Journal article
Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting
Genetics in medicine, Vol.25(10), pp.100918-100918
10/01/2023
DOI: 10.1016/j.gim.2023.100918
PMCID: PMC10592535
PMID: 37330696
Abstract
Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls.
We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria.
9.04% of cases and 1.02% of controls had “likely pathogenic” variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were “variants of uncertain significance”, occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance.
These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs.
Details
- Title: Subtitle
- Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting
- Creators
- Kimberly K. Diaz Perez - Emory University School of MedicineSarah W. Curtis - Emory UniversityAlba Sanchis-Juan - Broad InstituteXuefang Zhao - Broad InstituteTaylor Head - Emory UniversitySamantha Ho - Emory UniversityBridget Carter - Agnes Scott CollegeToby McHenry - University of PittsburghMadison R. Bishop - Emory UniversityLuz C. Valencia-Ramirez - Fundación Clinica Noel, Medellin, ColombiaClaudia Restrepo - Fundación Clinica Noel, Medellin, ColombiaJacqueline T. Hecht - The University of Texas Health Science Center at HoustonLina M. Uribe - University of IowaGeorge Wehby - University of IowaSeth M. Weinberg - University of PittsburghTerri H. Beaty - Johns Hopkins UniversityJeffrey C. Murray - University of IowaEleanor Feingold - University of PittsburghMary L. Marazita - University of PittsburghDavid J. Cutler - Emory UniversityMichael P. Epstein - Emory UniversityHarrison Brand - Massachusetts General HospitalElizabeth J. Leslie - Emory University
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.25(10), pp.100918-100918
- DOI
- 10.1016/j.gim.2023.100918
- PMID
- 37330696
- PMCID
- PMC10592535
- NLM abbreviation
- Genet Med
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 10/01/2023
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985035881502771
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