TCTN2 – Meckel-Gruber Syndrome

TCTN2, a member of the tectonic family, has been implicated in Meckel-Gruber syndrome, type 1, a severe ciliopathy defined by a triad of occipital encephalocele, polycystic kidney dysplasia, and postaxial polydactyly. The clinical diagnosis of Meckel-Gruber syndrome is complex, and an accurate molecular diagnosis can streamline management by preventing unnecessary investigations (PMID:32655147).

Genetic evidence for the role of TCTN2 in Meckel-Gruber syndrome is robust. In one case report, a Chinese MKS fetus was found to harbor two novel variants in TCTN2, including the nonsense variant c.1540C>T (p.Glu115Ter) (PMID:32655147). In a separate multipatient study involving a multiplex consanguineous family, segregation analysis further supported the association by demonstrating that the variant tracked with the phenotype in the family (PMID:21462283).

The genetic architecture in the reported cases is consistent with an autosomal recessive mode of inheritance. The occurrence of loss-of-function mutations, such as c.1540C>T (p.Glu115Ter), in unrelated probands reinforces the pathogenic contribution of TCTN2 to the Meckel-Gruber syndrome phenotype (PMID:32655147) (PMID:21462283).

Detailed clinical phenotyping disclosed that affected individuals present with occipital encephalocele, polycystic kidney dysplasia, and postaxial polydactyly. These features, along with the identification of deleterious variants in TCTN2, provide converging evidence linking this gene to the disorder and stress the need for early genetic testing in suspected cases.

Functional evaluations in patient-derived tissues have revealed that primary cilia formation appears to be preserved in kidney epithelial cells despite the presence of TCTN2 mutations. This finding suggests that the pathogenic mechanism may not hinge on disrupted ciliogenesis per se but could involve defects in ciliary signaling or structure that are subtler in nature (PMID:32655147).

In summary, the integration of genetic and limited functional data supports a strong association between TCTN2 variations and Meckel-Gruber syndrome, type 1. This evidence is critical for diagnostic decision-making, supports commercial genetic testing applications, and provides a solid foundation for future publication. A key take‑home message is that precise molecular diagnosis of ciliopathies such as Meckel-Gruber syndrome can dramatically enhance patient management and counseling.

References

• Journal of human genetics • 2020 • Two novel TCTN2 mutations cause Meckel-Gruber syndrome PMID:32655147
• Human mutation • 2011 • A TCTN2 mutation defines a novel Meckel Gruber syndrome locus PMID:21462283

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