TMEM147 – Intellectual Disability

In a consanguineous family, two affected individuals presented with profound intellectual disability and spasticity that are attributable to a biallelic loss‑of‑function variant in TMEM147. The reported variant, c.193-197del, is predicted to cause disruption of TMEM147 function and was confirmed by whole exome sequencing with segregation in the family (PMID:37668766). This autosomal recessive inheritance pattern is consistent with the molecular findings and supports the gene‑disease linkage. Although only two probands have been reported, the loss‑of‑function mechanism aligns with the known biology of TMEM147, which localizes to the endoplasmic reticulum membrane and nuclear envelope and is involved in the biogenesis of multi‑pass membrane proteins. The genetic data, while modest in sample size, are in concordance with the clinical presentation observed in the patients. Overall, these findings add to the growing evidence implicating TMEM147 in neurodevelopmental disorders.

The functional context further supports the pathogenicity of the variant; preliminary data indicate that disruption of TMEM147 function may impair membrane protein assembly, correlating with the neurological phenotype observed. Although comprehensive functional assays are still pending, the available experimental insights provide a biological rationale for a loss‑of‑function mechanism in TMEM147-associated intellectual disability. Importantly, there are no reported studies contradicting this association, which further consolidates the current understanding. Key take‑home sentence: TMEM147 loss‑of‑function variants, even when observed in limited numbers, are clinically useful markers for intellectual disability and spasticity and can inform diagnostic decision‑making.

References

• Neurogenetics • 2023 • A biallelic loss-of‑function variant in TMEM147 causes profound intellectual disability and spasticity PMID:37668766

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