Journal Article

LSM1 c.231+4A>C hotspot variant is associated with a novel neurodevelopmental syndrome: first patient cohort

Baris Feldman, Hagit, Damseh, Nadirah, Velmans, Clara, Reytan Miron, Sivan, Kurolap, Alina, Netzer, Christian, Al-Ashhab, Motee, Erger, Florian, Abu-Libdeh, Bassam, Lesmann, Hellen, Abu-Libdeh, Abdel Salam, Riehmer, Vera, Reches, Adi, Chai Gadot, Chofit, Hsieh, Tzung-Chien, Mory, Adi

2025

Overview

BackgroundThe LSM1 gene encodes a subunit of the conserved LSM1-7 protein complex involved in messenger RNA (mRNA) metabolism. Variants in the LSM1 gene have been described in two separate case reports. The first published report identified the homozygous splice-site variant c.231+4A>C, while the second reported a homozygous missense variant. Nevertheless, variation in LSM1 has yet to be established as disease-causing in humans.MethodsThrough exome sequencing and detailed phenotyping, we report six syndromic paediatric patients with the homozygous c.231+4A>C variant in the LSM1 gene, collected via GeneMatcher. GestaltMatcher was used to analyse facial feature similarity, and real-time quantitative PCR (RT-qPCR) confirmed the splice defect caused by the variant. Haplotype analysis assessed whether this variant resulted from independent occurrences or a common ancestral haplotype.ResultsPatients presented with dysmorphic facial features, developmental delay and multisystemic involvement, including urological, cardiac and skeletal manifestations, showcasing the phenotypic spectrum of this syndrome. RT-qPCR confirmed that the c.231+4A>C variant causes exon 3 skipping, producing negligible wild-type LSM1 mRNA expression. Elevated mutant isoform expression confirmed pathogenicity according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We identified this variant in the Muslim Arab and Ashkenazi Jewish populations and determined that it represents a hotspot variant through haplotype analysis.ConclusionOur findings establish LSM1, and specifically the c.231+4A>C homozygous variant, as causative for a novel autosomal recessive syndromic neurodevelopmental disorder. These results expand the understanding of LSM1-related diseases and provide a foundation for further investigation of its molecular mechanisms.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD
• Subject: Biodiversity hot spots / Case reports / Central Nervous System Diseases / Child / Child, Preschool / Cohort Studies / Congenital, Hereditary, and Neonatal Diseases and Abnormalities / Data analysis / Disease / Disease hot spots / Exome Sequencing / Female / Gene expression / Genetic Predisposition to Disease / Genetics / Genomes / Genomics / Genotype & phenotype / Haplotypes / Hereditary diseases / Homozygote / Humans / Inborn Genetic Diseases / Infant / Male / Molecular modelling / Mutation / Neurodevelopmental disorders / Neurodevelopmental Disorders - diagnosis / Neurodevelopmental Disorders - genetics / Neurodevelopmental Disorders - pathology / Pathogenicity / Patients / Pediatrics / Phenotype / Phenotypes / Phenotyping / Proteins / Proto-Oncogene Proteins / RNA-Binding Proteins - genetics / Siblings / Whole genome sequencing