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。
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.
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.