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

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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.1746-20C>G, 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 proband’s 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 child’s 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.

About the authors

Inna V. Sharkova

Research Centre for Medical Genetics

Author for correspondence.
Email: sharkova-inna@rambler.ru
ORCID iD: 0000-0002-5819-4835

Cand. Sci. (Med.), leading researcher, Scientific advisory department

Russian Federation, 115522, Russia, Moscow, Moskvorechie str., 1.

Maria V. Bulakh

Research Centre for Medical Genetics

Email: sharkova-inna@rambler.ru
ORCID iD: 0000-0002-8674-7230

Cand. Sci. (Med.), researcher, DNA diagnostics laboratory

Russian Federation, 115522, Russia, Moscow, Moskvorechie str., 1.

Liudmila А. Bessonova

Research Centre for Medical Genetics

Email: sharkova-inna@rambler.ru
ORCID iD: 0000-0002-5946-4577

geneticist, Advisory department

Russian Federation, 115522, Russia, Moscow, Moskvorechie str., 1.

Olga A. Shchagina

Research Centre for Medical Genetics

Email: sharkova-inna@rambler.ru
ORCID iD: 0000-0003-4905-1303

Cand. Sci. (Med.), leading researcher, DNA diagnostics laboratory

Russian Federation, 115522, Russia, Moscow, Moskvorechie str., 1.

Elena L. Dadaly

Research Centre for Medical Genetics

Email: sharkova-inna@rambler.ru
ORCID iD: 0000-0001-5602-2805

D. Sci. (Med.), Prof., Head, Scientific advisory department

Russian Federation, 115522, Russia, Moscow, Moskvorechie str., 1.


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Copyright (c) 2021 Sharkova I.V., Bulakh M.V., Bessonova L.А., Shchagina O.A., Dadaly E.L.

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