TBC1D7 – Megalencephaly

TBC1D7 is an essential member of the TSC1-TSC2 complex, which regulates mTORC1 signaling, a pathway critical for controlling cell growth. Recent studies have identified biallelic loss-of-function variants in TBC1D7 in individuals presenting with megalencephaly, a condition characterized by an abnormally large brain, in conjunction with intellectual disability (PMID:23687350).

In affected families, homozygous truncating mutations such as c.322dup (p.Tyr108fs) have been identified through exome sequencing and homozygosity mapping. These mutations were found to abolish TBC1D7 expression and lead to dysregulation of mTORC1 signaling, which has been consistently correlated with the megalencephaly phenotype (PMID:23687350, PMID:24515783).

Genetic evidence from multiple independent case reports demonstrates clear autosomal recessive inheritance in families with affected siblings. The observed segregation of truncating variants supports a strong gene–disease association, as similar phenotypes are seen in separate consanguineous families (PMID:23687350).

Functional studies further substantiate the pathogenic role of TBC1D7 mutations by showing that loss of the gene product leads to an increase in mTORC1 signaling activity. These assays, involving patient-derived cell lines and animal models, mimic the overgrowth observed in megalencephaly and establish a direct mechanistic link (PMID:23687350, PMID:35584673).

The integration of robust genetic evidence with concordant functional data supports a strong clinical validity for the association between TBC1D7 and megalencephaly. Notably, while TBC1D7 is also studied in the context of tuberous sclerosis, the pattern and severity of brain overgrowth along with distinct clinical features delineate a separate phenotypic spectrum focused on megalencephaly.

Key take‑home message: TBC1D7 loss-of-function mutations represent a strong genetic and functional basis for the development of megalencephaly, providing valuable insights for diagnostic decision‑making and potential therapeutic intervention.

References

• Journal of medical genetics • 2013 • Disruption of TBC1D7 in intellectual disability and megalencephaly PMID:23687350
• Human mutation • 2014 • TBC1D7 mutations associated with intellectual disability and macrocrania PMID:24515783
• Cell reports • 2022 • The non‑essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain growth PMID:35584673

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