Department of Forensic Medicine, Faculty of Health Sciences, Aarhus University, Brendstrupgaardsvej 100, 8200, Aarhus N, Denmark.
Int J Legal Med. 2013 Jan;127(1):139-44. doi: 10.1007/s00414-011-0658-2. Epub 2012 Jan 6.
The aim of this investigation was to identify pathogenic variants of the ryanodine receptor 2 (RYR2) gene in a cohort of persons aged 0-40 years who died of sudden unexpected death syndrome (SUD), including a cohort of infants who died of sudden infant death syndrome (SIDS). We genetically screened 29 of the 105 exons of the RYR2 gene associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 74 cases of SUD without reported structural abnormalities of the heart. Cases were selected from the case database at the Institute of Forensic Medicine, and subsequent mutational screening by DNA sequencing was performed to detect variants in DNA samples extracted from blood samples of deceased persons. A total of 7 of the examined 74 cases were heterozygous for a rare sequence variant in the RYR2 gene. We identified five novel missense variants (p.Q486H, p.D1872N, p.G2367R, p.E4213D, and p.H4579Y), one synonymous variant (p.L4767L), and one previously reported missense variant (p.G4315E). Follow-up studies were possible in family members of three probands (p.Q486H, p.D1872N, and p.H4579Y), and clinical examinations were conducted in family members of two of these probands (p.Q486H and p.H4579Y). In conclusion, we identified a higher prevalence of variants in the CPVT-associated gene RYR2 than in a previously reported cohort of SIDS (9.4% vs. 1-2%). Segregation studies show that one variant (p.H4579Y) co-segregates with CPVT and is presumed to be pathogenic.
本研究旨在鉴定年龄在 0-40 岁之间死于猝死后综合征（SUD）的患者中与儿茶酚胺多形性室性心动过速（CPVT）相关的兰尼碱受体 2（RYR2）基因的致病性变异，包括死于婴儿猝死综合征（SIDS）的婴儿队列。我们对 74 例无心脏结构异常的 SUD 病例的 RYR2 基因的 29 个与 CPVT 相关的外显子进行了基因筛查，这些病例均来自法医研究所的病例数据库，随后通过 DNA 测序进行了突变筛选，以检测从死者血液样本中提取的 DNA 样本中的变异。在检查的 74 例病例中，有 7 例为 RYR2 基因罕见序列变异的杂合子。我们鉴定了五个新的错义变异（p.Q486H、p.D1872N、p.G2367R、p.E4213D 和 p.H4579Y）、一个同义变异（p.L4767L）和一个先前报道的错义变异（p.G4315E）。三个先证者（p.Q486H、p.D1872N 和 p.H4579Y）的家族成员进行了后续研究，其中两个先证者（p.Q486H 和 p.H4579Y）的家族成员进行了临床检查。总之，我们发现与先前报道的 SIDS 队列相比，CPVT 相关基因 RYR2 的变异发生率更高（9.4%比 1-2%）。分离研究表明，一个变异（p.H4579Y）与 CPVT 共分离，被认为是致病性的。
