2871例先天性心脏病先证者中罕见遗传变异和新生变异的作用。
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.
作者信息
Jin Sheng Chih, Homsy Jason, Zaidi Samir, Lu Qiongshi, Morton Sarah, DePalma Steven R, Zeng Xue, Qi Hongjian, Chang Weni, Sierant Michael C, Hung Wei-Chien, Haider Shozeb, Zhang Junhui, Knight James, Bjornson Robert D, Castaldi Christopher, Tikhonoa Irina R, Bilguvar Kaya, Mane Shrikant M, Sanders Stephan J, Mital Seema, Russell Mark W, Gaynor J William, Deanfield John, Giardini Alessandro, Porter George A, Srivastava Deepak, Lo Cecelia W, Shen Yufeng, Watkins W Scott, Yandell Mark, Yost H Joseph, Tristani-Firouzi Martin, Newburger Jane W, Roberts Amy E, Kim Richard, Zhao Hongyu, Kaltman Jonathan R, Goldmuntz Elizabeth, Chung Wendy K, Seidman Jonathan G, Gelb Bruce D, Seidman Christine E, Lifton Richard P, Brueckner Martina
机构信息
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
出版信息
Nat Genet. 2017 Nov;49(11):1593-1601. doi: 10.1038/ng.3970. Epub 2017 Oct 9.
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.
先天性心脏病（CHD）是出生缺陷导致死亡的主要原因。在此，对一组2871名先天性心脏病先证者进行外显子组测序，其中包括2645个亲子三联体，发现1.8%的病例存在罕见的遗传突变，包括GDF1中的一个隐性奠基者突变，约占德系犹太人严重先天性心脏病的5%，MYH6中的隐性基因型约占肖恩综合征的11%，以及显性FLT4突变占法洛四联症的2.3%。新发突变（DNM）占病例的8%，包括约3%的孤立性先天性心脏病患者和约28%患有神经发育和心脏外先天性异常的患者。7个基因超过了全基因组显著性阈值，12个先前未与先天性心脏病相关的基因与疾病相关的概率超过70%。据推断，约440个基因中的新发突变与先天性心脏病有关。还发现先天性心脏病先证者中具有有害新发突变的基因与自闭症之间存在显著重叠。
Zotero 插件