Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Department of Statistics and Probability, Faculty of Informatics and Statistics, University of Economics, Prague, Czech Republic.
Mol Genet Genomic Med. 2023 Jun;11(6):e2154. doi: 10.1002/mgg3.2154. Epub 2023 Feb 24.
Congenital myasthenic syndromes (CMSs) are characterized by hypotonia, episodic apnea, muscle weakness, ptosis and generalized fatigability. CMS type 20 (CMS20) is a rare disorder caused by variants in SLC5A7. In contrast to most other CMSs, CMS20 is also associated with neurodevelopmental disorders (NDDs). Only 19 patients from 14 families have been reported so far.
We studied a 12-year-old boy with symptoms manifested at six weeks of age. Later, he also showed speech delay, moderate intellectual disability and autism. Analysis of CMS genes known at the time of clinical diagnosis yielded no results. Trio exome sequencing (ES) was performed.
ES revealed compound heterozygosity for two SLC5A7 variants, p.(Asn431Lys) and p.(Ile291Thr). While the first variant was absent from all databases, the second variant has already been described in one patient. In silico analysis of known pathogenic SLC5A7 variants showed that variants with a higher predicted deleteriousness may be associated with earlier onset and increased severity of neuromuscular manifestations.
Our patient confirms that CMS20 can be associated with NDDs. The study illustrates the strength of ES in deciphering the genetic basis of rare diseases, contributes to characterization of CMS20 and suggests trends in genotype-phenotype correlation in CMS20.
先天性肌无力综合征（CMSs）的特征是肌张力低下、发作性呼吸暂停、肌无力、眼睑下垂和全身易疲劳。CMS 型 20（CMS20）是一种由 SLC5A7 变异引起的罕见疾病。与大多数其他 CMSs 不同，CMS20 还与神经发育障碍（NDDs）有关。迄今为止，仅从 14 个家庭中报道了 19 名患者。
我们研究了一名 12 岁男孩，他在 6 周大时出现症状。后来，他还表现出言语迟缓、中度智力残疾和自闭症。在临床诊断时分析已知的 CMS 基因未得出结果。进行了三核苷酸外显子组测序（ES）。
ES 显示 SLC5A7 两种变异的复合杂合性，p.(Asn431Lys)和 p.(Ile291Thr)。虽然第一个变异在所有数据库中都不存在，但第二个变异已经在一名患者中描述过。对已知致病性 SLC5A7 变异的计算机分析表明，预测的致病变异程度较高的变异可能与神经肌肉表现的更早发病和更严重程度相关。
我们的患者证实 CMS20 可与 NDDs 相关。该研究说明了 ES 在解析罕见疾病遗传基础方面的优势，有助于 CMS20 的特征描述，并提示 CMS20 中基因型-表型相关性的趋势。
