuronal migration but also as possessing membrane activity: NDUFV2, GNAL, RHBDL2 and NELLl.
  • all of said 4 genes may be analysed in regulatory and/or coding regions. It may furthermore be preferred to analyse 2 or 3 genes from the list of genes 28 to 31 in Table 1. It may furthermore be possible to use only one gene in the case of a very strong association of said gene with dyslexia.
  • Genes implicated in neuronal migration as listed in Table 1 may thus be analysed with the genes RTN4, OTXl, HIFlA, FOXP2, DCDCl and TUBB6 being preferred. However, one may also use genes implicated in neuronal migration and the interaction with the cytoskeleton (genes 1 to 14 of Table 1) or genes implicated in neuronal migration and classified as semaphorins (genes 15 to 20 of Table 1). Furthermore, genes implicated in neuronal migration and the growth of nerve fibres may in another embodiment be used (genes 21 to 27 of Table 1) or genes being implicated in neuronal migration as well as showing membrane activity (genes 28 to 31 of Table 1).
  • the result of said analysis is compared to the result of an analysis of a non-dyslexic reference individual.
  • a mutant genotype in the tested individual is also found in a reference non-dyslexic individual, said mutant genotype may not be directly linked to dyslexia.
  • the non-dyslexic reference individual shows a homozygous wildtype situation whereas the tested individual displays a mutant situation leading e.g. to a non-functional gene product, this seems to suggest an association with dyslexia, particularly if said mutation is homozygous.
  • said non-dyslexic reference individual may not be a single individual but rather a large group of individuals not suffering from dyslexia.
  • Said large group of non-dyslexic individuals may comprise at least about 50, at least about 75, at least about 100, at least about 125, at least about 150, at least about 200, at least about 500, at least about 1000, at least about 5000, at least about 7000 or at least about 10.000 non-dyslexic individuals.
  • step d) of a method according to the present invention dyslexia is assigned to a human being based on the comparison as mentioned above.
  • said assignment is based on the number of differences between the tested individual and the reference individual or the reference non-dyslexic group, respectively.
  • the higher the number of differences between the results of the tested individual and the results of the reference non-dyslexic individual or group, respectively the higher the probability of a susceptibility to dyslexia in the tested individual.
  • polymorphism refers to variations among the genome of individuals of a population. Polymorphisms are usually detected by sequencing techniques. However, polymorphisms may also and have been determined by other techniques such as RFLP analysis. In case only one nucleotide within a certain region differs, this is referred to as “single nucleotide polymorphism” or "SNP".
  • SNP single nucleotide polymorphism
  • a SNP may be known to be in state A for the majority of the population (“major”) corresponding to one defined nucleotide/base, whereas in the minority of a population state B (“minor”) corresponding to a different nucleotide/base is present.
  • the region may also span over two or several nucleotides and may be an insertion or a deletion.
  • Polymorphisms in the human genome are not necessarily linked to a certain phenotype, i.e. a disease. However, they represent interesting "target" sites for being associated with a disease such as dyslexia as they represent regions varying in a population comprising inter alia dyslexic and non- dyslexic individuals.
  • deletions, insertions, point mutations and/or translocations in the DNA may be responsible for major downstream effects.
  • a polymorphism e.g. a SNP leading to an amino acid substitution in a crucial position of a protein
  • it may be associated with a disease and may be preferably analysed with a method according to the invention. It may be preferred to select deletions, insertions, point mutations and/or translocations in the coding regions of the genes as listed in Table 1 for analysis.
  • a way of experimentally determining genotypes associated with dyslexia is the comparison of said genotypes in dyslexic and non-dyslexic individuals.
  • one may collect information on the corresponding region e.g. by determining the genotype of a SNP) in two groups comprised of either dyslexic or non-dyslexic individuals.
  • Statistical analysis is then used for calculating whether a genotype of said analysed region is associating with dyslexia or not.
  • a SNP is in the minor or major state as defined above (plus, of course, the allelic state).
