Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies

Families diagnosed with Meckel-Gruber syndrome were recruited for research studies following informed consent. DNA samples were analyzed by microsatellite genotyping and direct Sanger sequencing.We now report the genetic analyses of 87 individuals from 49 consanguineous and 19 non-consanguineous families in an unselected cohort with reported MKS, or an associated severe ciliopathy in a kindred. Linkage and/or direct sequencing were prioritized for seven MKS genes (MKS1, TMEM216, TMEM67/MKS3, RPGRIP1L, CC2D2A, CEP290 and TMEM237) selected on the basis of reported frequency of mutations or ease of analysis. We have identified biallelic mutations in 39 individuals, of which 13 mutations are novel and previously unreported. We also confirm general genotype-phenotype correlations.TMEM67 was the most frequently mutated gene in this cohort, and we confirm two founder splice-site mutations (c.1546？+？1 G？>？A and c.870-2A？>？G) in families of Pakistani ethnic origin. In these families, we have also identified two separate founder mutations for RPGRIP1L (c. 1945 C？>？T p.R649X) and CC2D2A (c. 3540delA p.R1180SfsX6). Two missense mutations in TMEM67 (c. 755 T？>？C p.M252T, and c. 1392 C？>？T p.R441C) are also probable founder mutations. These findings will contribute to improved genetic diagnosis and carrier testing for affected families, and imply the existence of further genetic heterogeneity in this syndrome.MKS is an autosomal recessive lethal condition characterized by occipital meningoencephalocele, polycystic kidneys, postaxial polydactyly and ductal plate malformation of the liver. Other frequently observed features can include the Dandy-Walker malformation (or other posterior fossa defects), dextrocardia, bowing of long bones, cleft lip and/or palate, situs inversus, low set ears, microphthalmia and iris coloboma. To date, mutations in nine MKS genes are reported as causative (Table 1). The protein products of the nine MKS genes are all involved in the structure or functio