Ekanem N Ekure1, Adebowale Adeyemo2, Hanhan Liu3, Ogochukwu Sokunbi1, Nnenna Kalu1, Ariel F Martinez4, Babajide Owosela4, Cedrik Tekendo-Ngongang4, Yonit A Addissie4, Akinsanya Olusegun-Joseph5, Desmond Ikebudu6, Seth I Berger7, Maximilian Muenke4, Zhe Han3, Paul Kruszka4. 1. Department of Pediatrics (E.N.E., O.S., N.K.), College of Medicine, University of Lagos/Lagos University Teaching Hospital, Nigeria. 2. National Human Genome Research Institute (A.A.). 3. Center for Precision Disease Modeling, University of Maryland School of Medicine, Baltimore (H.L., Z.H.). 4. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda (A.F.M., B.O., C.T.-N., Y.A.A., M.M., P.K.). 5. Department of Medicine (A.O.-J.), College of Medicine, University of Lagos/Lagos University Teaching Hospital, Nigeria. 6. Central Research Laboratory, College of Medicine, University of Lagos, Idi-Araba, Nigeria (D.I.). 7. Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC (S.I.B.).
Abstract
BACKGROUND: Congenital heart disease (CHD) is the most common birth defect and affects roughly 1% of the global population. There have been many large CHD sequencing projects in developing countries but none in sub-Saharan Africa. In this exome sequencing study, we recruited families from Lagos, Nigeria, affected by structural heart disease. METHODS: Ninety-eight participants with CHD and an average age of 3.6 years were recruited from Lagos, Nigeria. Exome sequencing was performed on probands and parents when available. For genes of high interest, we conducted functional studies in Drosophila using a cardiac-specific RNA interference-based gene silencing system. RESULTS: The 3 most common CHDs were tetralogy of Fallot (20%), isolated ventricular septal defect (14%), and transposition of the great arteries (8%). Ten percent of the cohort had pathogenic or likely pathogenic variants in genes known to cause CHD. In 64 complete trios, we found 34 de novo variants that were not present in the African population in the Genome Aggregation Database (v3). Nineteen loss of function variants were identified using the genome-wide distribution of selection effects for heterozygous protein-truncating variants (shet). Nine genes caused a significant mortality when silenced in the Drosophila heart, including 4 novel disease genes not previously associated with CHD (UBB, EIF4G3, SREBF1, and METTL23). CONCLUSIONS: This study identifies novel candidate genes and variants for CHD and facilitates comparisons with previous CHD sequencing studies in predominantly European cohorts. The study represents an important first step in genomic studies of CHD in understudied populations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01952171.
BACKGROUND: Congenital heart disease (CHD) is the most common birth defect and affects roughly 1% of the global population. There have been many large CHD sequencing projects in developing countries but none in sub-Saharan Africa. In this exome sequencing study, we recruited families from Lagos, Nigeria, affected by structural heart disease. METHODS: Ninety-eight participants with CHD and an average age of 3.6 years were recruited from Lagos, Nigeria. Exome sequencing was performed on probands and parents when available. For genes of high interest, we conducted functional studies in Drosophila using a cardiac-specific RNA interference-based gene silencing system. RESULTS: The 3 most common CHDs were tetralogy of Fallot (20%), isolated ventricular septal defect (14%), and transposition of the great arteries (8%). Ten percent of the cohort had pathogenic or likely pathogenic variants in genes known to cause CHD. In 64 complete trios, we found 34 de novo variants that were not present in the African population in the Genome Aggregation Database (v3). Nineteen loss of function variants were identified using the genome-wide distribution of selection effects for heterozygous protein-truncating variants (shet). Nine genes caused a significant mortality when silenced in the Drosophila heart, including 4 novel disease genes not previously associated with CHD (UBB, EIF4G3, SREBF1, and METTL23). CONCLUSIONS: This study identifies novel candidate genes and variants for CHD and facilitates comparisons with previous CHD sequencing studies in predominantly European cohorts. The study represents an important first step in genomic studies of CHD in understudied populations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01952171.
Entities:
Keywords:
Drosophila; Nigeria; Tetralogy of Fallot; exome; heart disease
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