# Exploring Splice-Site Mutations in LAMA2-Related Muscular Dystrophies: A Comprehensive Analysis of Genotypic and Phenotypic Patterns

## TL;DR

This study explores how mutations in the LAMA2 gene affect muscular dystrophy severity, showing that splice-site mutations often lead to severe disease.

## Contribution

The study identifies a biallelic splice-site mutation in LAMA2 causing severe muscular dystrophy and highlights the role of WES and transcriptional analysis in understanding these mutations.

## Key findings

- Biallelic splice-site mutations in LAMA2 lead to severe MDC1A, often with exon skipping and loss of reading frame.
- Whole exome sequencing is effective in identifying causative mutations in LAMA2-related muscular dystrophies.
- Transcriptional analysis is crucial for understanding the impact of splice-site mutations on disease phenotype.

## Abstract

LAMA2-related muscular dystrophies (LAMA2-RDs) constitute the most prevalent subtype of congenital muscular dystrophies (CMDs). The clinical spectrum of LAMA2-RDs exhibits considerable diversity, particularly in motor development and disease progression. Phenotypic variability ranges from severe, early-onset presentation, known as merosin-deficient CMD type 1A, to milder, late-onset presentations, including limb-girdle muscular dystrophy-like phenotype. In this study, whole exome sequencing (WES) was applied to a family with a single proband affected by severe muscular dystrophy. The identified causative mutation was a biallelic splice-site mutation in intron 58 of the LAMA2 gene, leading to a premature termination codon in the critical G domain of laminin-α2 and resulting in a severe phenotype. Additionally, we summarized previously reported splice-site mutations to investigate the clinical and transcription consequences of these mutations. Our findings conclude that splice-site mutations predominantly lead to severe MDC1A, whether in a homozygous or heterozygous state, often associated with another loss-of-function mutation. Besides, splice-site mutations with available analysis of their transcriptional consequences were found to be responsible for exon skipping in most cases and the loss of the reading frame. These findings revealed the importance of WES in identifying disease-causing mutations, particularly in highly diversified pathologies like LAMA2-RDs. The results also underscore the importance of transcriptional analysis in determining the impact of splice-site mutations and the phenotype of LAMA2-RDs on patients.