BHLHE22 monoallelic and biallelic variants cause a neurodevelopmental disorder with agenesis of the corpus callosum, intellectual disability, abnormal muscle tone and movement abnormalities
Year: 2026
Type: article
Study design: Observational Study
Abstract: 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.
Source: Journal of Medical Genetics
Authors: Carolyn Le, Tugba Kalayci, Zehra Uyguner, Birsen Karaman, Tanju Demirören, Bodo Beck, Nora Winnerling, Elizabeth George, Stephanie DiTroia, Delphine Héron, Isabelle Sabatier, Lance H Rodan, Katta M Girisha, Periyasamy Radhakrishnan, Carol Saunders, Bonnie Sullivan, Emily Fleming, Javeria Raza Alvi, Tipu Sultan, Henry Houlden, Stephanie Efthymiou, Maria J Guillen Sacoto, Melanie Goodman, Lucie Pierron, Jean-Madeleine de Sainte Agathe, Alexandra Durr, Hector Rodrigo Mendez, Matthew T Wheeler, Jennefer N Carter, Jonathan A Bernstein, Biljana Gagachovska, Slavica Trajkova, Alfredo Brusco, Elliott Sherr, Emanuela Argilli
Institutions: University of California, San Francisco, Istanbul University, Yeditepe University, University of Cologne, University Hospital Cologne, Broad Institute, Paris-Sorbonne University, Hôpital Femme Mère Enfant, Boston Children's Hospital, Manipal Academy of Higher Education, Kasturba Medical College, Manipal, Children's Mercy Hospital, Children’s Mercy Research Institute, University of Child Health Sciences, UCL Queen Square Institute of Neurology, University College London, Ochsner Health System, Pitié-Salpêtrière Hospital, Sorbonne Université, Institut du Cerveau, Stanford University, Stanford Medicine, Ss. Cyril and Methodius University in Skopje, University of Turin
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: King Baudouin Foundation United States, Muscular Dystrophy Association, Wellcome Trust, Muscular Dystrophy UK, Multiple System Atrophy Trust, Brain Research UK, National Institute for Health and Care Research, Ataxia UK, University College London, Rosetrees Trust, Great Ormond Street Hospital Charity, Koning Boudewijnstichting, National Institutes of Health, Medical Research Council, UCLH Biomedical Research Centre, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, NextGenerationEU
Awards: G1043964965, A powerful web-based discovery platform for rare disease genetics, G1062904336, G1247727865, G1334424799, G1839063207, G1857207434, G1910334207, G196933922, G2033319461, Center for Undiagnosed Diseases at Stanford, G2191741699, G2445361521, G2652612411, G2801030838, G2920001861, G3142667248, G3190479294, G3267242055, G374229005, G3749942636, G3777639711, G3989318899, G436110613, G4639588712, G4702529995, G4814911389, Joint Center for Mendelian Genomics, G5842430364, G605089744, G6140582619, MRC Strategic Award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases, G6238416318, G668785241, G724433139, G7492172941, G7556113848, G755868891, G8129640651, G8297940485, G85824679, Leveraging the power of genomics and transcriptomics to revolutionise the diagnosis and understanding of neurological disorders, G8653647586, ACC: Callosal Agenesis as a Window into Common Neurodevelopmental Disorders, Broad Institute Mendelian Genomic Research Center, G918257111
OpenAlex ID: W7202283271