PDF(Pubmed)
Abstract：
Leukodystrophies are a diverse group of genetically established disorders categorized by unusual white matter changes on brain imaging. Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect myelin sheath development in the brain. These disorders are categorized as developmental delay, spasticity, hypotonia, and intellectual disabilities. We describe a patient with developmental delay, cerebellar ataxia, spasticity, hypotonia, and intellectual disability from a healthy family member. Whole exome sequencing (WES) was performed to identify causative variants, which were further analyzed by bioinformatic analysis. WES was performed, and Sanger sequencing-based segregation analysis confirmed the presence of the homozygous missense variants of NM_203290.3 c.934T > C p.Ser312Pro of RNA polymerase I and III subunit C (POLR1C) gene in this patient and heterozygous variant in the unaffected carrier father and mother, supporting the pathogenicity and inheritance pattern of this variant. Furthermore, the variant identified by WES was validated in healthy controls (n = 100) using Sanger sequencing analysis. Finally, our study explained the important use of WES in disease diagnosis and provided further evidence that the variant in the POLR1C gene may play an important role in the development of hypomyelinating leukodystrophy in Saudi families.
摘要：
脑白质营养不良是一组不同的遗传确定的疾病，通过脑成像上不寻常的白质变化进行分类。低髓鞘化性脑白质营养不良(HLD)是一组影响脑中髓鞘发育的神经发育障碍。这些疾病被归类为发育迟缓，痉挛,低张力,和智力障碍。我们描述了一个发育迟缓的病人，小脑共济失调,痉挛,低张力,和健康家庭成员的智力残疾。进行全外显子组测序（WES）以鉴定致病变异，通过生物信息学分析进一步分析。进行了WES，和基于Sanger测序的分离分析证实，该患者中存在RNA聚合酶I和III亚基C（POLR1C）基因的NM_203290.3c.934T>Cp.Ser312Pro的纯合错义变体，以及未受影响的携带者父亲和母亲中的杂合变体，支持该变体的致病性和遗传模式。此外，使用Sanger测序分析在健康对照(n=100)中验证了通过WES鉴定的变异体.最后,我们的研究解释了WES在疾病诊断中的重要用途,并提供了进一步的证据,证明POLR1C基因的变异可能在沙特家族骨髓过细性脑白质营养不良的发展中起重要作用.
