TRAPPC9 – Intellectual Disability

The TRAPPC9 gene encodes the trafficking protein particle complex subunit 9, a mediator of NF-κB signalling and vesicle trafficking, which is highly expressed in postmitotic neurons of the cerebral cortex. Biallelic pathogenic variants in TRAPPC9 underlie autosomal recessive intellectual disability, presenting with microcephaly, global developmental delay and variable dysmorphic features. Early identification of TRAPPC9 mutations informs accurate diagnosis, prognosis, and genetic counselling for affected families.

Genetic evidence for TRAPPC9–Intellectual Disability includes over 56 patients from more than 20 unrelated consanguineous and non-consanguineous families, all harboring biallelic loss-of-function variants. Homozygous and compound heterozygous nonsense, frameshift, and splice-site mutations segregate with disease in multiple large pedigrees, with segregation confirmed in at least 19 affected relatives across studies. A representative pathogenic variant is c.2416dup (p.Gln806ProfsTer5) (PMID:30853973).

The variant spectrum in TRAPPC9-related intellectual disability is dominated by protein-truncating alleles: frameshift insertions/deletions (e.g., c.2288dup (p.Val764GlyfsTer7)), nonsense substitutions (e.g., c.2113A>T (p.Arg705Ter)), and essential splice-site changes. Recurrent founder mutations have been reported in Pakistani, Tunisian, Iranian and Maltese cohorts, reflecting allelic heterogeneity but consistent autosomal recessive inheritance.

Functional studies demonstrate concordant pathogenicity of TRAPPC9 deficiency. Patient fibroblasts with nonsense variants exhibit impaired NF-κB activation and vesicle trafficking defects, with disrupted IκBα degradation upon TNF-α stimulation (PMID:20004764). A Trappc9⁻/⁻ mouse model recapitulates human microcephaly, obesity and cognitive deficits, while complementation rescues synaptic and metabolic phenotypes (PMID:32877400). Additional studies reveal N-glycosylation defects in patient fibroblasts supporting a TRAPPC9-CDG diagnosis (PMID:35042660).

No significant conflicting evidence has been reported; epigenetic and imprinting studies in neuropsychiatric cohorts found no aberrations at the TRAPPC9 locus, and TRAPPC9 variants were absent in Tourette syndrome or isolated ASD without ID.

In summary, autosomal recessive TRAPPC9 deficiency is a well-established cause of intellectual disability with strong genetic and functional support. TRAPPC9 should be included in diagnostic gene panels for intellectual disability and neurodevelopmental disorders, enabling early intervention and family planning.

References

• American Journal of Human Genetics • 2009 • Combination of linkage mapping and microarray-expression analysis identifies NF-kappaB signaling defect as a cause of autosomal-recessive mental retardation. PMID:20004764
• PLoS Genetics • 2020 • Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. PMID:32877400
• Genetics in Medicine • 2022 • TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability. PMID:35042660

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