A severe neurodevelopmental syndrome linked to a South Asian founder variant in the UFMylation adaptor CDK5RAP3

CDK5RAP3 (NM_176096.3:c.334+243G>A, homozygous intronic — South Asian founder variant)

Homozygous intronic variant activating a cryptic pseudo-exon → loss of CDK5RAP3 → defective UFMylation of RPL26 — full characterization by WGS, RNA-seq, RT-PCR, Western blot, co-IP, phosphoproteomics

Identification of CDK5RAP3 as the first human disease gene for a UFMylation adaptor. Three individuals from two unrelated South Asian families present with a severe, lethal neurodevelopmental disorder. The same homozygous intronic variant (c.334+243G>A) was identified by trio WGS (family A) and exome reanalysis (family B), with pseudo-exon activation documented by RT-PCR. Functional analyses — Western blot, co-immunoprecipitation and phosphoproteomics — confirm loss of CDK5RAP3 and defective UFMylation of the ribosomal protein RPL26.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

First human disease gene documented for a CDK5RAP3 UFMylation adaptor — a pathway in which five other genes already cause severe NDDs. The intronic nature of the variant highlights the value of RNA sequencing alongside exome sequencing in unresolved cases. Add to severe recessive NDD panels, especially in patients of South Asian ancestry.

new gene +3; biallelic AR +2; full multi-approach functional +2; 3 individuals 2 families +1; Acta Neuropathol +1