Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders

Abstract

The popliteal pterygia syndromes are a distinct subset of the hundreds of Mendelian orofacial clefting syndromes. Popliteal pterygia syndromes have considerable variability in severity and in the associated phenotypic features but are all characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, and genital malformations. Heterozygous mutations in IRF6 cause popliteal pterygium syndrome (PPS) while homozygous mutations in RIPK4 or CHUK (IKKA) cause the more severe Bartsocas-Papas syndrome (BPS) and Cocoon syndrome, respectively. In this study we report mutations in six pedigrees with children affected with PPS or BPS. Using a combination of Sanger and exome sequencing, we report the first case of an autosomal recessive popliteal pterygium syndrome caused by homozygous mutation of IRF6 and the first case of uniparental disomy of chromosome 21 leading to a recessive disorder. We also demonstrate that mutations in RIPK4 can cause features with a range of severity along the PPS-BPS spectrum and that mutations in IKKA can cause a range of features along the BPS-Cocoon spectrum. Our findings have clinical implications for genetic counseling of families with pterygia syndromes and further implicate IRF6, RIPK4, and CHUK (IKKA) in potentially interconnected pathways governing epidermal and craniofacial development.

Identification of paternal uniparental disomy on chromosome 22 and a de novo deletion on chromosome 18 in individuals with orofacial clefts

“…Previous UPD associated with clefts has been reported in other chromosomes and are mainly due to maternal UPDs as a result of advanced maternal age during pregnancy leading to trisomy rescue and error (Romanelli et al., ). A recent study reported an association with maternal UPD (matUPD) on chromosome 21 with Bartsocas Papas Syndrome (Leslie et al., ). In the absence of any other obvious large genetic aberration, it is possible that the affected individual has a recessive form of clefting arising from a heterozygous father and unmasked by the patUPD on chromosome 22.…”

Regional regulation of Filiform tongue papillae development by Ikkα/Irf6

“…Irf6 mutant mice showed identical filiform papillae phenotypes to Ikkα mutants. Interconnection between Ikkα and Irf6 in governing epidermal development has been assumed (Leslie et al, ). Although our findings could not establish a genetic interaction between Ikkα and Irf6 , the possibility of direct interaction between Ikkα and Irf6 (e.g., they function in the same pathway) could not be excluded in filiform papillae development.…”

Toward an orofacial gene regulatory network

“…Like IRF6 , mutations in RIPK4 can lead to PPS. Like RIPK4 , mutations in IKKA can lead to BPS (Leslie et al, ). Therefore, for the 27% of families without a known genetic mutation leading to VWS, 14‐3‐3σ , IKKA , KDF1 , and RIPK4 appear to be good candidate genes.…”