Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive disorder characterized mainly by symmetrical and selective atrophy of the proximal limb muscles. It derives from defects in the human CAPN3 gene, which encodes the skeletal muscle-specific member of the calpain family. This report represents a compilation of the mutations and variants identified so far in this gene. To date, 97 distinct pathogenic calpain 3 mutations have been identified (4 nonsense mutations, 32 deletions/insertions, 8 splice-site mutations, and 53 missense mutations), 56 of which have not been described previously, together with 12 polymorphisms and 5 nonclassified variants. The mutations are distributed along the entire length of the CAPN3 gene. Thus far, most mutations identified represent private variants, although particular mutations have been found more frequently. Knowledge of the mutation spectrum occurring in the CAPN3 gene may contribute significantly to structure/function and pathogenesis studies. It may also help in the design of efficient mutation-screening strategies for calpainopathies.

There is still around 50% of the familial breast cancer (BC) cases with an undefined genetic cause, here we have used next-generation sequencing (NGS) technology to identify new BC susceptibility genes. This approach has led to the identification of RECQL5, a member of RECQL-helicases family, as a new BC susceptibility candidate, which deserves further study. We have used a combination of whole exome sequencing in a family negative for mutations in BRCA1/2 throughout (BRCAX), in which we found a probably deleterious variant in RECQL5, and targeted NGS of the complete coding regions and exon-intron boundaries of the candidate gene in 699 BC Spanish BRCAX families and 665 controls. Functional characterization and in silico inference of pathogenicity were performed to evaluate the deleterious effect of detected variants. We found at least seven deleterious or likely deleterious variants among the cases and only one in controls. These results prompt us to propose RECQL5 as a gene that would be worth to analyze in larger studies to explore its possible implication in BC susceptibility. K E Y W O R D S breast cancer, germline pathogenic variant, RECQL5, whole exome sequencing Human Mutation. 2019;40:566-577. wileyonlinelibrary.com/journal/humu 566 |

The lack of additional mutations in our H63D homozygotes suggests that this genotype could be the primary cause of iron overload in these patients. Despite our results, we cannot entirely discount the possibility that one or more genetic modifier factor exists, simply because we were unable to find it, although there was a precedent in the HFE gene. Genetic modifier factors have been described for C282Y mutations in the HFE gene, but at the present time they have never been reported in H63D homozygotes.

Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, lead to recessive and dominant myotonia congenita. We report four novel mutations identified in this gene, after clinical, electromyographic, and genetic studies performed on 13 unrelated families. Two of the four mutations (2512insCTCA and A218T) were identified in families with Thomsen's disease, one (Q658X) in a family with Becker's disease, and the fourth (R669C) in a presumably sporadic patient with the Becker phenotype. Although identification of the mutations allows us to establish some genotype/phenotype correlations, this does not wholly account for the clinical heterogeneity and the inheritance patterns of the disease.

Limb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive muscular dystrophy with primary γ-sarcoglycan deficiency, generally associated with a severe clinical course. γ-sarcoglycan, a 35 kDa dystrophinassociated protein, is encoded by a single gene on chromosome 13q12. Six different mutations have been described in that gene, and it has been proved they are the origin of the disease. One of these mutations (C283Y), a G ® A transition in codon 283, was recently and exclusively identified in Gypsy patients from different European countries. We report the study of 11 LGMD2C unrelated Gypsy families (nine Spanish and two Portugese). The muscle biopsies of these patients showed a drastically decreased immunostaining with α and γ-sarcoglycan antibodies. All the patients were homozygous for C283Y missense mutation, and all affected chromosomes (patients and heterozygous relatives) carried the allele 5 (112 bp) of the intragenic microsatellite D13S232. Unexpectedly, this allele is most frequent in the Caucasian population but not in the normal Gypsy population. The clinical severity of all patients demonstrates that the C283Y missense mutation in a homozygous state causes a severe LGMD2C (DMD-like). The elevated number of families ascertained let us assume that LGMD2C is prevalent in the Gypsy population, and that all the families have inherited a founding mutation.