Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis

Abstract

Introduction Nonimmune hydrops fetalis (NIHF) has varied etiology. We assessed the etiological spectrum and evaluated the utility of fetal whole exome sequencing (fWES) for the diagnosis of NIHF. Methods In this prospective cohort study, we evaluated antenatally diagnosed fetuses with NIHF between July 2018 and December 2019 according to the routine diagnostic algorithm. Fetuses that remained undiagnosed after routine NIHF workup were subjected to fetal chromosomal microarray and/or WES. Pregnancies were followed up for clinical outcomes. Results Of the 45 fetuses, consanguinity and recurrent hydrops fetalis were observed in 13.3% (6/45) and 28.8% (13/45), respectively. Overall, an etiological diagnosis was possible in 75.5% (34/45) of fetuses, while the cause remained unknown in 24.4% (11/45). A genetic etiology was identified in 46.6% (21/45): aneuploidy and monogenic disorders in 28.8% (13/45) and 17.8% (8/45), respectively. fWES on 19 fetuses detected disease‐causing variants in 42.1% (8/19). Nine novel variants were detected in RAPSN, ASCC1, NEB, PKD1L1, GUSB, and PIEZO1. Only 8.8% (4/45) of the cohort survived without morbidity. Conclusions This study describes the etiological spectrum and the disease‐causing variants in an Indian cohort of hydropic fetuses.

Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta‐analysis

“… 32 , 41‐48 , 33‐40 Eight studies targeted ES analysis more tightly using phenotype‐specific gene panels, 7 , 12 , 15 , 49‐53 while the remainder took a whole ES approach 8 ,. 13 , 62‐71 , 54 , 72‐81 , 55 , 82‐88 , 56‐61 Where stated (15 studies), 7 , 8 , 74 , 75 , 78 , 82 , 84 , 15 , 29 , 36 , 52 , 53 , 55 , 62 , 73 the median turnaround time for ES was 20 days (range 4–141). Studies included fetuses with a range of structural abnormality phenotypes, with some studies recruiting cases with fetal anomalies in a specific body system (e.g.…”

“…14,32,[41][42][43][44][45][46][47][48][33][34][35][36][37][38][39][40] Eight studies targeted ES analysis more tightly using phenotypespecific gene panels, 7,12,15,[49][50][51][52][53] while the remainder took a whole ES approach. 8,13,[62][63][64][65][66][67][68][69][70][71]54,[72][73][74][75][76][77][78][79][80][81]55,[82][83]…”

Clinical Course and Outcome of Non-Immune Fetal Hydrops in Singleton Pregnancies

“…Recent studies already showed the advantage of further genetic follow-up using exome sequencing. These investigations showed diagnostic yields of exome sequencing in fetal hydrops between 29 and 42.1% [20][21][22], suggesting that exome sequencing will play an increasing role in the clinical workup of NIFH.…”

Perinatal presentations of nonimmune hydrops fetalis due to biallelic pathogenic variants in PIEZO1: underdiagnosed?

“…The 45% surviving the neonatal period demonstrated highly variable clinical presentation, ranging from complete resolution of the hydrops with childhood recurrence of lymphedema, to severe neonatal condition and recurrent cellulitis requiring prolonged intensive care, but with normal intelligence. Recent studies about ES for diagnosis in non-immune hydrops fetalis have found about 0.8 to 7% (1/127 and 2/28) of LMPHM6 with autosomal recessive variants in PIEZO1 (25,27).…”

“…Up to now about 32 LoF variants in PIEZO1 have been reported in 18 GLD families (7)(8)(9)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). The affected individuals exhibit highly variable clinical presentation, ranging from mild lymphedema of childhood onset to severe NIHF with intrauterine fetal demise or neonatal demise.…”