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

The 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.

Through 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.

Patients 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.

Our 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.