Muscarinic acetylcholine receptor M1 mutations causing neurodevelopmental disorder and epilepsy.

Anna Marcé‐Grau,Elisabet Gabau,Anna Ruiz‐Nel·Lo,Raúl Estévez,Xabier Elorza‐Vidal,Júlia Sala‐Coromina,Carla Pérez‐Rius,Alfons Macaya

doi:10.1002/humu.24252

Abstract

De novo rare damaging variants in genes involved in critical developmental pathways, notably regulation of synaptic transmission, have emerged as a frequent cause of neurodevelopmental disorders (NDD). NDD show great locus heterogeneity and for many of the associated genes, there is substantial phenotypic diversity, including epilepsy, intellectual disability, autism spectrum disorder, movement disorders, and combinations thereof. We report two unrelated patients, a young girl with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and a second girl with mild dysmorphism, global developmental delay, and moderate intellectual disability in whom trio-based whole-exome sequencing analysis uncovered de novo missense variants in CHRM1. Biochemical analyses of one of the NDD-associated variants proved that it caused a reduction in protein levels and impaired cellular trafficking. In addition, the mutated receptor showed defective activation of intracellular signaling pathways. Our data strengthen the concept that brain-reduced muscarinic signaling lowers the seizure threshold and severely impairs neurodevelopment.

Highlights

De novo rare damaging variants in genes involved in critical developmental pathways, notably regulation of synaptic transmission, have emerged as a frequent cause of neurodevelopmental disorders (NDD)
We report two unrelated patients, a young girl with early‐ onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and a second girl with mild dysmorphism, global developmental delay, and moderate intellectual disability in whom trio‐based whole‐exome sequencing analysis uncovered de novo missense variants in CHRM1
We identify two patients with point mutations in CHRM1, providing novel insight into the molecular mechanisms underlying Developmental and epileptic encephalopathies (DEE) and neurodevelopmental impairment and further implicate defects in the cholinergic pathway in severe infantile epilepsies

Summary

Introduction

De novo rare damaging variants in genes involved in critical developmental pathways, notably regulation of synaptic transmission, have emerged as a frequent cause of neurodevelopmental disorders (NDD). We report two unrelated patients, a young girl with early‐ onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and a second girl with mild dysmorphism, global developmental delay, and moderate intellectual disability in whom trio‐based whole‐exome sequencing analysis uncovered de novo missense variants in CHRM1.

Results

Conclusion