  • Information on said state i.e. minor or major, is the information relevant for diagnosing dyslexia; thus, in the column "type", the dyslexia-associating type of each SNP is listed; of course, the skilled person is aware that said minor or major state may be indicated by two different complementary nucleotides at the corresponding position of the SNP depending on the way, the analysis is done.
  • DNA is comprised of two complementary strands, the nucleotide, i.e.
  • an A, a T, a G or a C indicating said state at the SNP -position depends on the strand analysed: if the coding strand is analysed, a G may be the nucleotide associated with either a minor or a major state. However, if the complementary non-coding strand is analysed, a C will be the nucleotide associated with either a minor or a major state (and the other way around). The same, of course, applies for a T or an A. Thus, a T on the coding strand at the position of a SNP may be associated with dyslexia (e.g. as a minor type).
  • the state of a SNP i.e. minor or major, needs to be determined.
  • the nucleotide at said exact position may vary according to whether the coding or non- coding strand is analysed. Both, the nucleotides on the coding strand as given herein or their complementary nucleotides on the non-coding strands may be used for said analysis and are encompassed by the present invention.
  • a specific genotype of one of said SNPs present in an individual to be tested may thus be directly assigned as to be associated with dyslexia or not.
  • the comparison is not made to a non-dyslexic reference group, but rather to the results of data, which have been gathered for associated SNPs using the experimental setup comparing dyslexic and non-dyslexic individuals.
  • the SNPs as listed in the following are classified according to the rs-nomenclature. Each rs-number corresponds to exactly one position in the genome where a SNP has been detected. Said result has been submitted as variation to the dbSNP-database.
  • the dbSNP-database is available for the public and may be accessed via NCBI (http://www.ncbi.nlm.nih.gov/).
  • Said SNPs may thus be preferably selected from the group of SNPs 1 to 44 listed in Table 2 comprising rsl0210840, rsl2469804, rsl2713284, rsl3387751, rs2255112, rs2580765, rs2580772, rs2588517, rs2588518, rs2588521, rs2860453, rs2919129, rs2972097, rs6545466, rs6760429, rs7340476, rs7562292, rs7597198 in RTN4, rs2075375 in OTXl, rs2057482, rs2301113 in HIFlA, rslO15511, rsl0228494, rsl0249234, rsl0262103, rsl0262462, rsl0266297, rsl0280045, rsl
  • the inventors have found that the genotype (minor or major) as listed in Table 2 associates with dyslexia. This corresponds to a nucleotide/base at said exact position and may be homozygous or heterozygous as listed. Said result is based on the comparison of data gained for dyslexic individuals to the data of a non-dyslexic reference group. Thus, e.g. a minor genotype corresponding to a G on the coding strand in the SNP rs22555112 at position -76636 on both alleles of RTN4 (and thus the genotype homozygous minor at this position) has been found to associate with dyslexia.
  • a G in said position of the coding strand on both alleles of RTN4 in a tested individual indicates a susceptibility to dyslexia.
  • dyslexia is assigned to a human being based on the comparison of the genotype of a SNP as determined (e.g. genotype homozygous minor (i.e. G) at rs22555112) to a result indicating an association with dyslexia (genotype homozygous minor (i.e. G) at rs22555112).
  • Said results may also be referred to as indicating a risk for developing dyslexia and, thus, one may interpret "assignment of dyslexia” in this respect as “assignment of dyslexia based on the associating risk”. In case the two results match, this is interpreted as indicating dyslexia in the tested individual. Said assignment may, however, not be based on one result only. In case for example 10 out of 10 genotypes match, however, the probability of developing dyslexia in the tested individual seems to be very high.
  • the experimental data and results shown in the Example section have been gathered using about 91 selected dyslexic and about 184 non-dyslexic individuals wherein said numbers may vary for each individual analysed SNPs due to the viability of the results. From previous experimental studies, it seems that different genetic regions may be associated with dyslexia dependent on the race of the dyslexics/affected families analysed. Furthermore, there may be an association with a language. Thus, it may be preferred to interpret the results gathered with a method according to the present invention in the context of Caucasian human beings. Furthermore, said results may be interpreted in the context of a Caucasian human being preferably belonging to an Indo-Germanic-speaking population.
