Department of Pathology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia.
Genes (Basel). 2024 Oct 30;15(11):1405. doi: 10.3390/genes15111405.
Bethlem myopathy is a rare genetic disease caused by a variant mapped to 21q22, which harbors the collagen type VI alpha 2 chain and collagen type VI alpha 1 chain ( genes, and 2q37, which harbors the collagen type VI alpha 3 chain () gene. Disease onset can occur at any age, and the symptoms are related to those of muscular dystrophy. Since Bethlem myopathy is a rare disease, no previous studies have been conducted in Arab countries, including Saudi Arabia. Its variable presentation of nonspecific muscular contractions and severity represents a diagnostic dilemma. Here, we report a Saudi pediatric patient, who is 9 years old (proband), brought to the pediatric clinic of King Saud's Hospital by his mother. The boy presented with difficulty standing, walking, and running with his classmates and unaffected siblings. He has a younger sibling, aged 6 years old, who reported having a limping gait and difficulty bending his right knee. Laboratory results for the proband were unremarkable except for a slight increase in creatine kinase (CK). Whole-exome sequencing (WES) was performed for five family members, including the proband and his symptomatic brother, their mother and two asymptomatic siblings. A very rare 3' splice site acceptor intronic variant, NM_001849.4: c.1817-3C>G, located three nucleotides before exon 25, was identified in . Bioinformatics tools (SpliceAI, dbscSNV, FATHMM-MKL, and MaxEntScan) predicted this variant as pathogenic. The proband and his 6-year-old sibling presented a homozygous genotype for the variant, whereas the mother and one asymptomatic sibling were heterozygous, and the other sibling carried homozygous wild-type alleles. This is the first study to report a case of Bethlem myopathy confirmed by WES in Saudi Arabia and all Arab nations. The identified variant is rare, and its segregation pattern suggests autosomal recessive inheritance. The segregation pattern and bioinformatics tool results may qualify this variant to be annotated as pathogenic, addressing the reported uncertainty of its classification. Our findings contribute to linking and filling the knowledge gap of diagnosing and managing patients with collagen VI-related myopathies, providing greater clinical and genetic understanding to the existing knowledge.
贝氏肌病是一种罕见的遗传性疾病，由位于 21q22 上的变异引起，该区域包含胶原 VI 型 α2 链和胶原 VI 型 α1 链（基因，以及位于 2q37 上的胶原 VI 型 α3 链（基因。疾病发作可发生在任何年龄，症状与肌肉营养不良有关。由于贝氏肌病是一种罕见疾病，以前在包括沙特阿拉伯在内的阿拉伯国家没有进行过研究。其非特异性肌肉收缩和严重程度的多变表现构成了诊断难题。在这里，我们报告了一名沙特儿科患者，他 9 岁（先证者），由他的母亲带到沙特国王医院的儿科诊所。该男孩出现与同学和未受影响的兄弟姐妹一起站立、行走和跑步困难。他有一个 6 岁的弟弟，报告说步态跛行，右膝难以弯曲。先证者的实验室结果除肌酸激酶（CK）略有升高外无异常。对包括先证者和有症状的弟弟、他们的母亲和两个无症状的兄弟姐妹在内的五个家庭成员进行了全外显子组测序（WES）。在 基因中发现了一个非常罕见的 3' 剪接位点接受体内含子变异，NM_001849.4：c.1817-3C>G，位于外显子 25 之前三个核苷酸处。生物信息学工具（SpliceAI、dbscSNV、FATHMM-MKL 和 MaxEntScan）预测该变体为致病性。先证者和他 6 岁的弟弟携带该变体的纯合基因型，而母亲和一个无症状的兄弟姐妹为杂合基因型，另一个兄弟姐妹携带纯合野生型等位基因。这是第一项在沙特阿拉伯和所有阿拉伯国家通过 WES 报告贝氏肌病病例的研究。该变体非常罕见，其分离模式提示常染色体隐性遗传。分离模式和生物信息学工具结果可能使该变体有资格被注释为致病性，解决了其分类的不确定性报告。我们的研究结果有助于将与胶原 VI 相关的肌病患者的诊断和管理相关知识联系起来并填补空白，为现有知识提供更深入的临床和遗传理解。
