• Luke Carson and Deborah Merrick.
• School of Life Sciences, University of Nottingham, Nottingham, UK. luke.carson1@nhs.net.
• Ir J Med Sci. 2022 Dec 1; 191 (6): 274327502743-2750.

BackgroundMutations in the alpha-sarcoglycan gene cause limb-girdle muscular dystrophy 2D, an autosomal recessive muscle wasting disorder primarily affecting the muscles of the shoulder and pelvic girdles. To date, no previous study has collated all known mutations in alpha-sarcoglycan and mapped these to the associated phenotypes.AimsTo examine for correlations between mutation locations, or mutation type, and the phenotype caused in all reported mutations in alpha-sarcoglycan.MethodsWe present a systematic literature review examining correlations between mutation locations, or mutation type, and the phenotype caused in all reported cases of limb-girdle muscular dystrophy 2D.ResultsFrom 134 unique genotypes collated, a strong prevalence of missense mutations (64% of all unique mutations) was found in this gene. Mutation hotspots were noted in exon three and the extracellular domain, with mutation densities varying significantly between both exons and protein domains (p ≤ 0.01). All compound heterozygous limb-girdle muscular dystrophy 2D patients with cardiac involvement contained at least one mutation in exon three, a novel finding. All non-sense mutations in alpha-sarcoglycan give a severe phenotype, as do genotypes involving a combination of exons four and five. This study confirms on a large, diverse cohort the extremely high prevalence of the c.229C > T mutation.ConclusionsThis study demonstrates the vast variation in disease severity seen between patients possessing the same mutation, highlighting the difficulty identifying genotype-phenotype correlations in this condition. Novel findings including the involvement of exon three in all compound heterozygous patients who suffered from cardiomyopathy, and the severity of mutations involving exons four and five may help to guide investigations and therapeutic decisions in an era of personalised medicine.© 2021. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.

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