Diagnostic yield from prenatal exome sequencing for nonimmune hydrops fetalis: a systematic review and meta-analysis.

Nonimmune hydrops fetalis (NIHF) has multiple genetic etiologies diagnosable by exome sequencing (ES). We evaluated the yield of prenatal ES for NIHF, and the contribution of additional clinical findings and history. Systematic review was performed with PROSPERO tag 232951 using CINAHL, PubMed, and Ovid MEDLINE from 1/1/2000 through 12/1/2021. Selected studies performed ES to augment standard prenatal diagnostic approaches. Cases meeting a strict NIHF phenotype were tabulated with structured data imputed from papers or requested from authors. Genetic variants and diagnostic outcomes were harmonized across studies using current ACMG and ClinGen variant classification guidelines. 31 studies reporting 445 NIHF cases had a 37% [95% CI: 32%-41%] diagnostic rate. There was no significant difference between isolated NIHF and NIHF with fetal malformations or between recurrent and simplex cases Diagnostic rate was higher for consanguineous than nonconsanguineous cases. Disease categories included RASopathies (24%), neuromuscular (21%), metabolic (17%), lymphatic (13%), other syndromes (9%), cardiovascular (5%), hematologic (2%), skeletal (2%) and other categories (7%). Inheritance patterns included recessive (55%), dominant (41%), and X-linked (4%). ES should be considered in the diagnostic workup of NIHF with and without associated ultrasound findings regardless of history of recurrence or consanguinity.