{"doi":"10.1002/bdr2.2472","title":"Exome Sequencing to Identify Novel Susceptibility Genes for Nonsyndromic Split‐Hand/Ft Malformation: A Report From the National Birth Defects Prevention Study","abstract":"BACKGROUND: Split-hand/foot malformation (SHFM) is a rare, genetically heterogeneous, congenital limb defect. Some but not all associated genes are known; therefore, the aim was to identify genes underlying SHFM. METHODS: Buccal cell-derived DNA from 26 children with SHFM and their parents who participated in the National Birth Defects Prevention Study was exome sequenced. Family-based trio analyzes prioritized rare coding variants by inheritance patterns, predicted pathogenicity, and location within putative limb development genes. Copy-number variants in SHFM candidate genomic regions were also examined. Case-control analyzes compared coding variants between case children and 1191 controls (parents of children with non-limb birth defects). Variant validation was by Sanger sequencing or droplet digital polymerase chain reaction. RESULTS: In family-based analyzes, the prioritized and validated variants (each in a single family) included likely damaging variants that were heterozygous and de novo in speckle type BTB/POZ protein (SPOP) and ubiquitin-like modifier activating enzyme 2 (UBA2), X-linked recessive in fibroblast growth factor 13 (FGF13) and RNA binding motif protein 10 (RBM10), and compound heterozygous in interleukin enhancer binding factor 3 (ILF3). Validation assays did not confirm predicted de novo copy-number gains at chromosomes 10q24 and 19p13.11. Case-control analyzes did not identify statistically significant associations. CONCLUSION: Exome analysis nominated new susceptibility genes (FGF13, ILF3, RBM10, SPOP) and detected a variant in a known candidate gene (UBA2). Follow-up investigation is needed to ascertain damaging variants in these genes in additional cases with SHFM and evaluate the impact of the variants on gene expression, protein function, and limb development.","journal":"Birth Defects Research","year":2025,"id":552574,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.5756,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":356395,"name":"Denise M. 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Bamshad","orcid":"0000-0002-9647-0861","position":10,"is_corresponding":false},{"id":308557,"name":"Lorenzo D. Botto","orcid":"0000-0002-5322-7116","position":11,"is_corresponding":false},{"id":232075,"name":"Lawrence C. Brody","orcid":"0000-0001-9435-3592","position":12,"is_corresponding":false},{"id":1153291,"name":"Müge Güçsavaş‐Çalıkoğlu","orcid":null,"position":13,"is_corresponding":false},{"id":991,"name":"Jessica X. Chong","orcid":"0000-0002-1616-2448","position":14,"is_corresponding":false},{"id":378857,"name":"Horacio Gómez-Acevedo","orcid":"0000-0002-1570-1606","position":15,"is_corresponding":false},{"id":247448,"name":"Philip J. Lupo","orcid":"0000-0003-0978-5863","position":16,"is_corresponding":false},{"id":378227,"name":"Cynthia A. Moore","orcid":"0000-0003-4224-2692","position":17,"is_corresponding":false},{"id":268673,"name":"Wendy N. Nembhard","orcid":"0000-0002-8318-4049","position":18,"is_corresponding":false},{"id":1448956,"name":"Richard S. Olney","orcid":null,"position":19,"is_corresponding":false},{"id":261928,"name":"Andrew F. Olshan","orcid":"0000-0001-9115-5128","position":20,"is_corresponding":false},{"id":580266,"name":"Mohammed S. Orloff","orcid":"0000-0002-5920-0627","position":21,"is_corresponding":false},{"id":385369,"name":"Jennita Reefhuis","orcid":"0000-0002-4747-4831","position":22,"is_corresponding":false},{"id":371271,"name":"Paul A. Romitti","orcid":"0000-0001-5393-9984","position":23,"is_corresponding":false},{"id":17736,"name":"Gary M. Shaw","orcid":"0000-0001-7438-4914","position":24,"is_corresponding":false},{"id":379338,"name":"Martha M. Werler","orcid":"0000-0003-3392-6814","position":25,"is_corresponding":false},{"id":275142,"name":"Mahsa M. Yazdy","orcid":"0000-0002-7415-5350","position":26,"is_corresponding":false},{"id":275140,"name":"Marilyn L. Browne","orcid":"0000-0002-1872-2787","position":27,"is_corresponding":false},{"id":644680,"name":"Meredith M. 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