63 Hydrops-Yielding Diagnostic Results Of Prenatal Exome Sequencing (HYDROPS) Trial - Prenatal WES for NIHF

Abstract

NIHF can be caused by multiple etiologies. Standard genetic workup evaluates chromosomal and a few monogenic disorders. We explored the utility of prenatal exome sequencing (ES) for NIHF after a complete negative standard workup. Participants enrolled prospectively in the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) trial from MFM practices across the country (14 states). We used a strict phenotypic description for NIHF diagnosis, including at least two of the following: skin edema, ascites, pleural effusion, or pericardial effusion. The negative standard workup includes testing for infection (parvovirus, CMV, toxoplasmosis, syphilis), fetal-maternal hemorrhage (Kleihauer-Betke test or MCA Doppler), and chromosomal disorders (microarray). Trio ES from fetal samples and parental blood was performed at a CLIA-certified laboratory with reports returned by genetic counselors. Exomes were reanalyzed with information from subsequent ultrasounds and records. Twenty-two fetal exomes were analyzed with 11 (50%) diagnostic results and five possible diagnoses (22.7%). Diagnosed cases included seven de novo dominant disorders, three recessive disorders, and one inherited dominant disorder including four Noonan syndromes (PTPN11, RAF1, RIT1, RRAS2), three musculoskeletal disorders (RYR1, AMER1, BICD2), two metabolic disorders (sialidosis, multiple sulfatase deficiency), one Kabuki syndrome, and one congenital anemia (KLF1). Five cases with “Possible Diagnoses” included 3 compound heterozygous VOUS in genes known to cause NIHF (two cases PIEZO1, one case MPS VII) and 2 cases with de novo variants in candidate genes. This included HSPB1, a likely candidate for fetal akinesia and NIHF and NOTCH1 associated with Adams-Oliver syndrome. The etiology of NIHF predicts pregnancy viability, postnatal prognosis, and recurrence risk in future pregnancies. ES has high incremental diagnostic yield for NIHF after standard-of-care testing and should be considered in the workup. Genetic counseling is required for pretest counseling, clear interpretation, and result return.View Large Image Figure ViewerDownload Hi-res image Download (PPT)