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

Details

• Alternative Title:
  Birth Defects Research, 2025, v. 117, no. 5: Exome Sequencing to Identify Novel Susceptibility Genes For Nonsyndromic Split-Hand/Ft Malformation: a Report From the National Birth Defects Prevention Study.
• Journal Article:
  Birth Defects Research
• Personal Author:
  Carter, Tonia C. ; Kay, Denise M. ; Pangilinan, Faith ; Almli, Lynn M. ; Jenkins, Mary M. ; Blue, Elizabeth E. ; Sok, Pagna ; White, Janson J. ; Cunniff, Christopher M. ; Agopian, A. J. ; Bamshad, Michael J. ; Botto, Lorenzo D. ; Brody, Lawrence C. ; Gucsavas-Calikoglu, Muge ; Chong, Jessica X. ; Gomez-Acevedo, Horacio ; Lupo, Philip J. ; Moore, Cynthia A. ; Nembhard, Wendy N. ; Olney, Richard S. ; Olshan, Andrew F. ; Orloff, Mohammed S. ; Reefhuis, Jennita ; Romitti, Paul A. ; Shaw, Gary M. ; Werler, Martha M. ; Yazdy, Mahsa M. ; Browne, Marilyn L. ; Howley, Meredith M.
• Corporate Authors:
  University of Washington Center for Mendelian Genomics, NISC Comparative Sequencing Program, the National Birth Defects Prevention Study
• Description:
  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.
• Content Notes:
  Author manuscript
• Subjects:
  • Humans
  • Exome Sequencing
  • Female
  • Male
  • Genetic Predisposition to Disease
  • Case-Control Studies
  • Limb Deformities, Congenital
  • DNA Copy Number Variations
  • Exome
• Keywords:
  • birth defects
  • congenital limb malformation
  • ectrodactyly
  • exome sequencing
  • NBDPS
  • split foot
  • split hand
• Source:
  Birth Defects Research, 2025, v. 117, no. 5
• DOI:
  https://doi.org/10.1002/bdr2.2472
• ISSN:
  2472-1727
• Pubmed ID:
  40304391
• Pubmed Central ID:
  PMC12818101
• Document Type:
  Text
• Funding:
  HL/NHLBI NIH HHSUnited States/ ; U01DD001304/ACL/ACL HHSUnited States/ ; U01 DD001304/DD/NCBDD CDC HHSUnited States/ ; Marshfield Clinic Research Foundation/ ; CC999999/ImCDC/Intramural CDC HHSUnited States/ ; U24 HG008956/HG/NHGRI NIH HHSUnited States/ ; U01DD001309/ACL/ACL HHSUnited States/ ; CC/CDC HHSUnited States/ ; U01 DD001309/DD/NCBDD CDC HHSUnited States/ ; UM1 HG006493/HG/NHGRI NIH HHSUnited States/
• Genre:
  Journal Article
• Pages in Document:
  e2472 (25 pdf pages)
• Volume:
  117
• Issue:
  5
• Download URL:
  https://stacks.cdc.gov/view/cdc/261449/cdc_261449_DS1.pdf
• File Type:
  [PDF - 546.10 KB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:d87a0937a481622e514c3b73b5b1b582b476e8476ed6c22c110d2d5051b34accd92ba09a62c91d9c5b2561a1547fcf5249b5260df1955d4b2a568e7d2140f637