MKS1 – Meckel syndrome type 1

Meckel syndrome type 1 is an autosomal recessive lethal ciliopathy characterized by occipital encephalocele, cystic renal dysplasia and postaxial polydactyly (PMID:17437276, PMID:23351400). Biallelic loss-of-function and splicing mutations in MKS1 (HGNC:7121) disrupt basal body function and are the primary genetic cause of this syndrome.

Genetically, MKS1-related Meckel syndrome manifests exclusively with autosomal recessive inheritance. Compound heterozygous and homozygous variants have been identified in at least 49 probands from over 20 unrelated families, including recurrent Finnish founder splice deletions (c.1408-34_1408-6del) and truncating alleles (PMID:23351400). Notably, the missense variant c.240G>T (p.Trp80Cys) was reported in a Joubert syndrome case with overlapping features (PMID:27377014).

Segregation analyses in consanguineous pedigrees confirm co-segregation of MKS1 variants with disease in at least five multiplex families (PMID:17437276). The variant spectrum includes frameshift (e.g., c.811del (p.His271fs)), splice-site, intronic deletions and missense changes affecting conserved B9 motifs.

Functional studies demonstrate that MKS1 localizes to basal bodies and interacts with meckelin; siRNA knockdown in epithelial cells blocks ciliogenesis and 3D tissue assays impair epithelial branching (PMID:17185389). A knockout mouse recapitulates preaxial polydactyly, neural tube defects and renal cysts, implicating aberrant Wnt signaling and over-proliferation in pathogenesis (PMID:23454480).

Integration of robust genetic and experimental data meets ClinGen criteria for a Definitive gene–disease association. The abundant identification of pathogenic MKS1 variants, segregation in multiple families, and concordant functional models support clinical testing and variant interpretation.

Key take-home: Pathogenic MKS1 mutations cause autosomal recessive Meckel syndrome type 1, and genetic testing of MKS1 informs diagnosis, carrier screening and understanding of ciliopathy mechanisms.

References

• Human mutation • 2007 • Aberrant splicing is a common mutational mechanism in MKS1, a key player in Meckel-Gruber syndrome. PMID:17437276
• Cilia • 2012 • Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies. PMID:23351400
• European journal of medical genetics • 2016 • MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum. PMID:27377014
• Human molecular genetics • 2007 • The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. PMID:17185389
• Developmental biology • 2013 • Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel-Gruber syndrome. PMID:23454480

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