Pathogenic variants in BORCS5 cause a spectrum of neurodevelopmental and neurodegenerative disorders with lysosomal dysfunction.

BORCS5 loss of function (BORC complex subunit) → impaired lysosomal axonal trafficking and perinuclear clustering

16 individuals from 9 families with biallelic BORCS5 variants show a phenotypic spectrum ranging from prenatally lethal arthrogryposis multiplex congenita (homozygous protein-truncating variants) to developmental epileptic encephalopathy with microcephaly, optic atrophy, and hypomyelination (missense/splice variants). BORCS5 encodes a BORC complex subunit required for anterograde lysosomal transport and fusion. Borcs5 KO zebrafish recapitulate microcephaly, motor deficits, and seizure susceptibility.

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

BORCS5 joins the growing list of lysosomal trafficking genes implicated in severe NDD — with a concrete therapeutic angle as the BORC complex is an identified pharmacological target. The genotype-severity correlation (complete loss of function = prenatal lethality vs. missense = survival with NDD) is clinically useful for genetic counseling and prenatal decision-making.

Clinical impact: 2/3 · Evidence strength: 3/3 · Novelty: 2/2 · Sample size: 1/1 · Publication status: 1/1 → Total: 9/10