Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China; Henan Key Laboratory of Pediatric Inherited & Metabolic Diseases, Henan Children's Hospital, Zhengzhou Hospital of Beijing Children's Hospital, Zhengzhou, China.
Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Gene. 2021 Feb 5;768:145310. doi: 10.1016/j.gene.2020.145310. Epub 2020 Nov 18.
Hyperlipidemia is a group of conditions with abnormally elevated levels of any or all lipids or lipoproteins in the blood. It is highly heterogeneous both genetically and clinically, which contributes to diagnostic challenges and results in many patients to be underdiagnosed and undertreated in China. Precise diagnosis and early management are critical to reduce the incidence of potential coronary artery disease and cardiovascular disease.
We performed a single center study to demonstrate the clinical utility of the genome-first approach by whole exome sequencing (WES) for 12 pediatric patients with abnormal lipids or lipoproteins levels. In vitro experiments were performed in COS-7 cells to further evaluate the biological function of the novel variants. We identified ten pathogenic and likely pathogenic variants and three of them were novel. Molecular cause was uncovered in five (41.7%) patients including three lipoprotein lipase deficiency patients, one hypercholesterolemia patient and one sitosterolemia patient. We also found three patients with rare variants of uncertain significance. Copy number variant (CNV) analysis with WES data did not reveal any potential hyperlipidemia related CNVs in all patients.
We expanded the mutation and phenotype spectra of familial hyperlipidemia. Our study demonstrated the effectiveness of genome-first approach for evaluation pediatric hyperlipidemia patients and showed that WES can be used as the first-tier test for patients with suspected Mendelian hyperlipidemia disorder.
高脂血症是一组血液中任何或所有脂质或脂蛋白水平异常升高的病症。它在遗传和临床上都高度异质，这导致了诊断上的挑战，使得中国许多患者被漏诊和治疗不足。精确的诊断和早期管理对于降低潜在的冠心病和心血管疾病的发生率至关重要。
我们进行了一项单中心研究，通过全外显子组测序（WES）对 12 名血脂或脂蛋白水平异常的儿科患者进行了基因组优先方法的临床实用性研究。在 COS-7 细胞中进行了体外实验，以进一步评估新变体的生物学功能。我们鉴定出 10 个致病性和可能致病性的变体，其中 3 个是新的。在 5 名（41.7%）患者中发现了分子病因，包括 3 名脂蛋白脂肪酶缺乏症患者、1 名高胆固醇血症患者和 1 名甾醇血症患者。我们还发现了 3 名具有不确定意义的罕见变异患者。WES 数据的拷贝数变异（CNV）分析未在所有患者中发现任何潜在的与高脂血症相关的 CNV。
我们扩展了家族性高脂血症的突变和表型谱。我们的研究证明了基因组优先方法对儿科高脂血症患者评估的有效性，并表明 WES 可作为疑似孟德尔高脂血症患者的一线检测方法。
