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, the National Birth Defects Prevention Study

doi:10.1002/bdr2.2472

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

Birth Defects Res. 2025 May;117(5):e2472. doi: 10.1002/bdr2.2472.

Authors

Tonia C Carter¹, Denise M Kay², Faith Pangilinan³, Lynn M Almli⁴, Mary M Jenkins⁴, Elizabeth E Blue^{5

6}, Pagna Sok⁷, Janson J White⁸, Christopher M Cunniff⁹, A J Agopian¹⁰, Michael J Bamshad^{6

8

11}, Lorenzo D Botto¹², Lawrence C Brody³, Muge Gucsavas-Calikoglu¹³, Jessica X Chong^{6

8}, Horacio Gomez-Acevedo¹⁴, Philip J Lupo⁷, Cynthia A Moore^{4

15}, Wendy N Nembhard¹⁶, Richard S Olney¹⁷, Andrew F Olshan¹⁸, Mohammed S Orloff¹⁶, Jennita Reefhuis⁴, Paul A Romitti¹⁷, Gary M Shaw¹⁹, Martha M Werler²⁰, Mahsa M Yazdy²¹, Marilyn L Browne^{22

23}, Meredith M Howley^{22

23}; University of Washington Center for Mendelian Genomics, NISC Comparative Sequencing Program, the National Birth Defects Prevention Study

Affiliations

¹ Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, Wisconsin, USA.
² Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
³ Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴ National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
⁵ Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
⁶ Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA.
⁷ Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA.
⁸ Department of Pediatrics, University of Washington, Seattle, Washington, USA.
⁹ Department of Pediatrics, Weill Cornell Medical Center, New York, New York, USA.
¹⁰ Department of Epidemiology, Human Genetics Center, University of Texas School of Public Health, Houston, Texas, USA.
¹¹ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
¹² Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
¹³ Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
¹⁴ Department of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
¹⁵ Goldbelt Professional Services LLC, Chesapeake, Virginia, USA.
¹⁶ Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
¹⁷ Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, USA.
¹⁸ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
¹⁹ Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
²⁰ Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.
²¹ Massachusetts Department of Public Health, Boston, Massachusetts, USA.
²² Birth Defects Registry, New York State Department of Health, Albany, New York, USA.
²³ Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, New York, USA.

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.

Keywords: NBDPS; birth defects; congenital limb malformation; ectrodactyly; exome sequencing; split foot; split hand.

MeSH terms

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

Supplementary concepts

Split hand foot deformity

Abstract

MeSH terms

Supplementary concepts

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