Candidate genes for oral-facial clefts in Guatemalan families

Nonsyndromic cleft lip cleft palate (CUP) is a complex trait of unknown etiology. Most genetic studies of CUP define affection status in a way that ignores subtle subclinical manifestations, resulting in a potential loss of statistical power. This study investigated 10 candidate genes in 155 individuals from 25 Guatemalan CUP families. High-resolution ultrasound images of the orbicularis oris (00) muscle were obtained. CUP was present in 28 family members; an additional 10 had subcutaneous 00 muscle defects. Family-based association studies were performed for both narrow (CUP only) and broad (CUP plus 00 muscle defects) definitions of affection status. PVRL1 was significantly associated under both definitions (P = 0.04, narrow; P = 0.02, broad). Association with JAG2 improved from P = 0.09 under the narrow definition to P = 0.04 under the broad definition. Broadening the oral-facial cleft phenotype to include subclinical variants may improve power in genetic studies.