Early onset or syndromic epilepsy

Gene: BORCS5

Green List (high evidence)

Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and epilepsy. Hence, this gene should be promoted to Green at the next update.

Created: 26 May 2026, 10:15 a.m. | Last Modified: 26 May 2026, 10:15 a.m.

Panel Version: 9.7

PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."

Created: 26 May 2026, 10:13 a.m. | Last Modified: 26 May 2026, 10:13 a.m.

Panel Version: 9.7

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

Created: 20 Feb 2026, 1:15 p.m. | Last Modified: 20 Feb 2026, 1:15 p.m.

Panel Version: 8.119

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
• 42012897