美国加州大学旧金山分校Teresa N. Sparks团队探讨了外显子组测序在非免疫性胎儿水肿产前诊断中的应用。2020年10月7日，该研究发表在《新英格兰医学杂志》上。

大多数胎儿异常的原因尚不能在产前确定。外显子组测序改变了出生后的遗传诊断，但其在产前诊断中的用途仍方兴未艾。胎儿异常的非免疫性积水（NIHF）通常是致命的，有多种遗传原因。外显子组测序可帮助其诊断的程度尚不清楚。

研究组评估了一系列127例连续的不明原因的NIHF病例，定义为胎儿腹水、胸膜或心包积液、皮肤水肿、囊性湿疹、食管半透明性增高或这些情况的综合。主要结局是外显子组测序的诊断率，分为致病或可能致病的遗传变异。

127例病例中有37例（29％）确诊遗传变异，包括那些影响RAS-MAPK细胞信号通路的疾病（占遗传诊断的30％）；先天性新陈代谢错误和肌肉骨骼疾病（各占11％）；淋巴、神经发育、心血管和血液系统疾病（每次8％）；和其他。预后从围产期相对轻度结局至死亡不等。总体而言，确诊变异的病例中有68％（25例）是常染色体显性遗传，27％（10例）是常染色体隐性遗传，1例是X连锁隐性遗传，1例是不确定遗传。研究组在另外12例病例中发现了可能致病的遗传变异。

综上，患有未知病因的NIHF胎儿中大约三分之一被诊断出遗传变异。

附：英文原文

Title: Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

Author: Teresa N. Sparks, M.D.,, Billie R. Lianoglou, M.S.,, Rebecca R. Adami, M.D.,, Ilina D. Pluym, M.D.,, Kerry Holliman, M.D.,, Jennifer Duffy, M.D.,, Sarah L. Downum, B.S.,, Sachi Patel, B.S.,, Amanda Faubel, B.S.,, Nina M. Boe, M.D.,, Nancy T. Field, M.D.,, Aisling Murphy, M.D.,, Louise C. Laurent, M.D., Ph.D.,, Jennifer Jolley, M.D.,, Cherry Uy, M.D.,, Anne M. Slavotinek, M.B., B.S., Ph.D.,, Patrick Devine, M.D., Ph.D.,, Ugur Hodoglugil, M.D., Ph.D.,, Jessica Van Ziffle, Ph.D.,, Stephan J. Sanders, B.M., B.S., Ph.D.,, Tippi C. MacKenzie, M.D.,, and Mary E. Norton, M.D.

Issue&Volume: 2020-10-07

Abstract:

Background

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.

Methods

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.

Results

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.

Conclusions

In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases.

DOI: 10.1056/NEJMoa2023643

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2023643