TRAPPC9 – Autosomal Recessive Non-syndromic Intellectual Disability

TRAPPC9 encodes a trafficking protein particle complex subunit involved in NF-κB signaling and vesicle trafficking. Biallelic loss-of-function variants in TRAPPC9 cause autosomal recessive non-syndromic intellectual disability (MONDO:0019502), often accompanied by microcephaly and variable dysmorphic features.

Case reports have identified homozygous splice donor site mutation c.1024+1G>T leading to skipping of exon 3 and premature termination (PMID:22989526), as well as truncating variants such as c.484G>T (p.Glu162Ter) (PMID:36158060), c.2416dup (p.Gln806ProfsTer5) (PMID:30853973), and c.937C>T (p.Arg313Ter) (PMID:33513295). These and other homozygous or compound heterozygous loss-of-function variants have been documented in at least 17 affected individuals across 8 unrelated families ([PMID:22989526]; [PMID:29693325]; [PMID:36158060]; [PMID:30853973]; [PMID:34737153]; [PMID:33513295]; [PMID:33710595]; [PMID:36672789]).

Inheritance is autosomal recessive with consistent segregation of homozygous or compound heterozygous variants in consanguineous pedigrees. At least 19 additional affected relatives have been described carrying segregating TRAPPC9 variants.

Functional assays demonstrate impaired NF-κB signaling in patient fibroblasts, evidenced by defective IκBα degradation upon TNF-α stimulation (PMID:20004764). Trappc9 knockout mice exhibit microcephaly, cognitive deficits, obesity, and metabolic disturbances, mirroring the human phenotype and confirming haploinsufficiency as the principal mechanism (PMID:32877400).

Integration of robust genetic segregation, diverse loss-of-function alleles, and concordant functional and animal model data supports a Strong clinical validity for the TRAPPC9–autosomal recessive non-syndromic intellectual disability association. TRAPPC9 should be included in diagnostic panels for ARID and early-onset microcephaly.

Key Take-home: Biallelic loss-of-function variants in TRAPPC9 cause a clinically recognizable autosomal recessive intellectual disability syndrome with microcephaly via impaired NF-κB signaling and vesicle trafficking.

References

• European journal of medical genetics • 2012 • A homozygous splice site mutation in TRAPPC9 causes intellectual disability and microcephaly. PMID:22989526
• Molecular genetics & genomic medicine • 2018 • Phenotypes in siblings with homozygous mutations of TRAPPC9 and/or MCPH1 support a bifunctional model of MCPH1. PMID:29693325
• Molecular syndromology • 2022 • Distinct Autism Spectrum Disorder Phenotype and Hand-Flapping Stereotypes: Two Siblings with Novel Homozygous Mutation in TRAPPC9 Gene and Literature Review. PMID:36158060
• Frontiers in genetics • 2019 • Novel Compound Heterozygous Mutations in the TRAPPC9 Gene in Two Siblings With Autism and Intellectual Disability. PMID:30853973
• European journal of medical genetics • 2021 • Further insights into the spectrum phenotype of TRAPPC9 and CDK5RAP2 genes, segregating independently in a large Tunisian family with intellectual disability and microcephaly. PMID:34737153
• Molecular genetics & genomic medicine • 2021 • Identification of two novel homozygous nonsense mutations in TRAPPC9 in two unrelated consanguineous families with intellectual Disability from Iran. PMID:33513295
• Genes & genomics • 2021 • Whole exome sequencing revealed novel variants in consanguineous Pakistani families with intellectual disability. PMID:33710595
• Genes • 2022 • Whole-Exome Sequencing of Pakistani Consanguineous Families Identified Pathogenic Variants in Genes of Intellectual Disability. PMID:36672789
• 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

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