Early onset or syndromic epilepsy

Gene: BHLHE22

Green List (high evidence)

Comment on list classification: There are 11 individuals reported in literature with a BHLHE22-related neurodevelopmental disorder - some harboured monoallelic and some biallelic variants. None of the heterozygous individuals presented with epilepsy, but 4/7 probands with biallelic variants did. Hence, this gene can be promoted to Green on 'Early onset or syndromic epilepsy', with MOI set to BIALLELIC, autosomal or pseudoautosomal.

Created: 11 Nov 2026, 4:57 p.m. | Last Modified: 11 Nov 2026, 4:57 p.m.

Panel Version: 9.99

PMID: 42586785 - 11 individuals from 9 unrelated families with BHLHE22 variants, presenting with a neurodevelopmental disorder including absent or limited speech, impaired motor function, intellectual disability, involuntary movements, autistic traits, abnormal muscle tone. Most had partial or complete agenesis of the corpus callosum, and some also showed epilepsy (4/7 biallelic cases), dysmorphic features, and eye anomalies.

Four individuals had de novo missense variants within the helix-loop-helix domain, and seven carried a recurrent homozygous frameshift variant, p.(Gly74Alafs*18).

Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum, recapitulating the structural anomalies seen in affected humans.
Sources: Literature

Created: 11 Nov 2026, 4:54 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092

Publications

• 42586785