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.

中文翻译：

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一组 209 例病例中dysferlin病的遗传特征：基因型-表型关系和内部 DysF 结构域的热点。

Dysferlinopathy 是一组由dysferlin 基因（DYSF）变异引起的常染色体隐性肌营养不良症，近端和远端肌肉受累不一。我们进行了DYSF对 200 例疑似患有dysferlinopathy（队列1）的病例进行基因分析，并在129/200例中鉴定出诊断变异，包括19个新变异。为了获得dysferlinopathy的全面遗传谱，我们分析了来自不相关的209个家庭的209个受影响病例的变异数据，其中包括80个先前诊断的病例和129个新诊断的病例（队列2）。在209例中鉴定出的90种变异中，NM_003494.3：c.2997G>T；p.Trp999Cys 是最常见的（96/420；22.9%），其次是 c.1566C>G；p.Tyr522* (45/420; 10.7%) 在等位基因基础上。在 70/209 例 (33.5%) 中发现 p.Trp999Cys，其中 20/104 例 (19.2%) 具有 Miyoshi 肌肉表型和 43/82 例 (52.4%) 具有肢带表型。在对错义变体的分析中，p.Trp992Arg、p.Trp999Arg、p.Trp999Cys、p.Ser1000Phe、p. Arg1040Trp 和 p.Arg1046His 位于内部 DysF 域中，代表 113/160 错义变体 (70.6%)。这个大型队列强调了位于内部 DysF 域的频繁错义变异是我们 209 例病例（> 95%，日本人）队列中的错义变异热点，并暗示了它们作为未来治疗策略目标的潜力。