Exome Sequencing to Identify Novel Susceptibility Genes for Nonsyndromic Split-Hand/Ft Malformation: A Report From the National Birth Defects Prevention Study

Tonia C Carter; Denise M Kay; Faith Pangilinan; Lynn M Almli; Mary M Jenkins; Elizabeth E Blue; Pagna Sok; Janson J White; Christopher M Cunniff; A J Agopian; Michael J Bamshad; Lorenzo D Botto; Lawrence C Brody; Muge Gucsavas-Calikoglu; Jessica X Chong; Horacio Gomez-Acevedo; Philip J Lupo; Cynthia A Moore; Wendy N Nembhard; Richard S Olney; Andrew F Olshan; Mohammed S Orloff; Jennita Reefhuis; Paul A Romitti; Gary M Shaw; Martha M Werler; Mahsa M Yazdy; Marilyn L Browne; Meredith M Howley; University of Washington Center for Mendelian Genomics; NISC Comparative Sequencing Program; National Birth Defects Prevention Study

doi:10.1002/bdr2.2472

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Exome Sequencing to Identify Novel Susceptibility Genes for Nonsyndromic Split-Hand/Ft Malformation: A Report From the National Birth Defects Prevention Study

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Exome Sequencing to Identify Novel Susceptibility Genes for Nonsyndromic Split-Hand/Ft Malformation: A Report From the National Birth Defects Prevention Study

Tonia C Carter, Denise M Kay, Faith Pangilinan, Lynn M Almli, Mary M Jenkins, Elizabeth E Blue, Pagna Sok, Janson J White, Christopher M Cunniff, A J Agopian, …

Birth defects research, Vol.117(5), e2472

05/2025

DOI: 10.1002/bdr2.2472

PMCID: PMC12818101

PMID: 40304391

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https://pmc.ncbi.nlm.nih.gov/articles/PMC12818101/View

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Abstract

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. 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. 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. 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.

Case-Control Studies

DNA Copy Number Variations - genetics

Exome - genetics

Exome Sequencing - methods

Female

Genetic Predisposition to Disease - genetics

Humans

Limb Deformities, Congenital - genetics

Male

Details

Title: Subtitle: Exome Sequencing to Identify Novel Susceptibility Genes for Nonsyndromic Split-Hand/Ft Malformation: A Report From the National Birth Defects Prevention Study
Creators: Tonia C Carter - Marshfield Clinic
Denise M Kay - Wadsworth Center
Faith Pangilinan - National Human Genome Research Institute
Lynn M Almli - National Center on Birth Defects and Developmental Disabilities
Mary M Jenkins - National Center on Birth Defects and Developmental Disabilities
Elizabeth E Blue - Brotman Baty Institute
Pagna Sok - Baylor College of Medicine
Janson J White - University of Washington
Christopher M Cunniff - Weill Cornell Medicine
A J Agopian - The University of Texas Health Science Center at Houston
Michael J Bamshad - University of Washington
Lorenzo D Botto - University of Utah
Lawrence C Brody - National Human Genome Research Institute
Muge Gucsavas-Calikoglu - University of North Carolina School of Medicine
Jessica X Chong - University of Washington
Horacio Gomez-Acevedo - University of Arkansas for Medical Sciences
Philip J Lupo - Baylor College of Medicine
Cynthia A Moore - Goldbelt Professional Services LLC, Chesapeake, Virginia, USA
Wendy N Nembhard - University of Arkansas for Medical Sciences
Richard S Olney - University of Iowa
Andrew F Olshan - University of North Carolina at Chapel Hill
Mohammed S Orloff - University of Arkansas for Medical Sciences
Jennita Reefhuis - National Center on Birth Defects and Developmental Disabilities
Paul A Romitti - Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, USA
Gary M Shaw - Stanford University School of Medicine
Martha M Werler - Boston University
Mahsa M Yazdy - Massachusetts Department of Public Health
Marilyn L Browne - University at Albany, State University of New York
Meredith M Howley - University at Albany, State University of New York
University of Washington Center for Mendelian Genomics
NISC Comparative Sequencing Program
National Birth Defects Prevention Study
Resource Type: Journal article
Publication Details: Birth defects research, Vol.117(5), e2472
DOI: 10.1002/bdr2.2472
PMID: 40304391
PMCID: PMC12818101
NLM abbreviation: Birth Defects Res
ISSN: 2472-1727
eISSN: 2472-1727
Publisher: Wiley; HOBOKEN
Grant note: NHLBI NIH HHS NHGRI NIH HHS CDC HHS Marshfield Clinic Research Foundation
Language: English
Date published: 05/2025
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9984816008902771

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