Molecular diagnostics of Meckel–Gruber syndrome highlights phenotypic differences between MKS1 and MKS3

Abstract

Meckel-Gruber syndrome (MKS) is a recessively inherited, lethal disorder characterized by renal cystic dysplasia, occipital encephalocele, polydactyly and biliary dysgenesis. MKS is genetically heterogeneous with three loci mapped and two identified; MKS1 (17q23) and MKS3 (8q22.1). MKS1 is part of the Finnish disease heritage, while MKS3 has been described exclusively in consanguineous Asian families. Here we aimed to establish molecular diagnostics for MKS, determine the importance of MKS1 and MKS3 in non-consanguineous populations, and study genotype/phenotype correlations. The coding regions of MKS1 and MKS3 were screened for mutations by direct sequencing in 17 families clinically diagnosed with MKS in the US or The Netherlands. The clinical phenotype was compared to genic and allelic effects. Both mutations were identified in ten families; five MKS1 and five MKS3. All but two were compound heterozygotes, consistent with their non-consanguineous nature. The MKS1-Fin(major) mutation accounted for 7/10 MKS1 mutations; two novel changes were additionally detected. Seven novel mutations were found in MKS3, including three missense changes. We concluded that MKS1 and MKS3 account for the majority of MKS in non-consanguineous populations of European origin. Polydactyly is usually found in MKS1 but rare in MKS3. Cases with no, or milder, CNS phenotypes were only found in MKS3; hypomorphic missense mutations may be associated with less severe CNS outcomes. This study is consistent with further genetic heterogeneity of MKS, but underlines the value of molecular diagnostics of the known genes to aid family planning decisions.

Normal Ciliogenesis Requires Synergy between the Cystic Kidney Disease Genes MKS-3 and NPHP-4

“…This observation suggests that mks-1 and mks-3 contributions to the mks-1/mksr-1/mksr-2/ mks-3 pathway are similar but not identical, which could be reflective of how MKS-3 patients have some clear phenotypic differences from MKS-1 patients. 36 The mechanisms by which these genes and pathways influence cilia morphogenesis are not entirely clear. Ultrastructural data indicate that the nphp-1/nphp-4 pathway may be responsible for maintaining the integrity of the ciliary axoneme on the basis of observations of axonemal microtubule defects in these mutants.…”

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

“…4 Subsequently, nine additional genes have been identified, all similarly encoding ciliary proteins (TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9) and B9D2 (MKS10)). [4][5][6][7][8][9][10][11][12][13][14] The finding that defective ciliary biology is the core molecular pathology of MKS made it possible to dissect the pathogenesis of each of its manifestations. For instance, the primary cilium plays a critical role in SHH signaling that controls anteriorposterior and dorsal-ventral patterning of the developing limb buds and neural tube, respectively, thus explaining the polydactyly and neural tube defects that characterize MKS at the molecular level.…”

Meckel Gruber Syndrome diagnosed in two consecutive pregnancies

“…Since most of the diseases with similar clinical presentations (Trisomy 13, Trisomy 18, Joubert Syndrome, Bardet-Biedl syndrome) have an underlying genetic pathology, neonatal autopsy and genetic analysis are crucial for the final diagnosis. 6,13,14 …”