LIMS2 – limb‑girdle muscular dystrophy

This summary presents the association between LIMS2 (HGNC:16084) and limb‑girdle muscular dystrophy (MONDO_0016971). Early evidence originated from a case report where two siblings with childhood‑onset progressive muscle weakness, severe cardiomyopathy, and the unusual feature of triangular tongues were found to harbor compound heterozygous missense mutations in LIMS2 (PMID:25589244). Their clinical presentation and muscle biopsy findings, which demonstrated disrupted LIMS2 immunostaining, provided the first indication that LIMS2 disruption may underlie a novel muscular dystrophy phenotype.

Subsequently, multi‑patient studies employing next‑generation sequencing panels designed for limb‑girdle muscular dystrophies surveyed a cohort of 74 patients and identified pathogenic variants in 13 different genes, including LIMS2 (PMID:31066050). The inclusion of LIMS2 among the positive hits in a broad genetic screening emphasizes its contribution to the genetic heterogeneity of LGMD.

The genetic evidence is marked by the autosomal recessive inheritance pattern, with affected individuals showing compound heterozygous pathogenic variants. One key reported variant is c.290C>T (p.Pro97Leu), which meets the criteria as a complete coding sequence change with both c. and (p…) notations. This variant was identified in a family context and supports the hypothesis that loss‑of‑function or missense alterations in LIMS2 disrupt its normal function in muscle cells.

Furthermore, the functional assessment studies corroborate the genetic findings. Skeletal muscle biopsies from affected patients revealed a loss of normal LIMS2 immunostaining and disruption of the integrin linked kinase (ILK)-LIMS-parvin complex. Such mechanistic insights offer experimental confirmation that the LIMS2 variants directly compromise cellular processes essential for muscle integrity (PMID:25589244).

Collectively, both case‑based and multi‑patient evidence converge to support a moderate level of clinical validity for the LIMS2 and limb‑girdle muscular dystrophy association. The segregation of the mutations in a familial setting, along with consistent experimental findings, provides meaningful support for this gene‑disease relationship.

Key take‑home sentence: The identification of compound heterozygous LIMS2 mutations not only expands the genetic landscape of limb‑girdle muscular dystrophy but also offers valuable diagnostic and prognostic insights for affected patients.

References

• Clinical Genetics • 2015 • LIMS2 mutations are associated with a novel muscular dystrophy, severe cardiomyopathy and triangular tongues PMID:25589244
• Annals of Human Genetics • 2019 • Impact of next‑generation sequencing panels in the evaluation of limb‑girdle muscular dystrophies PMID:31066050

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