Le Carolyn, Argilli Emanuela, George Elizabeth, Kalaycı Tuğba, Uyguner Zehra Oya, Karaman Birsen, Demirören Tanju, DiTroia Stephanie, Heron Delphine, Sabatier Isabelle, Rodan Lance H, Girisha Katta Mohan, Radhakrishnan Periyasamy, Saunders Carol, Sullivan Bonnie, Fleming Emily, Alvi Javeria Raza, Sultan Tipu, Houlden Henry, Efthymiou Stephanie, Sacoto Maria J Guillen, Goodman Melanie, Pierron Lucie, De Sainte-Agathe Jean-Madeleine, Durr Alexandra, Sherr Elliott H
Department of Neurology, 675 Nelson Rising Lane, University of California, San Francisco, California, 94158, USA.
Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, California, 94158, USA.
medRxiv. 2024 Dec 17:2024.10.11.24312856. doi: 10.1101/2024.10.11.24312856.
encodes a Class II basic helix-loop-helix transcription factor (bHLH). It is expressed exclusively in the retina and central nervous system (CNS), and functions as an important regulator of retinogenesis and neuronal differentiation. Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum. Here we report eleven individuals from nine unrelated families with variants, with a neurodevelopmental disorder presenting with absent or limited speech, severely impaired motor abilities, intellectual disability (ID), involuntary movements, autistic traits with stereotypies, abnormal muscle tone. The majority of individuals have partial or complete agenesis of the corpus callosum (ACC). Additional symptoms comprised of epilepsy, variable dysmorphic features, and eye anomalies. One additional individual had spastic paraplegia without delayed development and ACC, expanding the phenotype to milder and later onset forms. Four individuals carry missense variants within the highly conserved helix-loop-helix domain while seven individuals from five unrelated families carry a recurrent homozygous frameshift variant, p.(Gly74Alafs*18). Our findings implicate variants in causing a previously unidentified autosomal dominant and recessive neurodevelopmental disorder associated with ACC, severe motor, language, and cognitive delays, abnormal tone, and involuntary movements. To our knowledge, this is the first report of Class II bHLH variants in humans shown to significantly disrupt brain development, cognition, and movement.
编码一种II类碱性螺旋-环-螺旋转录因子（bHLH）。它仅在视网膜和中枢神经系统（CNS）中表达，并作为视网膜发生和神经元分化的重要调节因子发挥作用。缺乏bhlhe22的小鼠显示出包括胼胝体在内的三个脑连合几乎完全缺失。在此，我们报告了来自九个不相关家庭的11名个体，他们携带变异，患有神经发育障碍，表现为言语缺失或受限、运动能力严重受损、智力残疾（ID）、不自主运动、伴有刻板行为的自闭症特征、肌张力异常。大多数个体患有部分或完全胼胝体发育不全（ACC）。其他症状包括癫痫、各种畸形特征和眼部异常。另有一名个体患有痉挛性截瘫，无发育延迟和ACC，将该表型扩展到较轻和较晚发病的形式。四名个体在高度保守的螺旋-环-螺旋结构域内携带错义变异，而来自五个不相关家庭的七名个体携带一个反复出现的纯合移码变异，p.(Gly74Alafs*18)。我们的研究结果表明，这些变异导致了一种先前未被识别的常染色体显性和隐性神经发育障碍，与ACC、严重的运动、语言和认知延迟、肌张力异常和不自主运动有关。据我们所知，这是人类中II类bHLH变异首次被报道会显著破坏大脑发育、认知和运动。