  • the SNP has been analysed and found to associate with dyslexia according to the data given in Example 1.
  • said SNP has been predicted using the SNPs of a gene of Example 1 as basis for a search for further associating SNPs located in said gene using HapMap with a cut off value of r ⁇ 0.05 for SNPs associating with dyslexia. It may be preferred to not only rely on the SNPs as listed in Table 2, but also on further polymorphisms such as further SNPs, deletions and/or insertions showing a strong linkage of about 0.7 to the identified SNPs.
  • G at rsl2533005, homozygous major (i.e. A) at rs4727799, heterozygous (i.e. T/G) at rs7121949 and homozygous minor (i.e. C) at rsl2960267 are associated with dyslexia.
  • Said classification is based on the so-called "p-values", which are indicative of probabilities associated with said genotype.
  • p-values which are indicative of probabilities associated with said genotype.
  • said listing at the beginning of this paragraph may also be used for a classification of how significant individual SNPs are starting with the most significant SNP.
  • the corresponding genes may be analysed for said 10 SNPs just mentioned together with at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31 , at least 32 or at least 33 other SNPs from the list of SNPs 1 to 44 of Table 2.
  • G at rs2255112, homozygous minor (i.e. C) at rs2580765, homozygous minor (i.e. T) at rs2580772, homozygous major (i.e. C) at rs2588517, homozygous minor (i.e. T) at rs2588518, homozygous minor (i.e. G) at rs2588521, homozygous minor (i.e. G) at rs2860453, homozygous minor (i.e. A) at rs2919129, homozygous minor (i.e. C) at rs2972097, homozygous minor (i.e.
  • G at rslO15511, homozygous major (i.e. G) at rsl0228494, homozygous major (i.e. A) at rsl0249234, homozygous major (i.e. A) at rsl0262103, homozygous major (i.e. G) at rsl0262462, homozygous major (i.e. T) at rsl0266297, homozygous major (i.e. G) at rsl0280045, homozygous major (i.e. G) at rsl2533005, homozygous major (i.e. G) at rsl989903, homozygous major (i.e.
  • homozygous major i.e. G
  • homozygous major i.e. G
  • homozygous major i.e. G
  • heterozygous i.e. T/G
  • homozygous minor i.e. C
  • one may analyse at least 43, at least 42, at least 41, at least 40, at least 39, at least 38, at least 37, at least 36, at least 35, at least 34, at least 33, at least 32, at least 31, at least 30, at least 29, at least 28, at least 27, at least 26, at least 25, at least 24, at least 23, at least 22, at least 21, at least 20, at least 19, at least 18, at least 17, at least 16, at least 15, at least 14, at least 13, at least 12, at least 11, at least 10, at least 9, at least 8, at least 7, at least 6, at least 5, at least 4, at least 3 or at least 2 of said SNPs.
  • the assignment of results may be done as described above.
  • the inventors have found that specific SNPs in DYXlCl as listed from SNPs 45 to 52 in Table 2 associate with dyslexia.
  • G at rsl989903, homozygous major (i.e. C) at rs2040658, homozygous major (i.e. A) at rs2189010, homozygous major (i.e. G) at rs2189015, homozygous major (i.e. A) at rs2396753, homozygous major (i.e. C) at rs2894699, homozygous major (i.e. A) at rs4727799, homozygous major (i.e. A) at rs6466488, homozygous major (i.e. A) at rs696936, homozygous major (i.e.
  • G at rs6974757, homozygous major (i.e. A) at rs6980093, homozygous major (i.e. G) at rs 727644, homozygous major (i.e. G) at rs7785701, heterozygous (i.e. T/G) at rs7121949, homozygous minor (i.e. C) at rsl2960267, homozygous major (i.e. G) and heterozygous (i.e. G/ A) at rslO75938, homozygous major (i.e. A) at rsl2324434, homozygous minor (i.e.
