Background: Meckel-Gruber syndrome (MKS) is a genetically heterogeneous severe ciliopathy characterised by early lethality, occipital encephalocele, polydactyly, and polycystic kidney disease.
Purpose: To report genetic analysis results in two families in which all known MKS diseases genes have been excluded.
Methods: In two consanguineous families with classical MKS in which autozygome-guided sequencing of previously reported MKS genes was negative, we performed exome sequencing followed by autozygome filtration.
Results: We identified one novel splicing mutation in TMEM231, which led to complete degradation of the mutant transcript in one family, and a novel missense mutation in the other, both in the homozygous state.
Conclusions: TMEM231 represents a novel MKS locus. The very recent identification of TMEM231 mutations in Joubert syndrome supports the growing appreciation of the overlap in the molecular pathogenesis between these two ciliopathies.