Recessive genetic contribution to congenital heart disease in 5,424 probands
成果类型：
Article
署名作者：
Dong, Weilai; Jin, Sheng Chih; Sierant, Michael C.; Lu, Ziyu; Li, Boyang; Lu, Qiongshi; Morton, Sarah U.; Zhang, Junhui; Lopez-Giraldez, Francesc; Nelson-Williams, Carol; Knight, James R.; Zhao, Hongyu; Cao, Junyue; Mane, Shrikant; Gruber, Peter J.; Lek, Monkol; Goldmuntz, Elizabeth; Deanfield, John; Giardini, Alessandro; Mital, Seema; Russell, Mark; Gaynor, J. William; Cnota, James F.; Wagner, Michael; Srivastava, Deepak; Bernstein, Daniel; Porter Jr, George A.; Newburger, Jane; Roberts, Amy E.; Yandell, Mark; Yost, H. Joseph; Tristani-Firouzi, Martin; Kim, Richard; Seidman, Jonathan; Chung, Wendy K.; Gelb, Bruce D.; Seidman, Christine E.; Lifton, Richard P.; Brueckner, Martina
署名单位：
Yale University; Rockefeller University; Washington University (WUSTL); Washington University (WUSTL); Rockefeller University; Yale University; University of Wisconsin System; University of Wisconsin Madison; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Yale University; Yale University; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of London; University College London; University of London; University College London; Great Ormond Street Hospital for Children NHS Foundation Trust; University of Toronto; Hospital for Sick Children (SickKids); University of Michigan System; University of Michigan; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Cincinnati Children's Hospital Medical Center; Cincinnati Children's Hospital Medical Center; Cincinnati Children's Hospital Medical Center; University of California System; University of California San Francisco; The J David Gladstone Institutes; Stanford University; University of Rochester; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Utah System of Higher Education; University of Utah; Catholic University of America; Utah System of Higher Education; University of Utah; Cedars Sinai Medical Center; Harvard University; Harvard Medical School; Columbia University; Columbia University; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Howard Hughes Medical Institute; Yale University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-11284
DOI：
10.1073/pnas.2419992122
发表日期：
2025-03-03
关键词：
genome-wide association
de-novo mutations
nad deficiency
defects
myosin
variants
population
phenotypes
chaperone
CHILDREN
摘要：
Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%). Among 108 curated human recessive CHD genes, there were 66 RGs, with 54 in 11 genes with >1 RG, 12 genes with 1 RG, and 85 genes with zero. RGs were more prevalent among offspring of consanguineous union (4.7%, 32/675) than among nonconsanguineous probands (0.7%, 34/4749). Founder variants in GDF1 and PLD1 accounted for 74% of the contribution of RGs among 410 Ashkenazi Jewish probands. We identified genome-wide significant enrichment of RGs in C1orf127, encoding a likely secreted protein expressed in embryonic mouse notochord and associated with laterality defects. Single-cell transcriptomes from gastrulation-stage mouse embryos revealed enrichment of RGs in genes highly expressed in the cardiomyocyte lineage, including contractility-related genes MYH6, UNC45B, MYO18B, and MYBPC3 in probands with left-sided CHD, consistent with abnormal contractile function contributing to these malformations. Genes with significant RG burden account for 1.3% of probands, more than half the inferred total. These results reveal the recessive contribution to CHD, and indicate that many genes remain to be discovered, with each likely accounting for a very small fraction of the total.