MKS1 – Meckel Syndrome Type 1

Meckel syndrome type 1 is a lethal autosomal recessive ciliopathy characterized by occipital encephalocele, postaxial polydactyly, multicystic kidney dysplasia, and hepatic ductal plate malformations. The MKS1 protein localizes to the ciliary transition zone basal body where it forms a complex with B9 domain–containing proteins, playing a critical role in ciliogenesis and Hedgehog signal transduction. Bi‐allelic loss‐of‐function variants in MKS1 abrogate cilium formation, leading to the pleiotropic embryonic defects observed in Meckel syndrome type 1.

Clinical Validity

MKS1 association with Meckel syndrome is classified as Definitive based on identification of MKS1 variants in numerous unrelated families, segregation in consanguineous and outbred pedigrees, and concordant functional data demonstrating loss of ciliogenesis. In a multiethnic cohort of 120 Meckel syndrome cases, MKS1 variants accounted for approximately 7% (∼8 probands) with homozygous or compound heterozygous alleles including a recurrent founder intronic deletion c.1408-35_1408-7del29 in three families ([PMID:17397051]). Additional case reports document novel truncating variants segregating in affected sibships and enabling preimplantation genetic testing ([PMID:35360848]).

Genetic Evidence

MKS1‐related Meckel syndrome follows an autosomal recessive inheritance pattern. To date, at least 12 probands with biallelic truncating or splice‐site mutations have been reported, including three with the Finnish/English founder deletion ([PMID:17397051], [PMID:35360848]). Segregation analysis in consanguineous families and PGT-M studies confirmed co-segregation of variants with disease in three affected pregnancies in one pedigree. Reported variant classes include nonsense (e.g., c.350C>A (p.Ser117Ter)), frameshift, canonical splice‐site, and multi‐exon deletions across diverse populations.

Functional Evidence

Experimental studies support a loss‐of‐function mechanism. siRNA knockdown of Mks1 in epithelial cell lines abrogates centriole migration and ciliogenesis, while co-immunoprecipitation shows MKS1–meckelin interaction is essential for epithelial morphogenesis ([PMID:17185389]). Mouse Mks1 knockout embryos recapitulate polydactyly, encephalocele, and renal cystic dysplasia with dysregulated Wnt and Hedgehog signalling pathways ([PMID:23454480]). Zebrafish mks1 crispants display tissue‐specific ciliary defects and phenotypic variability, reinforcing the role of MKS1 at the transition zone ([PMID:36533556]). Disruption of the B9 protein complex by MKS1 loss further supports pathogenicity ([PMID:21763481]).

Integration and Clinical Impact

The integration of robust genetic and functional datasets cements MKS1 as a definitive disease gene for Meckel syndrome type 1. Comprehensive mutation screening of MKS1 should be included in prenatal and preimplantation diagnostic panels for families at risk. Early molecular diagnosis enables informed reproductive planning, targeted imaging, and potential future therapies aimed at modulating ciliogenesis pathways.

Key Take-home: Biallelic loss‐of‐function variants in MKS1 cause definitive Meckel syndrome type 1 via disruption of the ciliary transition zone, supporting its inclusion in diagnostic and carrier screening panels.

References

• Human mutation | 2007 | Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. PMID:17397051
• Frontiers in genetics | 2022 | Case Report: Preimplantation Genetic Testing for Meckel Syndrome Induced by Novel Compound Heterozygous Mutations of MKS1. PMID:35360848
• Human molecular genetics | 2007 | The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. PMID:17185389
• American journal of human genetics | 2011 | Disruption of a ciliary B9 protein complex causes Meckel syndrome. PMID:21763481
• Disease models & mechanisms | 2022 | Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. PMID:36533556

Evidence Based Scoring (AI generated)