目的:异质核核糖核蛋白A1参与核酸稳态功能。编码基因HNRNPA1与几种神经肌肉疾病有关,包括肌萎缩侧索硬化样表型,远端遗传性运动神经病变,多系统蛋白病,和各种肌病。我们报告了两个不相关的个体,其单等位基因终止丢失变体影响HNRNPA1的相同密码子。
方法:根据批准的机构方案招募两名未解决的青少年起病肌病患者。收集表型数据并进行遗传分析,包括全外显子组测序(WES)。
结果:两个先证者(MNOT002-01和K1440-01)在青春期早期表现出类似的缓慢进行性肢体和面部无力发作。K1440-01表现为面部无力,翼状肩胛骨,血清肌酸激酶(CK)水平升高,轻微的颈部无力。MNOT002-01还表现出CK水平升高以及面部无力,心肌病,呼吸功能障碍,漏斗胸,轻微僵硬的脊柱,和步行的损失。股四头肌活检,K1440-01显示圆形肌纤维,纤维直径的轻微变化,和2型纤维肥大,而MNOT002-01显示有边缘的空泡。HNRNPA1中的单等位基因终止丢失变体被鉴定为两个先证者:c.1119A>Cp。*373Tyrext*6(K1440-01)和c.1118A>Cp。*373Serext*6(MNOT002-01)影响相同的密码子,并且都被预测会导致在替代终止密码子之前添加六个氨基酸。
结论:我们的先证者中的两种止损变异都可能具有致病性。我们的发现有助于HNRNPA1致病变体的疾病表征。应在散发性或显性青少年肌病的未解决病例的临床诊断测试中筛选该基因。
OBJECTIVE: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1.
METHODS: Two individuals with unsolved juvenile-onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole-exome sequencing (WES).
RESULTS: The two probands (MNOT002-01 and K1440-01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440-01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002-01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440-01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002-01 displayed rimmed vacuoles. Monoallelic stop-loss variants in HNRNPA1 were identified for both probands: c.1119A>C p.*373Tyrext*6 (K1440-01) and c.1118A>C p.*373Serext*6 (MNOT002-01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon.
CONCLUSIONS: Both stop-loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile-onset myopathy.