  • one may analyse at least 51, at least 50, at least 49, at least 48, at least 47, at least 46, at least 45, at least 44, at least 43, at least 42, at least 41, at least 40, at least 39, at least 38, at least 37, at least 36, at least 35, at least 34, at least 33, at least 32, at least 31, at least 30, at least 29, at least 28, at least 27, at least 26, at least 25, at least 24, at least 23, at least 22, at least 21, at least 20, at least 19, at least 18, at least 17, at least 16, at least 15, at least 14, at least 13, at least 12, at least 11, at least 10, at least 9, at least 8, at least 7, at least 6, at least 5, at least 4, at least 3 or at least 2 of said SNPs.
  • the assignment of results may be undertaken as described above.
  • G at rsl2533005, homozygous major (i.e. A) at rs4727799, heterozygous (i.e. T/G) at rs7121949, homozygous minor (i.e. C) at rs 12960267, homozygous major (i.e. A) at rsl2324434 and homozygous minor (i.e. A) at rs4255730 are associated with dyslexia.
  • Said classification is based on the so-called "p-values", which are indicative of probabilities associated with said genotype.
  • its probability may be classified according to its p-value, with the lowest p-value indicating the highest probability.
  • said listing at the beginning of the paragraph may also be used for a classification of how significant individual SNPs are starting with the most significant SNP.
  • the corresponding genes may be analysed for said 12 SNPs just mentioned together with at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38 or at least 39 other SNPs from the list of SNPs of Table 2.
  • the present invention is concerned with isolated oligonucleotides for the detection of at least one gene selected from the group of the genes as listed in table 1 comprising nucleic acid molecules specifically detecting regions in said genes associated with dyslexia.
  • the present invention is concerned with oligonucleotides for the detection of at least RTN4, OTXl, HIFlA, FOXP2, DCDCl and TUBB6 comprising nucleic acid molecules specifically detecting regions in said genes associated with dyslexia.
  • the present invention is concerned with nucleic acid molecules specifically detecting regions in RTN4 (SEQ ID NO. 1) associated with dyslexia.
  • the present invention is concerned with nucleic acid molecules specifically detecting regions in OTXl (SEQ ID NO. 2) associated with dyslexia.
  • the present invention is concerned with nucleic acid molecules specifically detecting regions in HIFlA (SEQ ID NO. 3) associated with dyslexia.
  • the present invention is concerned with nucleic acid molecules specifically detecting regions in FOXP2 (SEQ ID NO. 4) associated with dyslexia.
  • the present invention is concerned with nucleic acid molecules specifically detecting regions in DCDCl (SEQ ID NO. 5) associated with dyslexia.
  • nucleic acid molecules specifically detecting regions in TUBB6 (SEQ ID NO. 6) associated with dyslexia.
  • Said nucleic acid molecules may be in the range of about 12 to about 20 nucleotides with about 15 nucleotides being preferred spanning the regions in said genes associated with dyslexia.
  • said regions may be the SNPs as listed in the following.
  • the regions comprising the SNPs as listed in Table 2 may be identified and obtained by using the dbSNP-database as defined above wherein each SNP has a defined position in the genome.
  • each SNP has a defined position in the genome.
  • one may furthermore define the position of said SNP with respect to the ATG of said gene.
  • the SNP positions are given according to said definition with a "+" indicating a position upstream of the ATG and a "-" indicating a position downstream of the ATG of the corresponding gene.
  • the present invention is concerned with nucleic acid molecules specifically detecting the SNP rs2255112 at position -76636 in SEQ ID NO. 1 (RTN 4) wherein a G at said position represents the minor allele and a T represents the major allele.
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rs2588517 at position -56476 in SEQ ID NO. 1 (RTN4) wherein a T at said position represents the minor allele and a C represents the major allele.
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rs7597198 at position -21566 in SEQ ID NO. 1 (RTN4) wherein a G at said position represents the minor allele and an A represents the major allele.
