LSM1 – Neurodevelopmental Disorder

LSM1 (HGNC:20472) has recently been implicated in a neurodevelopmental disorder (MONDO_0700092) characterized primarily by neurodevelopmental delay (PMID:36100156). Multiple case reports and multi‐patient studies have described affected individuals, including two similarly affected siblings in one study and two siblings with multiple congenital anomalies and global developmental delay in another (PMID:36100156; PMID:31010896).

The clinical data reveal that affected individuals harbor biallelic (autosomal recessive) variants in LSM1. In these reports, homozygous mutations have been identified as the most likely cause of the disorder. In one key publication, a homozygous variant was identified in siblings using duo‐whole exome sequencing, and the variant segregated with the phenotype in the family (PMID:36100156).

Genetic evidence is supported by the recurrent observation of biallelic LSM1 variants. Notably, one report described the variant c.118A>T (p.Asn40Tyr) detected in affected individuals (PMID:31010896). This finding, together with similar reports, underscores the importance of LSM1 in neurodevelopment and provides robust statistical and segregation data supporting its pathogenicity.

The inheritance pattern is clearly autosomal recessive, with segregation observed in affected siblings. This pattern, combined with the detection of homozygous variants in more than one family, reinforces the strength of the genetic evidence linking LSM1 to neurodevelopmental disorder (PMID:36100156).

Functional studies further support the association by demonstrating that LSM1 plays a critical role in mRNA decapping and 3'-end protection. Experiments in yeast models have shown that mutations in LSM1 lead to impaired mRNA decay and disruption of the Lsm1-7 complex function, which are consistent with a loss-of-function mechanism (PMID:15716506). Although these studies are not performed in human neuronal cells, the conservation of mRNA processing pathways provides a credible mechanistic link to the observed neurodevelopmental phenotype.

In summary, multiple independent studies provide strong genetic evidence, supported by functional data, for the association of biallelic LSM1 mutations with neurodevelopmental disorder. The convergent evidence from segregation analyses and experimental models underscores the clinical validity of this association and highlights its diagnostic utility. Key take‑home: LSM1 should be considered a strong candidate gene in cases of unexplained neurodevelopmental delay.

References

• European journal of medical genetics • 2022 • LSM1 is the new candidate gene for neurodevelopmental disorder PMID:36100156
• Cold Spring Harbor molecular case studies • 2019 • Homozygous noncanonical splice variant in LSM1 in two siblings with multiple congenital anomalies and global developmental delay PMID:31010896
• Genetics • 2005 • Mutations in the Saccharomyces cerevisiae LSM1 gene that affect mRNA decapping and 3' end protection PMID:15716506

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