Preprint Epublish 1 citation
PubMed: 36798250 DOI: 10.1101/2023.02.01.23285340
Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?
medRxiv
Authors: Kimberly K Diaz Perez, Sydney Chung, S Taylor Head, Michael P Epstein, Jacqueline T Hecht, George L Wehby, Seth M Weinberg, Jeffrey C Murray, Mary L Marazita, Elizabeth J Leslie
Affiliations
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
- Department of Pediatrics, McGovern Medical, School and School of Dentistry, UT Health at Houston, Houston, TX 77030, USA.
- Department of Health Management and Policy, University of Iowa, Iowa City, IA, 52242, USA.
- Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA, 15213, USA.
- Department of Pediatrics, University of Iowa, Iowa City, IA, 52242, USA.
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 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 , and 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.
MeSH
Congenital Abnormalities, Inheritance Patterns, Phenotype, Exome