Abstract
Limb–girdle muscular dystrophy type R1 (LGMDR1) is caused by mutations in CAPN3 and is the most common type of recessive LGMD. Even with the use of whole-exome sequencing (WES), only one mutant allele of CAPN3 is found in a significant number of LGMDR patients. This points to a role of non-coding, intronic or regulatory, sequence variants in the disease pathogenesis. Targeted sequencing of the whole CAPN3 gene including not only intronic, 3′ and 5′ UTRs but also potential regulatory regions was performed in 27 patients suspected with LGMDR1. This group included 13 patients with only one mutated CAPN3 allele detected previously with exome sequencing. A second rare variant in the non-coding part of CAPN3 was found in 11 of 13 patients with previously identified single mutation. Intronic mutations were found in 10 cases, with c.1746-20C>G variant present in seven patients. In addition, a large deletion of exons 2–8 was found in one patient. In the patients with no causative mutation previously found, we detected rare CAPN3 variants in 5 out of 10 patients and in two of them in a compound heterozygous state. Rare variants within putative regulatory sequences distant from the CAPN3 gene were found in 15 patients, although in 11 of these cases, other variants are deemed causative. The results indicate that intronic mutations are common in Polish LGMDR patients, and testing for non-coding mutations in CAPN3 should be performed in apparently single heterozygous patients.
Highlights
Limb–girdle muscular dystrophies (LGMD) are a group of hereditary progressive diseases of the skeletal muscle
In the whole-exome sequencing (WES)-CAPN3het subgroup, a second mutation in the CAPN3 gene was found in 12/13 patients, including the probands carrying putative pathogenic mutations in other genes
This study demonstrates the relative prevalence of this variant among apparently heterozygous LGMDR1 patients
Summary
Limb–girdle muscular dystrophies (LGMD) are a group of hereditary progressive diseases of the skeletal muscle. Their genetic background is heterogeneous with about 30 different loci known to cause the disease. While LGMDs are rare diseases, with an estimated morbidity about 0.2–4 per 100,000 individuals (van der Kooi et al, 1996; Norwood et al, 2009), autosomal recessive LGMDR1 (in previous classification LGMD2A), caused by mutations in CAPN3, is one of the most frequent among them. In many European countries, including Poland, it is the most common form of an autosomal recessive LGMD (van der Kooi et al, 1996; Moore et al, 2006; Fanin et al, 2009; Fichna et al, 2018). The disease usually leads to significant disability, and loss of ambulation after 10–20 years is common
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