PVRL1 variants contribute to non-syndromic cleft lip and palate in multiple populations.

Poliovirus Receptor Like-1 (PVRL1) is a member of the immunoglobulin super family that acts in the initiation and maintenance of epithelial adherens junctions and is mutated in the cleft lip and palate/ectodermal dysplasia 1 syndrome (CLPED1, OMIM #225000). In addition, a common non-sense mutation in PVRL1 was discovered more often among non-syndromic sporadic clefting cases in Northern Venezuela in a previous case-control study. The present work sought to ascertain the role of PVRL1 in the sporadic forms of orofacial clefting in multiple populations. Multiple rare and common variants from all three splice isoforms were initially ascertained by sequencing 92 Iowan and 86 Filipino cases and CEPH controls. Using a family-based analysis to examine these variants, the common glycine allele of the G361V coding variant was significantly overtransmitted among all orofacial clefting phenotypes (P = 0.005). This represented G361V genotyping from over 800 Iowan, Danish, and Filipino families. Among four rare amino acid changes found within the V1 and C1 domains, S112T and T131A were found adjacent to critical amino acid positions within the V1 variable domain, regions previously shown to mediate cell-to-cell and cell-to-virus adhesion. The T131A variant was not found in over 1,300 non-affected control samples although the alanine is found in other species. The serine of the S112T variant position is conserved across all known PVRL1 sequences. Together these data suggest that both rare and common mutations within PVRL1 make a minor contribution to disrupting the initiation and regulation of cell-to-cell adhesion and downstream morphogenesis of the embryonic face.

Candidate genes for oral-facial clefts in Guatemalan families.

Nonsyndromic cleft lip +/- cleft palate (CL/P) is a complex trait of unknown etiology. Most genetic studies of CL/P 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 CL/P families. High-resolution ultrasound images of the orbicularis oris (OO) muscle were obtained. CL/P was present in 28 family members; an additional 10 had subcutaneous OO muscle defects. Family-based association studies were performed for both narrow (CL/P only) and broad (CL/P plus OO 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.