TCTN2 – Meckel syndrome

Biallelic pathogenic variants in TCTN2 (HGNC:25774) have been implicated in autosomal recessive Meckel syndrome (MONDO:0018921), a lethal ciliopathy characterized by occipital encephalocele, cystic renal dysplasia, and polydactyly. In a multiethnic cohort of 88 MKS families, targeted sequencing of six known MKS genes including TCTN2 identified homozygous causative variants in 62% of 26 unrelated consanguineous pedigrees (35 affected individuals)[PMID:26003401]. These variants consistently segregated with disease in homozygous state within families, though segregation beyond index cases was not formally quantified.

TCTN2 encodes a transition zone membrane protein essential for ciliary integrity. In mouse models, loss of Tctn2 disrupts ciliogenesis and Hedgehog signaling, leading to holoprosencephaly and neural tube defects that phenocopy aspects of human ciliopathies[PMID:28800946]. This concordance between human genetics and murine functional assays supports a loss‐of‐function mechanism in MKS.

Integration of genetic and experimental data establishes a limited but compelling association: homozygous TCTN2 variants impair ciliary transition zone function and Hedgehog pathway activity, underlying the multisystem defects of Meckel syndrome. Additional studies on variant spectrum and segregation in larger cohorts would strengthen clinical validity.

Key Take-home: Autosomal recessive TCTN2 variants disrupt ciliary transition zone function and cause Meckel syndrome, supporting their inclusion in diagnostic gene panels for syndromic ciliopathies.

References

• Molecular and cellular probes • 2015 • Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing. PMID:26003401
• Developmental biology • 2017 • Three Tctn proteins are functionally conserved in the regulation of neural tube patterning and Gli3 processing but not ciliogenesis and Hedgehog signaling in the mouse. PMID:28800946

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