JP2011147451A - 染色体異常の出生前診断のための方法 - Google Patents
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Abstract
【解決手段】染色体異常を含まない正常対照と比較した、父系対立遺伝子50%および母系対立遺伝子50%とは異なる対立遺伝子頻度における相違を検出する、胎児の染色体異常の検出方法。
【選択図】なし
Description
本発明は、染色体異常の非侵襲的出生前診断のための方法に関する。本発明の方法は、染色体DNAの欠失および重複を検出するために用いることができる。好ましい態様において、本方法は、染色体異数性および関連する障害(例えばダウン症候群およびターナー症候群)を診断するために用いられる。本発明はさらに、胎児の染色体異常の検出のために使うことができるメチル多型プローブを同定する方法を提供する。
本出願は、米国特許法第119条(e)項の下で、2003年10月8日に出願された米国特許仮出願第60/509,775号の恩典を主張するが、その内容は、全体にわたって本明細書において参照として組み入れられる。
染色体異常は、精神遅滞を含む、かなりの数の先天性欠損の原因となる。異常は、染色体DNA重複および欠失の形で、ならびに、(染色体全体の異常な存在または不在である)染色体異数性の形で現れうる。正常な二倍数を下回るまたは上回る染色体を生物が有する状態は、多数の異常特性を生じ、かつ、多くの症候群の原因となる。ダウン症候群すなわち21トリソミーは、染色体異数性の最も一般的な例であり、これは余分な第21染色体を含む。その他の一般的な染色体異数性とは、13トリソミー、18トリソミー、ターナー(Turner)症候群、およびクラインフェルター(Klinefelter)症候群である。
本発明は、胎児の染色体異常の検出のための方法を提供する。
本発明は、母系血漿試料中に存在する胎児DNAを濃縮する手段として、胎児DNAと母系DNAの相違を利用する。
本発明の方法により母系血漿DNAを用いて染色体異常の存在を診断するために、母系DNAを選択的に開裂する酵素による血漿DNAの消化によって、例えばDNAのメチル化状態に感受性の酵素を用いることによって、まず、胎児DNAに関して血漿DNAを濃縮することができる。差次的にメチル化された胎児DNA領域に隣接または内在する本明細書に記載のメチル多型マーカーなどの多型マーカーを用いて、父系または母系の対立遺伝子いずれかの対立遺伝子頻度を決定することができる。対立遺伝子頻度は、対照DNA試料(例えば染色体異常を有さない個人から得られるゲノムDNA)中に存在する対立遺伝子頻度と比較される。好ましくは、対照DNAは、健常な胎児を妊娠した女性の血漿から単離される。
Claims (21)
- 以下の段階を含む、所定のDNA領域における染色体異常の出生前診断のための方法であって、染色体異常を含まない正常対照と比較した、父系対立遺伝子50%および母系対立遺伝子50%とは異なる対立遺伝子頻度における相違が染色体異常を表す、方法:
a)妊婦から血漿試料を得る段階;
b)選択的かつ実質的に完全に母系DNAを消化する酵素で血漿試料由来のDNAを消化して、胎児DNA領域が濃縮されたDNA試料を得る段階;ならびに
c)段階b)の試料中の胎児DNA領域に隣接または内在する多型マーカーを使用して、父系または母系の対立遺伝子頻度を決定する段階。 - DNAが消化される前に血漿試料から単離される、請求項1記載の方法。
- 段階c)の父系または母系の対立遺伝子頻度の比較が、重複または欠失が診断の標的とならない染色体内に位置する少なくとも1つの内部対照に対して行われ、かつ、母系および父系の対立遺伝子の双方が等量で存在し、かつ、内部対照からの比率の偏差が染色体異常の存在を示す、請求項1記載の方法。
- 段階a)の後で段階c)の前に実行されるDNA増幅段階を更に含む、請求項1記載の方法。
- 段階b)の酵素がメチル感受性の酵素である、請求項1記載の方法。
- メチル感受性の酵素が、メチル化されていないDNA認識部位のみで消化し、かつ、母系または父系の対立遺伝子頻度が、メチル化された胎児DNA領域に隣接または内在する多型マーカーを用いて決定される、請求項5記載の方法。
- メチル感受性の酵素が、メチル化されたDNA認識部位のみで消化し、かつ、母系または父系の対立遺伝子頻度が、メチル化されていない胎児DNA領域に隣接または内在する多型マーカーを用いて決定される、請求項3記載の方法。
- 以下の段階を含む、染色体異常の出生前診断のための方法であって、母系50%および父系50%とは異なる対立遺伝子頻度における相違が染色体異常を表す、方法:
a)妊婦から血漿試料を得る段階;
b)血漿試料中に存在する核酸を、メチル化されていないDNAのみを消化するメチル感受性の酵素で消化する段階;
c)任意で、段階b)由来の未消化核酸を単離する段階;
d)初期のヘミメチル化核酸をメチル化するために、核酸メチラーゼを用いながら、段階b)またはc)から未消化核酸を増幅する段階;
e)増幅された段階d)の核酸を、メチル化されていない核酸のみを消化するメチル感受性の酵素で消化する段階;ならびに
f)メチル化されていない胎児核酸領域に隣接または内在する多型マーカーを用いて父系または母系の対立遺伝子頻度を決定する段階。 - 段階f)の父系または母系の対立遺伝子頻度の比較が、対照核酸試料に対して実行され、対照試料における比率と異なる相違が染色体異常を表す、請求項8記載の方法。
