Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Ultrasound Obstet Gynecol. 2022 Oct;60(4):487-493. doi: 10.1002/uog.24911. Epub 2022 Aug 30.
To investigate the diagnostic yield of clinical whole-genome sequencing (WGS) in prenatally diagnosed non-immune hydrops fetalis (NIHF).
This was a retrospective study of 23 fetuses with prenatally diagnosed NIHF, negative for trisomies and copy-number variants, referred for analysis by WGS with an in-silico panel of 281 genes associated with hydrops fetalis. Due to identification of a high proportion of causative variants in the HRAS gene in the main cohort, Sanger sequencing of HRAS was performed in a replication cohort, consisting of 24 additional fetuses with NIHF that were negative for trisomies and copy-number variants and had not undergone WGS.
Of the 23 fetuses in the main cohort, a molecular diagnosis was achieved in 12 (52.2%). Pathogenic or likely pathogenic variants were identified in seven genes: HRAS (n = 5), RIT1 (n = 2), FOXP3 (n = 1), GLB1 (n = 1), MAP2K1 (n = 1), PTPN11 (n = 1) and RASA1 (n = 1). The inheritance pattern of the 12 causative variants was autosomal dominant in 10 cases (HRAS, MAP2K1, PTPN11, RASA1, RIT1), autosomal recessive in one (GLB1) and X-linked recessive in one (FOXP3). Of the 24 fetuses in the replication cohort, a pathogenic variant in HRAS was identified in one, resulting in an overall frequency of causative HRAS variants of 12.8% (6/47) in our two cohorts.
We demonstrate a diagnostic yield of 52% with clinical WGS in NIHF using an in-silico panel of 281 genes. However, the high diagnostic yield may be attributed to the small sample size and possible over-representation of severe phenotypes in the included fetuses. Bearing in mind that chromosomal abnormalities were excluded in our cohorts, a detection rate of up to 75% is possible in prenatally diagnosed NIHF when WGS analysis includes calling of chromosomal aberrations. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
探讨临床全基因组测序（WGS）在产前诊断非免疫性胎儿水肿（NIHF）中的诊断效能。
这是一项回顾性研究，纳入 23 例产前诊断为 NIHF、染色体非整倍体和拷贝数变异均为阴性的胎儿，采用 WGS 进行分析，使用与胎儿水肿相关的 281 个基因的计算机panel。由于在主要队列中 HRAS 基因中发现了很高比例的致病变异，因此在一个由 24 例 NIHF 胎儿组成的复制队列中进行了 HRAS 的 Sanger 测序，这些胎儿的染色体非整倍体和拷贝数变异均为阴性，且未行 WGS。
在主要队列的 23 例胎儿中，12 例（52.2%）获得了分子诊断。在 7 个基因中发现了致病性或可能致病性变异：HRAS（n=5）、RIT1（n=2）、FOXP3（n=1）、GLB1（n=1）、MAP2K1（n=1）、PTPN11（n=1）和 RASA1（n=1）。12 个致病变异的遗传模式为 10 例（HRAS、MAP2K1、PTPN11、RASA1、RIT1）为常染色体显性遗传，1 例（GLB1）为常染色体隐性遗传，1 例（FOXP3）为 X 连锁隐性遗传。在复制队列的 24 例胎儿中，有 1 例 HRAS 存在致病性变异，导致我们两个队列中 HRAS 致病变异的总发生率为 12.8%（6/47）。
我们使用 281 个基因的计算机panel 进行临床 WGS，在 NIHF 中显示出 52%的诊断效能。然而，高诊断率可能归因于样本量小，且纳入的胎儿可能存在严重表型的过度代表。鉴于我们的队列中排除了染色体异常，当 WGS 分析包括染色体异常的检测时，产前诊断的 NIHF 的检出率可达 75%。
