Article Text
Abstract
Background LMNA-related muscular dystrophy is caused by mutations in LMNA gene. We aimed to identify genetic variations and clinical features in a large cohort of Chinese patients with LMNA mutations in an attempt to establish genotype-phenotype correlation.
Methods The clinical presentations of patients with LMNA-related muscular dystrophy were recorded using retrospective and prospective cohort study. LMNA mutation analysis was performed by Sanger sequencing or next-generation sequencing. Mosaicism was detected by personal genome machine amplicon deep sequencing for mosaicism.
Results Eighty-four patients were identified to harbour LMNA mutations. Forty-one of those were diagnosed with LMNA-related congenital muscular dystrophy (L-CMD), 32 with Emery-Dreifuss muscular dystrophy (EDMD) and 11 with limb-girdle muscular dystrophy type 1B (LGMD1B). We identified 21 novel and 29 known LMNA mutations. Two frequent mutations were identified: c.745C>T and c.1357C>T. A correlation between the location of mutation and the clinical phenotype was observed: mutations affecting the head and coil 2A domains mainly occurred in L-CMD, while the coil 2B and Ig-like domains mainly related to EDMD and LGMD1B. We found somatic mosaicism in one parent of four probands. Muscle biopsies revealed 11 of 20 biopsied L-CMD exhibited inflammatory changes, and muscle cell ultrastructure showed abnormal nuclear morphology.
Conclusions Our detailed clinical and genetic analysis of 84 patients with LMNA-related muscular dystrophy expands clinical spectrum and broadens genetic variations caused by LMNA mutations. We identified 21 novel and 29 known LMNA mutations and found two frequent mutations. A correlation between the location of mutation and the clinical severity was observed. Preliminary data suggested that low-dose corticosteroid treatment may be effective.
- clinical genetics
- muscle disease
- neuromuscular disease
Data availability statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Data availability statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
Footnotes
Contributors YF and DT conducted the patient follow-up and wrote the first draft of the manuscript. DS, LG and H Yang collected the clinical and laboratory data and followed up on patients. JL took part in drafting the manuscript. XZ and SuW analysed the muscle cell ultrastructure of the patients. ZW, YY, CZ, SH-SC, LW and BM provided patients data as multicentre participants. XC analysed muscle biopsies of the patients and ShW conducted and analysed EMG. H Yan helped analyse the cardiac data of all the patients. CB, XW, HZ and HX took part in study design and critical discussions. HZ and HX conceived the study and participated in its design and coordination and helped to draft the manuscript. All authors participated in drafting and critically revising the article and approved the final manuscript.
Funding This work was supported by the National Key Research and Development Program of China (No. 2016YFC0901505); National Natural Science Foundation of China (No. 81571220); Beijing key laboratory of molecular diagnosis and study on pediatric genetic diseases (No. BZ0317); Peking University Medicine Seed Fund for Interdisciplinary Research supported by the Fundamental Research Funds for the Central Universities (No. BMU2017MX003, BMU2018MX001); Natural Science Foundation of Jiangxi Province (No. 20161BAB215192).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.