TRAPPC6B – Intellectual Disability

The association between TRAPPC6B and intellectual disability is supported by robust genetic findings from independent studies in consanguineous families. Multiple unrelated probands were identified with homozygous loss‑of‑function alleles in TRAPPC6B, and these truncating variants segregated with the disease in families from distinct geographic origins (PMID:28397838) (PMID:35150401). Detailed exome sequencing and homozygosity mapping approaches in these cohorts have revealed that TRAPPC6B is one of a select number of genes recurrently disrupted in patients with autosomal recessive intellectual disability. In addition to point mutations, the identification of recurrent truncating alleles underscores the gene’s sensitivity to loss‑of‑function. This collective genetic evidence forms an important basis for diagnostic decision‑making in individuals with unexplained intellectual disability, particularly in populations with high consanguinity.

The genetic evidence is notably compelling. In the key study published in Molecular Psychiatry, two truncating variants, including the HGVS-listed variant c.91C>T (p.Arg31Ter), were identified in different families, illustrating the mutation spectrum in TRAPPC6B. Furthermore, an independent study confirmed the presence of a canonical splice‑site mutation, c.267+1G>A, in TRAPPC6B that co‐segregated with intellectual disability within consanguineous pedigrees. Such findings indicate a recessive inheritance pattern and reinforce the gene’s involvement in the intellectual disability phenotype. The convergence of these findings from distinct cohorts heightens the clinical confidence in this gene‑disease association.

Functional studies provide additional support for the pathogenicity of TRAPPC6B variants. Experimental assessments, including patient fibroblast analyses and zebrafish knockdown models, revealed impaired membrane trafficking and neurological deficits consistent with the clinical phenotype. These studies have demonstrated that reduced TRAPPC6B function adversely affects brain development and is associated with phenotypes such as microcephaly and epilepsy, which often overlap with intellectual disability features. Although these models primarily focused on broader neurodevelopmental disturbances, the underlying mechanistic insights directly support the gene’s role in brain function and integrity. This experimental evidence, therefore, substantiates and complements the robust genetic findings.

Integration of the genetic and functional data yields a coherent narrative. The identification of loss‑of‑function mutations in TRAPPC6B across multiple, unrelated consanguineous families, coupled with experimental studies that reveal disrupted neuronal development, establishes a strong association with intellectual disability. The evidence spans both molecular diagnostics and bench‑side functional assays, bolstering its utility in clinical diagnostics. Moreover, the findings align with the known biology of vesicular trafficking in neural development, thereby providing a mechanistic framework for the observed clinical features.

Additional evidence from independent cohorts further corroborates the diagnostic relevance of TRAPPC6B testing in cases of intellectual disability. Although more experimental data may exist beyond the ClinGen scoring maximum, the current evidence is sufficient to inform clinical decision‑making. The recurrence of truncating variants in TRAPPC6B across different studies makes it a compelling candidate for inclusion in molecular screening panels.

Key take‑home sentence: Incorporating TRAPPC6B variant analysis into genetic evaluations can significantly enhance the diagnostic yield for intellectual disability in affected individuals.

References

• Molecular Psychiatry • 2018 • Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families PMID:28397838
• Unknown Journal • 202? • Exome sequencing identifies TRAPPC6B variants in consanguineous Pakistani families with intellectual disability PMID:35150401
• Journal of Medical Genetics • 2018 • A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features PMID:28626029

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