PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, COL6A3) 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, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, COL6A3) 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, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD.
UNASSIGNED: 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.
摘要：
引言肢带肌营养不良(LGMDs)是一组遗传异质性的常染色体疾病,具有一定程度的表型同质性。LGMD被定义为发病年龄>2岁，进行性近端无力，血清肌酸激酶水平升高和肌肉活检的营养不良特征。大规模平行测序的进展导致与LGMD相关的基因激增。方法ClinGen肌营养不良和肌病基因策展专家小组（MDMGCEP，以前的四肢环带肌营养不良GCEP）召开会议，以使用ClinGen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，以评估与LGMD相关的31个基因。结果GDR完全是17个基因的LGMD，而另外14个基因与更广泛的表型相关，包括先天性虚弱。四个基因（CAPN3，COL6A1，COL6A2，COL6A3）被分为两个独立的疾病实体，基于每个显示显性和隐性遗传模式，导致35个GDR的策展。其中,30人(86%)被归类为确定性，4（11%）为中度，1（3%）为有限。两个基因,POMGNT1和DAG1，虽然明确与肌病有关，目前没有足够的证据支持与LGMD的关系。结论专家审查的关于LGMDs中涉及的基因的临床有效性的断言为临床医生和分子遗传学家提供了宝贵的资源。我们鼓励全球神经肌肉界发布病例级数据，以帮助澄清有争议或新颖的LGMD关联。
