The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype–phenotype relationship and a hotspot on the inner DysF domain

Abstract

Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by variants in the dysferlin gene (DYSF), with variable proximal and distal muscle involvement. We performed DYSF gene analyses of 200 cases suspected of having dysferlinopathy (Cohort 1), and identified diagnostic variants in 129/200 cases, including 19 novel variants. To achieve a comprehensive genetic profile of dysferlinopathy, we analyzed the variant data from 209 affected cases from unrelated 209 families, including 80 previously diagnosed and 129 newly diagnosed cases (Cohort 2). Among the 90 types of variants identified in 209 cases, the NM_003494.3: c.2997G>T; p.Trp999Cys, was the most frequent (96/420; 22.9%), followed by c.1566C>G; p.Tyr522* (45/420; 10.7%) on an allele base. p.Trp999Cys was found in 70/209 cases (33.5%), including 20/104 cases (19.2%) with the Miyoshi muscular phenotype and 43/82 cases (52.4%) with the limb‐girdle phenotype. In the analysis of missense variants, p.Trp992Arg, p.Trp999Arg, p.Trp999Cys, p.Ser1000Phe, p.Arg1040Trp, and p.Arg1046His were located in the inner DysF domain, representing in 113/160 missense variants (70.6%). This large cohort highlighted the frequent missense variants located in the inner DysF domain as a hotspot for missense variants among our cohort of 209 cases (>95%, Japanese) and hinted at their potential as targets for future therapeutic strategies.

Null variants in DYSF result in earlier symptom onset

“…The most common initial phenotype was Miyoshi myopathy, followed by limb‐girdle muscular dystrophy. This finding was compatible with that observed in previous studies on Japanese patients with dysferlinopathy 22,23 . Our study demonstrated that about one‐fifth of the patients had previously maintained high‐performance levels of physical activities before symptom onset; this finding was compatible with that of a recent large international cohort study 23 .…”

“…Additionally, late clinical onset in the N/M group was associated with both the c.2997G > T and other‐missense variants. Among several previous studies on the genotype–phenotype relationship in dysferlinopathy, three Japanese studies have shown that the c.2997G > T variant is associated with a late clinical onset 18,20,22 . However, other previous studies have shown no definite genotype–phenotype relationship, mainly in Western countries 3,5,14,33,34 .…”

The Role of Autophagy in Skeletal Muscle Diseases

“…Different types of DYSF mutations have been uncovered in LGMD2B and MMD patients, and the most frequently observed pathogenic variant is rs28937581 (c.2997 G > T; p.Trp999Cys) located in a DysF domain (Izumi et al, 2020). Crystal structures of the DysF domain indicate that mutations like p.Arg959Trp, p.Trp999Cys, and p.Arg1046His may disrupt an aromatic/arginine stack motif, leading to instability of the protein (Sula et al, 2014).…”

Deep phenotyping of an international series of patients with late‐onset dysferlinopathy

“…We found a wide variety of variants among the LO patients, without a mutational hotspot. In the Japanese population, the p. Trp999Cys variant has been reported to be associated with a later onset and lower CK values [34] and, more recently, a hotspot of six missense variants was reported in the inner dysfF domain, also in Japanese patients [35] Although we found variants targeting the dysfF domain (14/48 or 26.2%), we were not able to confirm this finding in our primarily Caucasian series as only two patients carried the p. Trp999Cys variant. We found almost double the frequency of missense variants in LO versus EO patients, which has also been recently reported [36] and would support a milder protein disruption of this variant type.…”