Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time.
Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time.
复制标题
DOI：
10.1038/s41436-020-0900-8
复制
发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Verkerk AJMH
中科院分区：
文献类型：
--
作者：
van Rooij J;Arp P;Broer L;Verlouw J;van Rooij F;Kraaij R;Uitterlinden A;Verkerk AJMH
我们通过鹿特丹研究研究了荷兰老年人群中致病分类变异的外显率，对此可以进行深度表型分析。我们筛选了美国医学遗传学和基因组学学院 (ACMG) 建议报告已知致病变异的 59 个可操作基因，并证明确定已知致病变异的构成可能相当具有挑战性。我们将“已知致病性”定义为 ClinVar 和人类基因突变数据库 (HGMD) 分类的致病性。我们对 2628 名个体进行了外显子组测序并鉴定了已知的致病变异。我们调查了携带者的临床记录，并评估了 25 年随访期间的临床事件，以寻找变异致病性的证据。在 59 个 ACMG 基因中检测到的 3815 个变异中，有 17 个变异被认为是已知致病的。对于 14/17 变体，ClinVar 分类随着时间的推移而发生变化。在 24 名已确认的这些变异携带者中，我们仅在三名参与者 (13%) 中观察到至少一项可能由该变异引起的临床事件。我们表明，“已知致病菌”的定义通常不明确，应谨慎对待。此外，标记为已知致病性的变异并不总是对其携带者产生临床影响。应仔细定义真实（个体）预期致病影响的定义和分类。
We studied the penetrance of pathogenically classified variants in an elderly Dutch population from the Rotterdam Study, for which deep phenotyping is available. We screened the 59 actionable genes for which reporting of known pathogenic variants was recommended by the American College of Medical Genetics and Genomics (ACMG), and demonstrate that determining what constitutes a known pathogenic variant can be quite challenging. We defined “known pathogenic” as classified pathogenic by both ClinVar and the Human Gene Mutation Database (HGMD). In 2628 individuals, we performed exome sequencing and identified known pathogenic variants. We investigated the clinical records of carriers and evaluated clinical events during 25 years of follow-up for evidence of variant pathogenicity. Of 3815 variants detected in the 59 ACMG genes, 17 variants were considered known pathogenic. For 14/17 variants the ClinVar classification had changed over time. Of 24 confirmed carriers of these variants, we observed at least one clinical event possibly caused by the variant in only three participants (13%). We show that the definition of “known pathogenic” is often unclear and should be approached carefully. Additionally variants marked as known pathogenic do not always have clinical impact on their carriers. Definition and classification of true (individual) expected pathogenic impact should be defined carefully.
登录
查看更多内容
DOI：
10.1038/gim.2014.196
发表时间：
2015-10
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1038/gim.2013.73
发表时间：
2013-07
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
9.3
作者：
Beck TF;Mullikin JC;NISC Comparative Sequencing Program;Biesecker LG
通讯作者：
Biesecker LG
影响因子：
8.8
作者：
Mighton, Chloe;Charames, George S.;Lerner-Ellis, Jordan
通讯作者：
Lerner-Ellis, Jordan
稀有基因敲除的健康和人口影响与相关父母的成年人。
DOI：
10.1126/science.aac8624
发表时间：
2016-04-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Narasimhan VM;Hunt KA;Mason D;Baker CL;Karczewski KJ;Barnes MR;Barnett AH;Bates C;Bellary S;Bockett NA;Giorda K;Griffiths CJ;Hemingway H;Jia Z;Kelly MA;Khawaja HA;Lek M;McCarthy S;McEachan R;O'Donnell-Luria A;Paigen K;Parisinos CA;Sheridan E;Southgate L;Tee L;Thomas M;Xue Y;Schnall-Levin M;Petkov PM;Tyler-Smith C;Maher ER;Trembath RC;MacArthur DG;Wright J;Durbin R;van Heel DA
通讯作者：
van Heel DA