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.

Pathogenic Variants in SHROOM3 Associated with Hemifacial Microsomia

“…Notably, SHROOM3 has also been implicated in facial development, as evidenced by signi cant association between SHROOM3 and HFM 89 , cleft lip with or without cleft palate or cleft palate 1213 , orofacial clefts 14 , neural tube defects 1516 , and Keratoconus 17 . However, no study has yet investigated whether pathogenic variants in SHROOM3 contribute to HFM.…”