Background Limb-girdle muscular dystrophy type R1 (LGMDR1) can be caused by recessive CAPN3 mutations accounting for the majority of LGMD. To date, no systemic evaluation has been performed to analyse the detrimental and normal mutations on CAPN3 and its hotspots.
Methods CAPN3 variants (n=112) from a total of 124 patients with LGMDR1 recruited in four centres in China were retrospectively analysed. Then external CAPN3 variants (n=2031) from online databases were integrated with our Chinese cohort data to achieve a worldwide perspective on CAPN3 mutations. According to their related phenotypes (LGMDR1 or normal), we analysed consequence, distribution, ethnicity and severity scores of CAPN3 mutations.
Results Two hotspot mutations were identified including c.2120A>G in Chinese population and c.550del in Europe. According to the integrated dataset, 521 mutations were classified as LGMDR1-related and converged on exons 1, 10, 5, 22 and 13 of CAPN3. The remaining 1585 variants were classified as normal-population related. The deleterious ratio of LGMDR1-relevant variants to total variants in each population was 0.26 on average with a maximum of 0.35 in Finns and a minimum of 0.21 in South Asians. Severity evaluation showed that Chinese LGMDR1-related variants exhibited a higher risk (Combined Annotation Dependent Depletion score +1.10) than that from database patients (p<0.001).
Conclusions This study confirmed two hotspots and LGMDR1-related CAPN3 variants, highlighting the advantages in using a data-based comprehensive analysis to achieve a genetic landscape for patients with LGMDR1.
- neuromuscular diseases
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HZ and YZ contributed equally.
Contributors All authors contributed to the development of the project and data collection and management. SL and YY devised the study. HZ and YZ analysed the data and wrote the first draft of the manuscript. JLu, ZW, JHu, CY and CZ revised the manuscript. All authors read and approved the final version of the manuscript.
Funding This work was supported by financial grants from the National Key Research and Development Program of China (No.2016YFC0901504), the National Natural Science Foundation of China (No. 81701236 and 81870988), and Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX03) and ZJLab.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by Medical Ethics Committee of Huashan Hospital, Shanghai Medical College, Fudan University (approval no. 2019-409).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as online supplemental information. The variants of Chinese LGMD2A cohort have been collected in online supplemental file 2. Other datasets used and analysed during the study are available from the corresponding author on reasonable request.
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