Variants in CAPN3 Causing Autosomal Dominant Limb–Girdle Muscular Dystrophy Combined With Calpain-3 Deficiency

Abstract: Limb–girdle muscular dystrophy Type 2A/R1 or calpain-3 deficiency is the most common autosomal recessive limb–girdle muscular dystrophy. However, in recent years, autosomal dominant cases and families with calpain-3 deficiency have been reported, and there is an emerging interest in looking for single variants in the calpain-3 gene in mildly to moderately affected patients with limb–girdle muscular dystrophy without biallelic gene variants in CAPN3. Here, we report four cases with creatine kinase levels above 1500 U/L, mild-to-moderate proximal weakness, waddling gait, and scapular winging. Two patients, a son and his father, are heterozygous for the CAPN3 variant c.304C>T; p.(Pro102Ser), which has previously been reported in patients with compound heterozygous variants in CAPN3. The third and fourth patients were heterozygous for c.1371C>G; p.(Asn457Lys) and c.1490C>T; p.Ala497_Glu508del, respectively, neither of which has been reported before. All four patients had a near-complete loss of calpain-3 as determined by western blotting. While inherited autosomal dominant calpainopathy has now been firmly established, additional single cases of dominant calpainopathy are likely to emerge; some will be associated with clinical findings from parents or siblings, while others will arise from spontaneous mutations, but nevertheless with similar clinical findings of mild-to-moderate proximal weakness, increased level of creatine kinase, and near-complete loss of calpain-3 protein in affected individuals. This report expands the known number of variants causing dominant calpainopathy from 8 to 11 that appears to exclusively reside in two out of four domains that make up calpain-3. This information could aid in determining whether a CAPN3 variant of unknown significance is pathological.