Pediatrics Department, Cardiogenetics Unit, College of Medicine, Taibah University, Al-Madinah, Kingdom of Saudi Arabia.
Eur Rev Med Pharmacol Sci. 2019 Feb;23(4):1710-1721. doi: 10.26355/eurrev_201902_17133.
Pediatric familial dilated cardiomyopathy (DCM) is a rare and severe heart disease. The genetics of familial DCM are complex and include over 100 known disease-causing genes, but many causative genes are unknown. We aimed to identify the causative gene for DCM in a consanguineous Saudi Arabian family with affected family members and a history of sudden death.
Affected (two children) and unaffected (one sibling and the mother) family members were screened by next-generation sequencing (NGS) for 181 candidate DCM genes and underwent metabolic screening. Fifty-seven clinically annotated controls and 46 DCM cases were then tested for the identified mutation. In silico structural and functional analyses including protein modeling, structure prediction and dynamic simulations were performed.
A homozygous missense mutation in exon 15 of the acyl-CoA dehydrogenase very long chain gene (ACADVL; chr17:7127303; G>A) was identified in affected subjects that substituted histidine for arginine at codon 450 (p.R450H). The variant was heterozygous in the mother and unaffected sister. The mutation was absent in 57 clinically annotated controls and 48 pediatric DCM cases. The mutation was predicted to cause a significant and deleterious change in the ACADVL protein structure that affected drug binding, stability, and conformation. Metabolic screening confirmed VLCAD deficiency in affected individuals.
The ACADVL R450H mutation is an uncommon cause of the DCM phenotype that appears to be autosomal recessive. Targeted NGS is useful for identifying the causative mutation(s) in familial DCM of unknown genetic cause.
儿科家族性扩张型心肌病（DCM）是一种罕见且严重的心脏病。家族性 DCM 的遗传学较为复杂，包括 100 多个已知的致病基因，但许多致病基因尚不清楚。我们旨在鉴定一个沙特阿拉伯的近亲家系中 DCM 的致病基因，该家系中有受影响的家庭成员和猝死的病史。
受影响的（两个孩子）和未受影响的（一个兄弟姐妹和母亲）家庭成员通过下一代测序（NGS）对 181 个候选 DCM 基因进行筛查，并进行代谢筛查。然后对鉴定出的突变对 57 个临床注释对照和 46 个 DCM 病例进行检测。进行了包括蛋白质建模、结构预测和动态模拟在内的结构和功能分析。
在受影响的个体中发现酰基辅酶 A 脱氢酶长链基因（ACADVL；chr17:7127303；G>A）外显子 15 中的纯合错义突变，导致密码子 450 处的组氨酸取代精氨酸（p.R450H）。该变体在母亲和未受影响的姐妹中为杂合子。该突变在 57 个临床注释对照和 48 个儿科 DCM 病例中均不存在。该突变被预测会导致 ACADVL 蛋白结构的显著和有害变化，从而影响药物结合、稳定性和构象。代谢筛查证实了受影响个体中存在 VLCAD 缺乏。
ACADVL R450H 突变是 DCM 表型的一个不常见原因，似乎是常染色体隐性遗传。靶向 NGS 可用于鉴定遗传原因不明的家族性 DCM 的致病突变。