- 核酸がDNAである、請求項8記載の方法。
- 核酸が消化される前に血漿試料から単離される、請求項8記載の方法。
- 染色体異常がDNA重複である、請求項1または8記載の方法。
- 染色体異常がDNA欠失である、請求項1または8記載の方法。
- 染色体異常が異数性である、請求項1または8記載の方法。
- 異数性が、21トリソミー、18トリソミー、および13トリソミーからなる群より選択される、請求項14記載の方法。
- 以下の段階を含む、胎児の染色体異常の診断法であって、父系対立遺伝子50%および母系対立遺伝子50%とは異なる対立遺伝子頻度における相違が染色体異常を表す、方法:
a)妊婦から血漿試料を得る段階;
b)少なくとも一つの胎児核酸領域について試料を濃縮するために、選択的に血漿試料を処置する段階;
c)段階b)の試料中の少なくとも1つの胎児核酸領域に隣接または内在する少なくとも1つの多型マーカーを使用して、父系または母系の対立遺伝子頻度を決定する段階;ならびに
d)段階c)の父系または母系の対立遺伝子頻度を対照DNA試料と比較する段階。 - 以下の段階を含む、胎児の染色体異常の診断法であって、対照と比較して父系対立遺伝子50%および母系対立遺伝子50%とは異なる対立遺伝子頻度における相違が染色体異常を表す、方法:
a)妊婦から血漿試料を得る段階;
b)少なくとも一つの胎児核酸領域について試料を濃縮するために、選択的に血漿試料を処置する段階;
c)段階b)の試料中の少なくとも1つの胎児核酸領域に隣接または内在する少なくとも1つの多型マーカーを使用して、父系または母系の対立遺伝子頻度を決定する段階;ならびに
d)段階c)の父系または母系の対立遺伝子頻度を、母系および父系の対立遺伝子が所定の量で存在する対照DNA試料と比較する段階。 - 以下を含む、染色体異常の出生前診断のためのキット:
メチル化感受性の酵素;
母系血漿中に存在する胎児DNAおよび母系DNA中の差次的にメチル化された領域内に少なくとも一つの多型遺伝子座を含む部位に隣接する領域をアニーリングでき、かつしたがって増幅できる、少なくとも一対の核酸増幅プライマー;
少なくとも一つの多型遺伝子座における対立遺伝子の検出を可能にする少なくとも一つのプライマーまたはプローブ;ならびに
妊婦から血漿試料を得る段階、血漿試料中に存在する核酸をメチル化感受性の酵素で選択的に消化して、試料中の胎児核酸を濃縮する段階、増幅プライマーを用いて核酸増幅を実行し、胎児核酸が濃縮された試料中に存在する対立遺伝子を検出する段階、および遺伝子座における2つの異なる対立遺伝子の比率が対立遺伝子が等量で存在する対照から離れている場合には胎児が染色体異常に冒されているように結果を解釈する段階を実行するためにユーザに指示する取扱説明書。 - 対照核酸パネルをさらに含むキットであって、対照が、既知の染色体異常を有する胎児を妊娠した女性、および染色体異常のない胎児を妊娠した女性から単離された核酸を含む、請求項18記載のキット。
- 少なくとも一対の増幅プライマーおよび検出プライマーまたはプローブの内部対照をさらに含むキットであって、プライマーおよび/またはプローブが、内部対照を提供するために、母系血漿中に存在する胎児DNAおよび母系DNAにおいて差次的にメチル化されるが重複または欠失がまれである染色体中に生じる核酸領域から選択される、請求項19記載のキット。
- 出生前診断が第13染色体、第18染色体、または第21染色体の重複に関し、かつ、内部対照が第13染色体、第18染色体、または第21染色体以外の任意の常染色体に位置する、請求項19記載のキット。
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WO2005035725A2 (en) | 2005-04-21 |
US20110244451A1 (en) | 2011-10-06 |
CA2541706C (en) | 2014-02-18 |
JP2007508017A (ja) | 2007-04-05 |
EP1689884A2 (en) | 2006-08-16 |
US20070059707A1 (en) | 2007-03-15 |
US20130203051A1 (en) | 2013-08-08 |
CN101985619A (zh) | 2011-03-16 |
CN1930303A (zh) | 2007-03-14 |
US20090325232A1 (en) | 2009-12-31 |
CN101985619B (zh) | 2014-08-20 |
CN1930303B (zh) | 2013-11-20 |
US7655399B2 (en) | 2010-02-02 |
EP2395111B1 (en) | 2015-05-13 |
CA2541706A1 (en) | 2005-04-21 |
EP2395111A1 (en) | 2011-12-14 |
WO2005035725A3 (en) | 2006-06-29 |
EP1689884A4 (en) | 2007-04-04 |
US7785798B2 (en) | 2010-08-31 |
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