A case of pseudodominant inheritance of limb-girdle muscular dystrophy caused by mutations in the CAPN3 gene

Abstract

Introduction. Limb-girdle muscular dystrophy (LGMD) includes more than 30 forms caused by mutations in genes located on autosomes. The most common form is calpain-3-related LGMD, with autosomal recessive inheritance pattern (OMIM 253600). An autosomal dominant form of LGMD (OMIM 618129) caused by c.643_663del heterozygous mutation in the CAPN3 gene is also supposed to exist.
 This article describes a family case of LGMD caused by mutations in the CAPN3 gene with pseudodominant inheritance.
 Materials and methods. Two patients with LGMD were studied: a 59-year-old woman and her 38-year-old daughter. Clinical, genealogical and molecular genetics methods were used: limb girdle muscular dystrophy MPS panel, Sanger sequencing of DNA of the proband, her affected daughter, and six first- and second-degree relatives across four generations.
 Results. It was found that identical variants of the nucleotide sequence, c.598_612del and c.1746-20CG, identified in the CAPN3 gene of the proband and her daughter, are in the trans position (compound heterozygous state), causing autosomal recessive calpain-3-related LGMD. This is an example of an incredibly rare pseudodominant inheritance of an autosomal recessive disease, established through indirect evidence that the probands husband is a heterozygous carrier of a nucleotide substitution in the CAPN3 gene.
 Conclusion. It is crucial to examine the marriage partner for heterozygous carrier status of a gene mutation responsible for the disease in family planning and when clarifying the childs prognosis for a patient with an autosomal recessive disease. Considering the existence of a late-onset (after 30 years) LGMD phenotype associated with the CAPN3 gene, differential diagnosis should begin with testing this gene in families with late disease onset.

CAPN3 c.1746‐20C>G variant is hypomorphic for LGMD R1 calpain 3‐related

“…(Evilä et al, 2017). Recently a pseudo‐dominant inheritance of heterozygous c.598_612del and c.1746‐20C>G variants in trans position in the CAPN3 gene has been reported in a Russian family (Sharkova et al, 2021). Both mother and daughter carried both variants, whereas other family members carried only one of the variants and were asymptomatic.…”