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

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

METHODS: 15 individuals from 13 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 (ID; 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 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 characterised by abnormalities in brain development, cognition, tone and movement.