Two novel TCTN2 mutations cause Meckel-Gruber syndrome

Area of Science:

• Genetics
• Developmental Biology
• Medical Research

Background:

• Meckel-Gruber syndrome (MKS) is a ciliopathy with a known genetic basis, often involving primary cilia dysfunction.
• Mutations in Tectonic2 (TCTN2) are rare causes of MKS, with limited understanding of their impact on ciliogenesis.
• Previous reports lack direct evidence of ciliogenesis in MKS patients with TCTN2 mutations.

Purpose of the Study:

• To identify novel genetic variants associated with Meckel-Gruber syndrome.
• To investigate the role of Tectonic2 (TCTN2) in ciliogenesis in a human MKS case.
• To report a unique clinical presentation in an MKS fetus with TCTN2 mutations.

Main Methods:

• Genetic sequencing to identify variants in the TCTN2 gene.
• Phenotypic analysis of a Chinese MKS fetus, including examination of kidney development.
• Comparative analysis of primary cilia in affected fetal kidney tubules versus controls.

Main Results:

• Two novel nonsense variants (c.343G>T, p.E115* and c.1540C>T, p.Q514*) in the TCTN2 gene were identified in the MKS fetus.
• The fetus exhibited an endocardial pad defect, a previously unreported feature in TCTN2-related MKS.
• Primary cilia were observed to protrude normally from kidney tubule epithelial cells, suggesting TCTN2 is not required for kidney ciliogenesis.

Conclusions:

• This is the first reported case of Meckel-Gruber syndrome caused by TCTN2 mutations in China.
• Tectonic2 (TCTN2) mutations do not appear to be essential for primary cilia formation in the developing kidney.
• The findings expand the known spectrum of MKS phenotypes associated with TCTN2 mutations.