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rs2075375 at position +564 in SEQ ID NO. 2 (OTXl) wherein a G at said position represents the minor allele and an A represents the major allele.
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rs2057482 at position +51325 in SEQ ID NO. 3 (HIFlA) wherein an A at said position represents the minor allele and a G represents the major allele.
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rs2301113 at position +44025 in SEQ ID NO. 3 (HIFlA) wherein a C at said position represents the minor allele and an A represents the major allele.
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rsl2533005 at position -10512 in SEQ ID NO. 4 (FOXP2) wherein a C at said position represents the minor allele and a G represents the major allele.
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rs4727799 at position +44001 in SEQ ID NO. 4 (FOXP2) wherein a G at said position represents the minor allele and an A represents the major allele.
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rs7121949 at position -61667 in SEQ ID NO. 5 (DCDCl) wherein a T at said position represents the minor allele and a G represents the major allele.
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rs 12960267 at position +4200 in SEQ ID NO. 6
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rsl2324434 at position -76092 in SEQ ID NO. 7 (DYXlCl) wherein a G at said position represents the minor allele and an A represents the major allele.
  • the present invention is furthermore concerned with nucleic acid molecules specifically detecting the SNP rs4255730 at position -2746 in SEQ ID NO. 7 (DYXlCl) wherein an A at said position represents the minor allele and a G represents the major allele.
  • Said nucleic acid molecules may be used as probes (and thus may be referred to as "probe nucleotides”) in a DNA-microarray as described below.
  • the methods which may be used in order to analyse DNA may be selected from the group of methods comprising DNA-sequencing, DNA-microarray, real-time PCR or mass spectrometry.
  • any other method known to the person skilled in the art may be used in order to detect the genotype of an individual.
  • DNA sequencing is a routine method performed in order to detect the sequence of a certain DNA region. It uses a primer designed as flanking the region to be analysed together with labelled nucleotides in a PCR-like setup. By analysing the labels at the corresponding positions, it is possible to determine the sequence of DNA starting from the regions to which the primer is hybridising. Furthermore, it is possible to determine the genotype of an allele by sequencing as a peak corresponding to two different bases may be detected.
  • DNA-microarray techniques are also well known to the person skilled in the art. Said techniques are based on hybridisation events between the test-DNA and so- called “probes" immobilised on defined spots of a Microarray in a chamber. Today, such microarrays are routinely used to determine DNA-sequences even down to the level of a single base and thus for the detection of SNPs. This is possible by selecting the probes accordingly and using specific hybridisation conditions. In said techniques, the DNA may be labelled for detecting purposes. Routinely, probes covering the different sequences at the position of an SNP may be used in combination with corresponding controls; thus, also the genotype of the corresponding SNP may be analysed.
  • the term "chamber" of the array defines a closed room wherein the probes are arranged such that their capture oligonucleotides parts (apart from the anchoring parts) are presented into the defined room such that they are able to contact other molecules present in said room.
  • said room or chamber may be open for a certain step during the experimental procedure such as the loading of a liquid sample into said room.
  • the chamber may be closed to account for a closed reaction system with defined reaction parameters such as the concentrations of certain molecules within said chamber.
  • Real-time PCR methods may also be used in order to analyses DNA-regions.
  • real-time PCR is based on the incorporation of double strand specific dyes into DNA while said DNA is amplified. Said dyes are detected only in case they are incorporated. Thus, the more DNA amplified, the higher the detection signal of the corresponding dye.
  • primers accordingly and/or by adding suited probe-nucleotides hybridising to a specific DNA-sequence only (and thus able to discriminate between SNPs) and using specific hybridisation conditions, DNA regions and preferably polymorphisms may be analysed.
  • mass-spectrometry may be used in order to analyse the samples comprising DNA.
  • a sample is mixed with a solution containing a matrix material and a drop of the liquid is placed on the surface of a probe.
  • the matrix solution then e.g. co-crystallises with the biological sample and the probe is inserted into the mass spectrometer and laser energy is then directed to the probe surface where it absorbs and ionises the biological molecules without significantly fragmenting them.
