DENND5A – Intellectual Disability

DENND5A has emerged as a candidate gene for intellectual disability, with multiple independent studies implicating biallelic loss‑of‑function variants as a contributing factor to the disease phenotype (PMID:27431290). In cohorts where genomic sequencing was applied as a first‑tier diagnostic test, patients with intellectual disability were found to harbor homozygous and compound heterozygous truncating variants in DENND5A, underscoring its role in the expanding morbid genome of this condition (PMID:27431290).

The genetic evidence is bolstered by the recessive inheritance pattern observed in the affected families. Multiple affected individuals present with homozygous loss‑of‑function variants, including the recurrent variant c.955C>T (p.Gln319Ter), which disrupts DENND5A function. This variant, along with others reported in the literature, supports a robust genetic mechanism leading to the intellectual disability phenotype (PMID:27431290).

Segregation analyses in familial cases have demonstrated that the identified DENND5A variants co‐segregate with disease, further strengthening the association. Although precise counts of affected relatives are not consistently detailed, the observed inheritance pattern across unrelated families is consistent with autosomal recessive transmission.

In terms of the variant spectrum, the truncating variant c.955C>T (p.Gln319Ter) represents one example of the deleterious changes observed. The presence of multiple loss‑of‑function alleles argues for haploinsufficiency as a key pathogenic mechanism, which is in line with the disruption of critical protein domains necessary for neural development.

Although direct functional studies linking DENND5A to neurodevelopmental impairment are currently limited, complementary functional evidence from a melanoma study provides insight into the loss‐of‐function mechanism. In that study, a truncating variant in DENND5A led to impaired cargo transport via disrupted interaction with vesicular trafficking proteins (PMID:34906508). While this work was conducted in a pigmentation context, it lends biological plausibility to the notion that reduced DENND5A function can have deleterious cellular consequences. Additional studies in neural models are necessary to clarify its specific role in intellectual disability.

Integrating the genetic and experimental findings, the association of DENND5A with intellectual disability is supported by multiple independent probands carrying homologous loss‑of‑function variants and conforming to a recessive inheritance pattern. The evidence suggests that DENND5A disruption contributes to the disease process, though further experimental validation in relevant neurological systems is warranted.

Key Take‑Home: DENND5A should be considered in the diagnostic evaluation of intellectual disability, with current genomic evidence providing significant support for its pathogenic role and underscoring the utility of comprehensive genetic testing.

References

• Molecular Psychiatry • 2017 • Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield PMID:27431290
• Genetics in Medicine • 2022 • Novel loss-of‑function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma PMID:34906508

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