Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?
Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?
ABSTRACT Whole-exome sequencing (WES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for WES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed whole-exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, KLF4, SHROOM3, SMC3, TP63, and TBX3 in seven families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.
Head S. Taylor、Hecht Jacqueline T.、Weinberg Seth M.、Marazita Mary L.、Murray Jeffrey C.、Leslie Elizabeth J.、Chung Sydney、Wehby George L.、Epstein Michael P.、Diaz Perez Kimberly K.
Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory UniversityDepartment of Pediatrics, McGovern Medical, School and School of Dentistry, UT Health at HoustonCenter for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh School of Dental MedicineCenter for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh School of Dental MedicineDepartment of Pediatrics, University of IowaDepartment of Human Genetics, Emory University School of MedicineDepartment of Human Genetics, Emory University School of MedicineDepartment of Health Management and Policy, University of IowaDepartment of Human Genetics, Emory University School of MedicineDepartment of Human Genetics, Emory University School of Medicine
医学研究方法口腔科学遗传学
orofacial cleftsexome sequencingmultiplex familiesvariant segregation
Head S. Taylor,Hecht Jacqueline T.,Weinberg Seth M.,Marazita Mary L.,Murray Jeffrey C.,Leslie Elizabeth J.,Chung Sydney,Wehby George L.,Epstein Michael P.,Diaz Perez Kimberly K..Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?[EB/OL].(2025-03-28)[2025-06-14].https://www.medrxiv.org/content/10.1101/2023.02.01.23285340.点此复制
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