  • the matrix may be first crystallised as a thin film with the biological sample being added later on or vice versa.
  • the probe surface can e.g. be modified such that it forms an active participant in the sample preparation process. In one variant, this probe surface may therefore be derivatised with affinity matrices that provide an ion exchange characteristics to allow for pre-fractionation of the biological samples.
  • SEAC surface-enhanced affinity capture
  • SEND surface-enhanced need disorption
  • SEPAR surface-enhanced photo label attachment and release
  • All of said techniques may be combined with prior purification and/or amplification of the DNA as set out above, but also may be combined with certain restriction digests in order to cut the DNA and be able to analyse smaller fragments of the DNA.
  • All aspects and embodiments of a method according to the present invention may be used in order to diagnose a human being with dyslexia and/or to substantiate a diagnosis of dyslexia in a human being, which has already been tested by conventional testing methods such as reading and/or writing tests.
  • the method of the present invention may be used independent of the age a human being to be tested. This may be during a routine medical check for children in order to detect dyslexia as early as possible.
  • Corresponding aid may then in the following be provided at an early stage of development.
  • a method of diagnosing dyslexia in a human being comprising: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) analysing said DNA in regulatory and/or coding regions of at least one gene implicated in neuronal migration selected from the group of genes comprising RELN, CDK5, DCX, MDCR, SMPDl, TUBB6, DCDCl, VAPA, SMPDL3B, DCDC2B, DCDC2C, LOC728597,
  • Method according to 1 wherein said DNA is analysed in step b) for the presence of established SNPs and/or deletions and/or insertions in regulatory and/or coding regions of said at least one gene. 4. Method according to 3 wherein the established SNPs and/or deletions and/or insertions can be deduced from databases and are established polymorphisms in the human DNA.
  • Method of diagnosing dyslexia in a human being comprising: a) providing a sample of said human being outside the human body wherein said sample comprises DNA; b) determining the genotype of at least one SNP present in said DNA selected from the group of SNPs comprising rsl0210840, rsl2469804, rsl2713284, rsl3387751, rs2255112, rs2580765, rs2580772, rs2588517, rs2588518, rs2588521, rs2860453, rs2919129, rs2972097, rs6545466, rs6760429, rs7340476, rs7562292, rs7597198, rs2075375, rs2057482, rs2301113, rslO15511, rsl0228494, rsl0249234, rsl0262103, rsl02
  • G at rs2860453, homozygous minor (i.e. A) at rs2919129, homozygous minor (i.e. C) at rs2972097, homozygous minor (i.e. C) at rs6545466, homozygous minor (i.e. C) at rs6760429, homozygous minor (i.e. G) at rs7340476, homozygous minor (i.e. C) at rs7562292, homozygous minor (i.e. G) at rs7597198, homozygous major (i.e. A) at rs2075375, homozygous major (i.e.
  • heterozygous i.e. A/G
  • homozygous minor i.e. C
  • homozygous major i.e. G
  • homozygous major i.e. G
  • homozygous major i.e. G
  • homozygous major i.e. G
  • homozygous major i.e. T
  • homozygous major i.e. T
  • G at rsl0280045, homozygous major (i.e. G) at rsl2533005, homozygous major (i.e. G) at rsl989903, homozygous major (i.e. C) at rs2040658, homozygous major (i.e. A) at rs2189010, homozygous major (i.e. G) at rs2189015, homozygous major (i.e. A) at rs2396753, homozygous major (i.e. C) at rs2894699, homozygous major (i.e. A) at rs4727799, homozygous major (i.e.
  • step b) the genotype of at least one SNP selected from the group of SNPs comprising rs2255112, rs2588517, rs7597198, rs2075375, rs2057482, rs2301113, rsl2533005, rs4727799, rs7121949, rsl2960267, rsl2324434 and rs4255730 is determined and in step c) compared to genotypes associated with dyslexia wherein the genotypes homozygous minor (i.e. G) at rs2255112, homozygous major (i.e. C) at rs2588517, homozygous minor (i.e. G) at rs7597198, homozygous major (i.e.
