Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

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

doi:10.1101/2023.02.01.23285340

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Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

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Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

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 and Elizabeth J Leslie

medRxiv : the preprint server for health sciences

02/07/2023

DOI: 10.1101/2023.02.01.23285340

PMCID: PMC9934724

PMID: 36798250

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https://doi.org/10.1101/2023.02.01.23285340View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

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.

Details

Title: Subtitle: Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?
Creators: 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
Resource Type: Preprint
Publication Details: medRxiv : the preprint server for health sciences
DOI: 10.1101/2023.02.01.23285340
PMID: 36798250
PMCID: PMC9934724
Language: English
Date posted: 02/07/2023
Academic Unit: Preventive and Community Dentistry; Anatomy and Cell Biology; Health Management and Policy; Stead Family Department of Pediatrics; Epidemiology; Economics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Public Policy Center (Archive); Dental Research
Record Identifier: 9984367716302771

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