BHLHE22 monoallelic and biallelic variants cause a neurodevelopmental disorder with agenesis of the corpus callosum, intellectual disability, abnormal muscle tone and movement abnormalities

Document Type

Article

Publication Date

10-22-2026

Identifier

DOI: 10.1136/jmg-2025-111432; MCID: PMC13598404

Abstract

BACKGROUND:BHLHE22 encodes a basic helix-loop-helix transcription factor (bHLH) expressed exclusively in the retina and central nervous system (CNS), and functions as an important regulator of neuronal differentiation. However, BHLHE22 has not yet been associated with a Mendelian neurodevelopmental or neurological disorder.

METHODS: Fifteen individuals from thirteen unrelated families carrying BHLHE22 variants identified by exome sequencing were collected through an international collaboration.

RESULTS: De novo missense variants located in the highly conserved helix-loop-helix domain of the protein were found in six individuals, and one recurrent homozygous frameshift variant, NP_689627.1:p.Gly74AlafsTer18, was found in nine individuals. Frequent clinical features include absent or limited speech (10/13), delayed or impaired motor abilities (11/13), intellectual disability (9/12), partial or complete agenesis of the corpus callosum (12/15), involuntary movements and/or stereotypies (11/13), and abnormal muscle tone (13/13), depending on data availability. Two individuals developed spastic paraplegia, without intellectual disability (ID) or callosal anomalies. One individual had moderate developmental delay and ID, but without callosal anomalies.

CONCLUSION: Collectively, our data establish BHLHE22 as a previously unrecognized neurodevelopmental disease gene. Disruption of BHLHE22, through either dominant or recessive variants, results in a distinct syndrome characterized by abnormalities in brain development, cognition, tone, and movement.

Journal Title

Journal of medical genetics

Volume

63

Issue

11

First Page

749

Last Page

754

PubMed ID

42586785

Keywords

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Exome Sequencing; Human Genetics; Nervous System Malformations; Phenotype

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