  • dyslexia is assigned to a human being with a probability dependent on the number of consensuses between the genotypes of the SNPs analysed and the SNPs associated with dyslexia, i.e. the higher the number of consensuses between said SNPs the higher the probability of dyslexia in said human being.
  • Method according to any of 1 to 10 wherein the sample comprising DNA is obtained from a tissue sample such as blood, skin or saliva of the human being.
  • DNA-sequencing DNA-microarray, real-time PCR and mass-spectrometry.
  • Use according to 14 and 15 in order to obtain an early diagnosis and let children diagnosed with dyslexia have special medical and/or educational treatment.
  • Microarray device comprising: a) a chamber suitable for containing a liquid sample wherein said liquid sample comprises DNA of the individual to be tested for dyslexia; b) one or more different probe nucleotides which are positioned on different locations on a surface of the chamber wherein the probe nucleotides comprise probe nucleotides specifically detecting at least one of the SNP comprising SNP rs2255112, rs2588517, rs7597198, rs2075375, rs2057482, rs2301113, rsl2533005, rs4727799, rs7121949, rsl2960267, rsl2324434 and rs4255730.
  • Identification of SNPs associated with dyslexia by determining the sequence of the corresponding regions in dyslexic patients as well as in healthy reference individuals and analysing the results gathered for said two groups by statistically determining whether there is an association of the corresponding SNP with dyslexia.
  • the study group consisted of 91 dyslexics of German origin. Controls were 184 healthy blood donors of German origin.
  • Genotyping DNA was extracted from a saliva sample.
  • PCR-primer design was implemented by use of the NCBI dbSNP and Ensembl data bases and the computer programmes muPlex (Rachlin et al. 2005), ePCR (Schuler 1997), HumanBlat (Kent 2002) and Netprimer (PREMIER Biosoft International, Palo Alto, CA). All PCR-primers were obtained from MWG-Biotech (Ebersberg, Germany).
  • SNP-genotyping was done using the GenoSNIP method with slight modifications (Wenzel et al. 2003; Kirsten et al. 2007). PCR reactions were performed under standard conditions. The resulting PCR-product was digested at 37°C for Ih in the same tube by adding 2 ⁇ l of a mix containing exonuclease I (0.2U) and shrimp alkaline phosphatase (0.3U). Enzymes were inactivated at 80 0 C for 20min.
  • SBE single base extension reactions
  • Reactions consisted of l ⁇ l buffer C 10x, l ⁇ l MgCl 2 10OmM, 0.2 TermiPol (all from Solis Biodyne, Tartu, Estonia), 0.9 ⁇ l ddNTP 4xl0mM (Carl Roth GmbH), 12 ⁇ l digested PCR-product, completed to 18 ⁇ l with primer and aqua bidest.
  • SBE products were detected using MALDI-TOF mass spectrometry (Bruker Daltonics, Leipzig, Germany) according to standard protocols. Genotype calling was done using GenoTools (Pusch et al. 2001) and in-house software.
  • SNP rs2255112 is established at position -76636 of RTN4 with a G at said position being the minor allele and a T at said position being the major allele. 90 dyslexic individuals and 181 healthy reference individuals were tested.

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Abstract

La présente invention concerne un procédé de diagnostic de la dyslexie basé sur une analyse des gènes impliqués dans la migration neuronale dans le matériel génétique d’un individu.
PCT/EP2009/058995 2008-07-14 2009-07-14 Procédé de diagnostic de la dyslexie WO2010007063A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3103882A1 (fr) * 2015-06-09 2016-12-14 Universität Leipzig Procédé de diagnostic génétique d'un risque de dyslexie
CN105603111A (zh) * 2016-03-29 2016-05-25 博奥颐和健康科学技术（北京）有限公司 Cntn4基因snp位点的应用及其检测引物与试剂盒

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