Division of Fetomaternal Medicine, Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
Sci Rep. 2021 Mar 24;11(1):6737. doi: 10.1038/s41598-021-85893-0.
To describe the prevalence and spectrum of cardio-pathogenic variants in singleton fetuses after unexplained intrauterine fetal death (IUFD). DNA from post-mortem fibroblastic tissue samples of 16 fetuses after unexplained IUFD was retrieved at two tertiary university hospitals for clinical exome sequencing with subsequent filtering of 122 cardio-specific genes to elucidate underlying cardio-pathogenic variants. In total, we included 12 (75%) male and four (25%) female fetuses who were stillborn at a median gestational age of 34 (23-40) weeks. In two (12.5%) fetuses no cardio-pathogenic variants were found. In 14 (87.5%) fetuses, overall 33 variants were detected in 22 cardio-specific genes, involving 14 (63.63%) genes associated with cardiomyopathy, six (27.27%) arrhythmogenic susceptibility genes and two (9.09%) arrhythmia and cardiomyopathy associated genes. Among the 33 variants, five (15.2%) were classified as likely benign according to the American College of Medical Genetics and Genomics; 28 (84.8%) variants were considered as variants of uncertain significance. Compared to a cohort of explained IUFDs, the cases with and without fetal variants in cardiac genes differed not significantly regarding maternal age, previous history of stillbirth, time of stillbirth or fetal sex. Unexplained stillbirth may be caused by cardio-genetic pathologies, yet a high number of variants of uncertain significance merit a more detailed post-mortem examination including family segregation analysis.
描述不明原因宫内胎儿死亡（IUFD）后 singleton 胎儿中心血管致病变体的流行率和谱。在两家三级大学医院，从 16 例不明原因 IUFD 后的死后纤维母细胞组织样本中提取 DNA，进行临床外显子组测序，随后对 122 个心脏特异性基因进行过滤，以阐明潜在的心脏致病变体。总共纳入了 12 名（75%）男性和 4 名（25%）女性胎儿，他们在中位妊娠年龄为 34 周（23-40 周）时仍为死胎。在 2 名（12.5%）胎儿中未发现心脏致病变体。在 14 名（87.5%）胎儿中，总共在 22 个心脏特异性基因中检测到 33 个变体，涉及 14 个（63.63%）与心肌病相关的基因、6 个（27.27%）心律失常易感性基因和 2 个（9.09%）心律失常和心肌病相关基因。在 33 个变体中，根据美国医学遗传学和基因组学学院的标准，有 5 个（15.2%）被归类为可能良性；28 个（84.8%）变体被认为是意义不明的变体。与解释性 IUFD 队列相比，心脏基因有或无胎儿变体的病例在母亲年龄、先前死产史、死产时间或胎儿性别方面无显著差异。不明原因的死产可能是由心脏遗传病理学引起的，但大量意义不明的变体需要更详细的死后检查，包括家族分离分析。
