Submission Details

Dystroglycanopathies are muscular dystrophies with reduced glycosylation of α-dystroglycan (α-DG) and contain a phenotypic spectrum with range from Walker-Warburg syndrome (severe structural brain and eye involvement) to mild adult onset limb girdle muscular dystrophy. Muscular dystrophy-dystroglycanopathy due to biallelic inherited variants of *LARGE1 *was first described in 2003 by Longman et al. (PMID: 12966029). The proband was reported to have global developmental delay, hypotonia, mobility deterioration, calf and arm muscle hypertrophy, horizontal nystagmus, increased muscle tone, elevated creatine kinase. Additionally the proband had myopathic changes in the EMG and brain malformations that included cobblestone malformation, white matter changes, abnormal neuronal migration, mild pachygyria with moderately thick and dysplastic cortex in the frontal lobes and mildly simplified gyri with shallow sulci in the posterior frontal, temporal and parietal regions. All affected individuals described thus far carry compound heterozygous or homozygous variants in *LARGE1 *. One single report (PMID:17878207) of a patient with a heterozygous pathogenic variant in the gene was not included for the purposes of this curation. Additionally, the family described in PMID: 21248746, carried a homozygous loss of function variant but they were also excluded due to the complex genetic rearrangement that was identified in the affected probands.

LARGE1 protein is a putative glycosyltranferase required for the addition of glycans onto the α-DG protein. Dystroglycan is part of the dystrophin-glycoprotein complex (DGC) in the muscle and comprises two subunits the extracellular α-DG and the transmembrane β-DG. α-DG in the muscle acts as bridge between the extracellular matrix laminin and the actin cytoskeleton through the transmembranal β-dystroglycan; and in the brain binds to laminin and neurexin which are important for neuronal migration in the neocortex and the integrity of the glia limitants (PMID: 17436019).

The mechanism of pathogenicity is biallelic inherited loss-of-function variants. Five missense, 2 frameshift, 8 single or multiple exon deletions and 1 multiple exon duplication were reported in 9 patients and 3 affected fetuses from 10 families across 6 publications (PMIDs: 12966029, 17436019, 19067344, 19299310, 24709677, 21727005). Not all variants from the aforementioned PMIDs were scored because maximum genetic evidence points were reached. The gene-disease relationship is also supported by experimental evidence that include the natural mouse model Largemyd exhibiting same phenotypic features as the affected individuals (PMID: 12354792) and the rescue of the phenotype that was observed in cells from affected individuals when adenovirus expressing *LARGE1 *was used (PMID: 15184894) and in transgenic myd mice with overexpression of human *LARGE1 *in muscle (PMID: 23222475). In summary, *LARGE1 *is definitively associated with autosomal recessive muscular dystrophy-dystroglycanopathy. This has been repeatedly demonstrated and has been upheld over time. This was approved by the ClinGen Brain Malformation GCEP on 9/4/2024.