Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.
Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.
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DOI：
10.1056/nejmoa2023643
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发表时间：
2020-10-29
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影响因子：
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通讯作者：
University of California, San Francisco Center for Maternal–Fetal Precision Medicine
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作者：
Sparks TN;Lianoglou BR;Adami RR;Pluym ID;Holliman K;Duffy J;Downum SL;Patel S;Faubel A;Boe NM;Field NT;Murphy A;Laurent LC;Jolley J;Uy C;Slavotinek AM;Devine P;Hodoglugil U;Van Ziffle J;Sanders SJ;MacKenzie TC;Norton ME;University of California Fetal–Maternal Consortium;University of California, San Francisco Center for Maternal–Fetal Precision Medicine
大多数胎儿畸形的原因在产前无法确定。外显子组测序已经改变了出生后的遗传诊断，但其用于产前诊断的有用性仍在出现。非免疫性胎儿水肿（NIHF）是一种胎儿异常，通常是致命的，有许多遗传原因;外显子组测序在多大程度上可以帮助其诊断尚不清楚。我们评估了一系列的127例连续的原因不明的NIHF病例，这些病例被定义为胎儿腹水，胸膜或心包积液，皮肤水肿，囊状水瘤，颈部通透性增加，或这些条件的组合。主要结果是外显子组测序的诊断率，用于检测根据美国医学遗传学和基因组学学院标准分类为致病性或可能致病性的遗传变异。次要结果是与特定遗传疾病相关的病例百分比和遗传变异的比例。在127例病例中的37例（29%）中，我们确定了诊断性遗传变异，包括影响RAS-MAPK细胞信号通路的疾病（称为RASopathies）（占遗传诊断的30%）;先天性代谢缺陷和肌肉骨骼疾病（各11%）;淋巴，神经发育，心血管和血液系统疾病（各8%）;以及其他。预后范围从相对较轻的结果到围产期死亡。总体而言，68%的诊断变异病例（37例中的25例）为常染色体显性（其中12%为遗传，88%为新发），27%（37例中的10例）为常染色体隐性（其中95%为遗传，5%为新发），1例为遗传性X连锁隐性，1例为不确定遗传。我们在另外12例病例中发现了潜在的诊断变异。在这个包含127例不明原因NIHF胎儿的大型病例系列中，我们在大约三分之一的病例中发现了诊断性遗传变异。（由UCSF母胎精准医学中心和其他机构资助; ClinicalTrials.gov编号，NCT 03412760。
The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear. We evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited. In 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS–MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases. In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.)