Childhood onset hereditary spastic paraplegia

Gene: BORCS5

Green List (high evidence)

Comment on list classification: Gene will not be tagged for promotion to Green until PMID: 40385417 pre-print is published.

Created: 20 Feb 2026, 1:14 p.m. | Last Modified: 20 Feb 2026, 1:14 p.m.

Panel Version: 8.30

PMID: 40621786 Fisher et al., 2025
Report of 2 fetal cases in a consanguineous Pakistani family. Exome seq revealed a homozygous nonsense variant c.283C>T, p.(Arg95Ter) in BORCS5 (NM_058169.4). Individuals showed neuroaxonal dystrophy with osteopetrosis.

PMID: 40385417 Mencacci et al., 2025 - pre-print
Report of 12 individuals from 7 unrelated families with biallelic BORCS5 variants (NM_058169.4): two missense variants (c.284G>A, p.R95Q; c.296A>C, p.H99P) and four LoF alleles (c.203–1G>T, p.?; c.316delG, p.A106Pfs*20; c.382_383delAG, p.L128Vfs*86; c.417C>G, p.Y139*).
Table 1 = phenotypic spectrum of 6 individuals from families 1-4: profound ID (6/6), severe spasticity (6/6), seizures (6/6), hyperreflexia (6/6), Parkinsonism/dystonia (3/6), limb contractures (5/6), optic atrophy (5/6), abnormal brain MRI including cerebral atrophy and/or corpus callosum agenesis (5/6), microcephaly (6/6 - severity not stated), muscle atrophy (5/6). Infantile onset.
Neuroimaging in 5 cases showed cerebral atrophy, white matter loss, hypomyelination, small T2-hypointense thalami, thin brainstem, and optic nerve atrophy.

PMID: 27435318 Charng et al., 2016
Patient BAB6775 homozygous for NM_058169.4 BORCS5: c.203-1G>T, with DD, microcephaly, seizures, cortical malformations, polymicrogyria, agenesis of corpus callosum. Also reported with more details in PMID:40385417 (do not count).

Additional functional evidence: Zebrafish borcs5 knockout leads to neurodevelopmental defects:microcephaly, ventriculomegaly, movement disorders and epilepsy.

BORCS5 is not yet associated with a disease in OMIM (accessed 20th Feb 2026).
Sources: Literature

Created: 20 Feb 2026, 1:12 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
arthrogryposis multiplex congenita, MONDO:0015168; neurodevelopmental disorder, MONDO:0700092

Publications

• 27435318
• 40385417
• 40621786