**Clinical spectrum and genetic variations ofLMNA-related muscular dystrophies in a large cohort of Chinese patients**

Fan, Yanbin
Tan, Dandan
Song, Danyu
Zhang, Xu
Chang, Xingzhi
Wang, Zhaoxia
Zhang, Cheng
Chan, Sophelia Hoi-Shan
Wu, Qixi
Wu, Liwen
Wang, Shuang
Yan, Hui
Ge, Lin
Yang, Haipo
Mao, Bing
Bönnemann, Carsten
Liu, Jingying
Wang, Suxia
Yuan, Yun
Wu, Xiru
Zhang, Hong
Xiong, Hui

¹Department of Pediatrics, Peking University First Hospital, Beijing, China,
²Department of Neurology, Jiujiang University Clinical Medical College, Jiujiang University Hospital, Jiujiang, Jiangxi, China,
³Center of Ultrastructural Pathology, Lab of Electron Microscopy, Peking University First Hospital, Beijing, China,
⁴Department of Neurology, Peking University First Hospital, Beijing, China,
⁵Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China,
⁶Department of Pediatrics & Adolescent Medicine, The University of Hong Kong Queen Mary Hospital, Hong Kong, China,
⁷School of Life Sciences, Peking University, Beijing, China,
⁸Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China,
⁹Department of Neurology, Wuhan Children's Hospital, Wuhan, Hubei, China,
¹⁰Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA,
¹¹Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Peking University Health Science Centre, Beijing, China,

Correspondence to Dr Hui Xiong, Department of Pediatrics, Peking University First Hospital, Beijing 100034, China; e-mail; [email protected]; Dr Hong Zhang, Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Peking University Health Science Center, Beijing, China; e-mail; [email protected]

Received November 01, 2019; revision received April 11, 2020; Accepted May 02, 2020; previously published online June 22, 2020

Journal of Medical Genetics 58(5):p 326-333, May 2021. | DOI: 10.1136/jmedgenet-2019-106671

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.