A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome

Abstract

Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.

Further evidence of muscle involvement in neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy

“…Elevated CPK were also observed in P1 and P3, thus reiterating the significance of assessing CPK levels for this condition. Additionally, P1 also had elevated serum lactate levels as observed in two individuals reported by Kaur et al (2020) and Ghosh et al (2021).…”

“…Involuntary movements in the form of ataxia, tremors, and dystonia which were previously reported in 12 out of 33 individuals, also noted in P1 and P2. Hearing and ophthalmological abnormalities (cortical visual defects, no tracking, roving eye movements, nystagmus, and optic atrophy) as seen in P1 are also reported in 30 out of 31 previously affected individuals (Ghosh et al, 2021;Kaur et al, 2020;Saad et al, 2020;van Bergen et al, 2020).…”

“…P1 presented in the early infantile period with developmental delay, feeding difficulties, and seizures as observed in most of the individuals with recurrent splicing TRAPPC4 variant (Ghosh et al, 2021;Kaur et al, 2020;van Bergen et al, 2020). On the other hand, P2 and P3 presented with cognitive delay in early childhood.…”

“…Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA; MIM# 618741) is a recently described TRAPPopathy associated with pathogenic variants in TRAPPC4. Surprisingly, of the 33 individuals from 22 families reported to date, 31 individuals from 21 families have been reported with a recurrent homozygous pathogenic variant, NC_000011.9: c.454+3A>G (Ghosh et al, 2021;Kaur et al, 2020;van Bergen et al, 2020). Only two individuals from one family with milder manifestation of this disorder are reported with an in-frame variant (NM_016146.6: c.638_*4del) in TRAPPC4 (Saad et al, 2020).…”

seqr : a web-based analysis and collaboration tool for rare disease genomics

“…Due to joint-calling, the allele count across the Broad CMG callset is displayed for all variants in the search results and aggregation of cases with common etiologies is easily enabled. For example, analysts at Broad identified three other cases with the same homozygous splice variant in TRAPPC4, which led to its association as a relatively common cause of early-infantile neurodegenerative syndrome (Supplementary Figure 5) (Ghosh et al, 2021).…”