Mohan Shruthi, McNulty Shannon, Thaxton Courtney, Elnagheeb Marwa, Owens Emma, Flowers May, Nunnery Teagan, Self Autumn, Palus Brooke, Gorokhova Svetlana, Kennedy April, Niu Zhiyv, Johari Mridul, Maiga Alassane Baneye, Macalalad Kelly, Clause Amanda R, Beckmann Jacques S, Bronicki Lucas, Cooper Sandra T, Ganesh Vijay S, Kang Peter B, Kesari Akanchha, Lek Monkol, Levy Jennifer, Rufibach Laura, Savarese Marco, Spencer Melissa J, Straub Volker, Tasca Giorgio, Weihl Conrad C
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
Aix Marseille Univ, INSERM, MMG, U 1251, Marseille, France.
bioRxiv. 2024 May 6:2024.05.03.592369. doi: 10.1101/2024.05.03.592369.
Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD.
The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD.
The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes () were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as Definitive, 4 (11%) as Moderate and 1 (3%) as Limited. Two genes, and , though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD.
The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations.
肢带型肌营养不良症（LGMDs）是一组具有一定程度表型同质性的遗传性异质性常染色体疾病。LGMD的定义为发病年龄>2岁，伴有进行性近端肌无力、血清肌酸激酶水平升高以及肌肉活检显示营养不良特征。大规模平行测序技术的进展导致与LGMD相关的基因数量激增。
临床基因组学肌营养不良症和肌病基因评估专家小组（MDM GCEP，前身为肢带型肌营养不良症GCEP）召开会议，使用临床基因组学基因-疾病临床有效性框架评估支持基因-疾病关系（GDR）的证据强度，以评估31个与LGMD相关的基因。
17个基因的GDR仅为LGMD，而另外14个基因与包括先天性肌无力在内的更广泛表型相关。4个基因基于各自显示显性和隐性遗传模式，被分为两个独立的疾病实体，从而产生了35个GDR。其中，30个（86%）被归类为确定性，4个（11%）为中等，1个（3%）为有限。两个基因， 和 ，虽然确实与肌病相关，但目前没有足够的证据支持它们与LGMD有特定关系。
关于LGMD相关基因临床有效性的专家评审断言为临床医生和分子遗传学家提供了宝贵资源。我们鼓励全球神经肌肉疾病领域的研究人员发表病例水平的数据，以帮助澄清有争议的或新的LGMD关联。
