Table_1_Case report: Adult-onset limb girdle muscular dystrophy in sibling pair due to novel homozygous LAMA2 missense variant.xlsx

Recessive pathogenic variants in the laminin subunit alpha 2 (LAMA2) gene cause a spectrum of disease ranging from severe congenital muscular dystrophy to later-onset limb girdle muscular dystrophy (LGMDR23). The phenotype of LGMDR23 is characterized by slowly progressive proximal limb weakness, contractures, raised creatine kinase, and sometimes distinctive cerebral white matter changes and/or epilepsy. We present two siblings, born to consanguineous parents, who developed adult-onset LGMDR23 associated with typical cerebral white matter changes and who both later developed dementia. The male proband also had epilepsy and upper motor neuron signs when he presented at age 72. Merosin immunohistochemistry and Western blot on muscle biopsies taken from both subjects was normal. Whole exome sequencing revealed a previously unreported homozygous missense variant in LAMA2 [Chr6(GRCh38):g.129297734G>A; NM_000426.3:c.2906G>A; p.(Cys969Tyr)] in the proband. The same homozygous LAMA2 variant was confirmed by Sanger sequencing in the proband's affected sister. These findings expand the genotypic and phenotypic spectrum of LGMDR23.

隐性致病性变异位于层粘连蛋白亚基α2（LAMA2）基因中，可导致从严重先天性肌营养不良症至晚发性肢体围裙样肌营养不良症（LGMDR23）等一系列疾病。LGMDR23的临床特征表现为缓慢进展的近端肢体无力、关节挛缩、肌酸激酶升高，有时伴有独特的脑白质改变及/或癫痫。我们报道了两位近亲结婚的夫妇所生的一对兄妹，他们于成年期发生LGMDR23，并伴有典型的脑白质改变，两人后均发展为痴呆。男性受试者在72岁时出现癫痫和上运动神经元体征。对两位受试者进行的肌活检的髓蛋白免疫组化和Western blot分析结果正常。全外显子测序发现，受试者LAMA2基因中存在一个此前未曾报道的同义突变[染色体6（GRCh38）：g.129297734G>A；NM_000426.3:c.2906G>A；p.(Cys969Tyr)]。通过Sanger测序，在同一受试者的受影响妹妹中也确认了相同的LAMA2同义突变。这些发现扩展了LGMDR23的基因型和表型谱系。