Expanded clinical and genetic characterization of autosomal recessive HMGCR-related muscular dystrophy

Autosomal recessive Limb-Girdle Muscular Dystrophy type R28 (LGMDR28; OMIM #620375) is one of the most recently identified subtypes of recessive LGMD. To date, 17 affected individuals from eight unrelated families have been reported to harbor biallelic variants in the <i>HMGCR</i> gene. Here, we report eleven individuals from six unrelated Middle Eastern families diagnosed with LGMDR28 and carrying homozygous variants in <i>HMGCR</i>. Our cohort recapitulated most of the previously described clinical features of the HMGCR-related phenotype. In addition, we also report a family with congenital onset of the condition as well as two affected individuals with liver failure. Through genome and exome sequencing, we identified three novel homozygous missense variants; c.2519G >A, p.(Arg840Gln), c.1784G >A, p.(Arg595His), and c.1783C>T, p.(Arg595Cys) and a homozygous in-frame deletion (c.1522_1524del, p.(Ser508del)) previously reported in compound heterozygous state with a second relevant variant and very recently as homozygous in an unrelated proband. This study consolidates the pathogenic role of <i>HMGCR</i> in LGMDR28 while expanding the phenotypic and mutations spectrum of LGMDR28.