TRAPPC4 – Neurodevelopmental Disorder with Epilepsy, Spasticity, and Brain Atrophy

TRAPPC4 encodes a core subunit of the TRAPP complex, which mediates vesicular tethering in intracellular membrane trafficking. Biallelic loss-of-function variants in TRAPPC4 have been linked to a severe neurodevelopmental disorder characterized by early-onset epilepsy, spasticity, and progressive brain atrophy. The autosomal recessive inheritance and concordant clinical features across unrelated families support a robust gene–disease relationship.

In a 2025 report, two sisters with homozygous splice-region variant c.454+3A>G in TRAPPC4 presented with infantile-onset seizures, spasticity, and MRI evidence of cerebral atrophy after exhaustive diagnostic evaluations (PMID:40173375). This reinforced the recessive inheritance model and demonstrated clinical recognition delays despite a relatively common carrier frequency.

An earlier study described 23 affected individuals from 17 independent families homozygous for the same c.454+3A>G variant or harboring a second frameshift allele, c.23_24del (p.Val8fs), all exhibiting profound psychomotor delay, developmental regression, microcephaly, early-onset epilepsy, and spastic tetraplegia (PMID:32901138). No other TRAPPC4 variants were identified in over 10,000 neurodevelopmental exomes, underscoring the specificity of this recurrent splice change.

Population screening revealed a carrier frequency of 2.4–5.4 per 10,000 individuals for c.454+3A>G, suggesting a founder effect in certain populations and emphasizing the need for targeted genetic testing in undiagnosed infantile encephalopathies.

Functional assays demonstrated that c.454+3A>G causes partial skipping of exon 3 with activation of a cryptic donor site, leading to a premature stop codon and nonsense-mediated decay of TRAPPC4 transcripts. Moreover, patient-derived iPSC lines with homozygous c.454+3A>G showed reduced TRAPPC4 expression, which was restored upon CRISPR/Cas9 heterozygous correction in isogenic controls (PMID:39787667). These data confirm a loss-of-function mechanism in disease pathogenesis.

Overall, 25 probands across 18 families have been identified with homozygous or compound heterozygous TRAPPC4 variants, with segregation fitting an autosomal recessive model and concordant functional studies. Additional patient numbers and deep-intronic variant screens may further refine the mutation spectrum. TRAPPC4 genetic testing should be considered in infants presenting with early epilepsy, spasticity, and brain atrophy.

Key Take-home: Biallelic TRAPPC4 loss-of-function variants cause a recognisable, autosomal recessive neurodevelopmental syndrome with epilepsy, spasticity, and progressive cerebral atrophy, supporting clinical genetic testing for early diagnosis and family counselling.

References

• Neurology • 2025 • Child Neurology: TRAPPC4-Related Neurodevelopmental Disorder. PMID:40173375
• European Journal of Human Genetics • 2021 • A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome. PMID:32901138
• Stem Cell Research • 2025 • Generation and heterozygous repair of human iPSC lines from two individuals with the neurodevelopmental disorder, TRAPPC4 deficiency. PMID:39787667

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