TBC1D20 – Martsolf Syndrome

TBC1D20 has emerged as a critical gene in the context of Martsolf syndrome, a rare autosomal recessive disorder characterized by ocular, neurological, and endocrine abnormalities. The association is supported by case reports and multi‐patient studies that identify novel loss‑of‑function mutations in affected individuals. The clinical phenotypes include optic atrophy, developmental glaucoma, seizures, hypogonadism, and congenital cataracts, underscoring the complex multisystem involvement of this condition (PMID:32162791).

A detailed case report from an Iranian family revealed two affected siblings carrying a novel homozygous nonsense mutation, c.1060C>T (p.Arg354Ter), in TBC1D20 (PMID:32162791). Furthermore, a multi‐patient study examining 34 new patients, including seven with Martsolf syndrome, confirmed the relevance of TBC1D20 mutations through segregation analysis and expanded the phenotypic spectrum observed in this disorder (PMID:32740904). Such findings provide robust genetic support for the gene–disease association.

Genetic evidence for this association is compelling, with multiple independent families demonstrating autosomal recessive inheritance. The identification of the c.1060C>T (p.Arg354Ter) variant in the index family establishes a clear loss‑of‑function mechanism, and additional variants (e.g. c.199C>T, p.Arg67Ter found in other studies) further corroborate the role of TBC1D20. In total, segregation data from approximately nine affected relatives across these reports underscores a strong genetic contribution to Martsolf syndrome (PMID:32162791; PMID:32740904).

Functional studies, although primarily focused on Warburg micro syndrome, have characterized TBC1D20 as a key regulator of intracellular trafficking and autophagosome maturation. Loss‐of‐function experiments in murine models and cellular assays have demonstrated that TBC1D20 deficiency leads to disruptions in Golgi morphology and lipid droplet formation, supporting its biological role in disease pathogenesis (PMID:24239381). This experimental evidence, while not exclusively performed in a Martsolf syndrome context, reinforces the mechanistic plausibility of the gene–disease relationship.

Notably, some studies have explored the broader spectrum of related syndromes, including Warburg micro syndrome, which shares overlapping phenotypic features with Martsolf syndrome. This overlapping evidence accentuates the allelic heterogeneity of TBC1D20 and highlights the need for careful phenotype delineation in clinical practice. However, the consistency in the identification of pathogenic variants in Martsolf syndrome patients strengthens the argument for a distinct association with this milder phenotype.

In conclusion, converging genetic and functional evidence supports a strong association between TBC1D20 and Martsolf syndrome. The identification of a novel nonsense mutation and its segregation in multiple affected individuals, together with convergent functional data, provide clinicians and researchers with a robust basis for diagnostic decision‑making and further study. Key Take‑home: TBC1D20 mutations represent a strong, reproducible molecular marker for Martsolf syndrome with significant clinical utility.

References

• American journal of medical genetics. Part A • 2020 • Martsolf syndrome with novel mutation in the TBC1D20 gene in a family from Iran PMID:32162791
• Clinical genetics • 2020 • Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights PMID:32740904
• American journal of human genetics • 2013 • Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans PMID:24239381

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