Incremental yield of genome sequencing after exome sequencing for nonimmune hydrops fetalis spectrum.

objectiveExome sequencing (ES) detects a monogenic disorder in approximately 30% of pregnancies with unexplained nonimmune hydrops fetalis spectrum (NIHFS), defined as the presence of one or more pathologic fetal fluid collection. Since genome sequencing (GS) can identify additional genetic variants not detectable by ES, we sought to determine the proportion of cases with new reportable findings on GS following nondiagnostic standard of care testing, including ES, for NIHFS. STUDY

designCohort study of pregnancies with NIHFS that had nondiagnostic results of karyotype and/or chromosomal microarray analysis (CMA) and ES. Eligible fetal fluid collections included at least one of: ascites, pleural or pericardial effusions, skin edema, cystic hygroma, and/or nuchal translucency ≥3.5 mm. Pregnancies with NIHFS that did not receive a clear diagnosis with prior testing underwent additional testing with GS. ES and GS were performed in a Clinical Laboratory Improvement Amendments-approved laboratory, and genetic variants were classified according to the American College of Medical Genetics and Genomics guidelines. Primary outcome was the proportion of new reportable pathogenic or likely pathogenic (P/LP) variants identified on GS and resulting in a new diagnosis. Secondary outcome was the incremental yield of GS for detecting new secondary findings and variants of uncertain significance (VUSs).

resultsOverall, 118 fetal samples underwent GS following negative (n=102) or inconclusive (n=16) ES. GS identified four P/LP copy number variants previously not detected by karyotype, CMA, or ES that led to a new genetic diagnosis in three pregnancies, providing a new positive finding yield of 2.5% (3/118). Additionally, one secondary finding and four VUSs were identified by GS in four different pregnancies. In contrast to the primary outcome, these additional findings were largely the result of updated analytical tools and literature rather than GS-specific technology.

conclusionGS has a small but clinically relevant increased diagnostic yield over chromosome studies and ES for NIHFS, particularly for identifying copy number variants. As interpretation of noncoding regions and complex genomic variations improves, the incremental positive finding yield of GS is expected to further increase.