Novel Compound Heterozygous Variants in the TCTN2 Gene Causing Meckel-Gruber Syndrome 8 in a Non-Consanguineous...

Meckel-Gruber syndrome (MKS, OMIM 24,900), also known as Meckel syndrome, is a rare and severe autosomal recessive disorder. The syndrome is typically characterized by a triad of occipital encephalocele, bilateral renal cystic dysplasia, and postaxial polydactyly. MKS shows significant clinical heterogeneity, which poses challenges for accurate prenatal diagnosis. Prenatal ultrasound is an important tool for detecting potential cases, but the complexity of MKS often requires additional advanced techniques such as prenatal whole-exome sequencing (WES) to provide more accurate molecular genetic evidence.

In this study, we used whole-exome sequencing (WES) to analyze the genetic causes of suspected MKS in a Chinese fetus. Sanger sequencing was used to confirm the origin of the variants. The classification of variants was carried out in accordance with the guidelines of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP).

A 26-year-old pregnant woman was referred to our antenatal centre for genetic diagnosis at 13 + 5 weeks of gestation due to fetal occipital encephalocele and renal cysts detected by ultrasound. Two novel heterozygous variants, c.1047delA (p.Val351fs*1) and c.1336C>T (p.Arg446*), were identified in TCTN2. Sanger sequencing revealed that the c.1047delA (p.Val351fs*1) variant was inherited from the mother and the c.1336C>T (p.Arg446*) variant was inherited from the father. According to the ACMG/AMP guidelines, these two variants were evaluated as pathogenic.

This study further expands the genetic mutation spectrum of TCTN2 and is conducive to further clarifying the relationship between the genotype and phenotype of MKS8. Severe variants in the TCTN2 gene appear to be more likely to lead to MKS8. Clinically, the triad is an important basis for the diagnosis of MKS8, while other variable phenotypes of MKS8 can provide additional information for prenatal diagnosis. The combination of prenatal ultrasound and WES can provide a more comprehensive and accurate diagnosis of MKS8, which will greatly aid support for early intervention and treatment.