Resolving clinical diagnoses for syndromic cleft lip and/or palate phenotypes using whole-exome sequencing

Individuals from three families ascertained in Bogota, Colombia, showing syndromic phenotypes, including cleft lip and/or palate, were exome sequenced. In each case sequencing revealed underlying causal variation confirming or establishing diagnoses. The findings include very rare and novel variants providing insights into genotype and phenotype relationships. These include the molecular diagnosis of an individual with Nager syndrome and a family exhibiting an atypical Incontinentia Pigmenti phenotype with a missense mutation in IKBKG. IKBKG mutations are typically associated with pre-term male death but this variant is associated with survival for 8–15 days. The third family exhibits unusual phenotypic features and the proband received a provisional diagnosis of Pierre Robin Sequence (PRS). Affected individuals share a novel deleterious mutation in IRF6. Mutations in IRF6 cause Van der Woude and Popliteal pterygium syndrome and contribute to nonsyndromic cleft lip phenotypes but have not previously been associated with a PRS phenotype. Exome sequencing followed by in silico screening to identify candidate causal variant(s), and functional assay in some cases, offers a powerful route to establishing molecular diagnoses. This approach is invaluable for conditions showing phenotypic and/or genetic heterogeneity including cleft lip and/or palate phenotypes where many underlying causal genes have not been identified.