Data_Sheet_1_Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene.doc

BackgroundSevere hyperlipidemia is characterized by markedly elevated blood triglyceride levels and severe early-onset cardiovascular diseases, pancreatitis, pancreatic necrosis or persistent multiple organ failure if left untreated. It is a rare autosomal recessive metabolic disorder originated from the variants of lipoprotein lipase gene, and previous studies have demonstrated that most cases with severe hyperlipidemia are closely related to the variants of some key genes for lipolysis, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1. Meanwhile, other unidentified causes also exist and are equally worthy of attention.
MethodsThe 29-day-old infant was diagnosed with severe hyperlipidemia, registering a plasma triglyceride level as high as 25.46 mmol/L. Whole exome sequencing was conducted to explore the possible pathogenic gene variants for this patient.
ResultsThe infant was put on a low-fat diet combined with pharmacological therapy, which was successful in restraining the level of serum triglyceride and total cholesterol to a low to medium range during the follow-ups. The patient was found to be a rare novel homozygous duplication variant-c.45_48dupGCGG (Pro17Alafs*22) in GPIHBP1 gene-leading to a frameshift which failed to form the canonical termination codon TGA. The mutant messenger RNA should presumably produce a peptide consisting of 16 amino acids at the N-terminus, with 21 novel amino acids on the heels of the wild-type protein.
ConclusionsOur study expands on the spectrum of GPIHBP1 variants and contributes to a more comprehensive understanding of the genetic diagnosis, genetic counseling, and multimodality therapy of families with severe hyperlipidemia. Our experience gained in this study is also contributory to a deeper insight into severe hyperlipidemia and highlights the importance of molecular genetic tests.

背景：严重高脂血症以血液甘油三酯水平显著升高为特征，若未接受治疗，可引发严重早发性心血管疾病、胰腺炎、胰腺坏死或持续性多器官功能衰竭。该病是一种罕见的常染色体隐性代谢紊乱疾病，由脂蛋白脂酶基因（lipoprotein lipase gene, LPL）变异所致；既往研究表明，多数严重高脂血症病例与脂解关键基因的变异密切相关，如LPL、载脂蛋白C2（APOC2）、载脂蛋白A5（APOA5）、脂蛋白脂肪酶成熟因子1（LMF1）以及GPIHBP1基因。此外，尚有部分未明确的致病原因，同样值得关注。
方法：本研究纳入1例29日龄的严重高脂血症患儿，其血浆甘油三酯水平高达25.46 mmol/L。研究对该患儿开展全外显子测序（whole exome sequencing），以探究潜在的致病基因变异。
结果：患儿接受低脂饮食联合药物治疗后，随访期间血清甘油三酯与总胆固醇水平均被有效控制在中低范围。检测发现，该患儿携带GPIHBP1基因上1种罕见的新型纯合重复变异c.45_48dupGCGG (Pro17Alafs*22)，该变异可引发移码突变，无法形成典型的终止密码子TGA。推测突变型信使RNA（messenger RNA, mRNA）将编码一段由16个氨基酸组成的N端肽段，其后接野生型蛋白序列，并新增21个氨基酸残基。
结论：本研究拓展了GPIHBP1基因变异的频谱，有助于更全面地理解严重高脂血症家族的遗传诊断、遗传咨询以及多模式治疗方案。本研究获得的临床经验也有助于深化对严重高脂血症的认识，并凸显了分子遗传检测的重要性。