Value of Exome Sequencing in Diagnosis and Management of Recurrent Non-immune Hydrops Fetalis: A Retrospective Analysis

Abstract

The purpose of the study was to use exome sequencing (ES) to study the contribution of single-gene disorders to recurrent non-immune hydrops fetalis (NIHF) and retrospectively evaluate the value of genetic diagnosis on prenatal management and pregnancy outcome. From January 2012 to October 2018, a cohort of 28 fetuses with recurrent NIHF was analyzed by trio ES. Fetuses with immune hydrops, non-genetic factors (including infection, etc.), karyotype, or CNV abnormalities were excluded. Variants were interpreted based on ACMG/AMP guidelines. Fetal therapy was performed on seven fetuses. Of the 28 fetuses, 10 (36%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in eight genes (GBA, GUSB, GBE1, RAPSN, FOXC2, PIEZO1, LZTR1, and FOXP3). Five (18%) fetuses had variant(s) of uncertain significance (VUS). Of the 10 fetuses with definitive molecular diagnosis, five (50%) were diagnosed with inborn errors of metabolism. Among the seven fetuses who received fetal therapy, two had definitive molecular diagnosis and resulted in neonatal death. Among the remaining five fetuses with negative results, four had newborn survival and one had intrauterine fetal death. Trio ES could facilitate genetic diagnosis of recurrent NIHF and improve the prenatal management and pregnancy outcome.

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]…”

The diagnostic utility of exome‐based carrier screening in families with a positive family history

“…In Family 10, a heterozygous LP variant was detected in GBE1 in both. A fatal perinatal neuromuscular phenotype leading to nonimmune hydrops has been reported with GBE1 but the same could not be tested on any of the affected (Zhou et al, 2021).…”

Molecular Approaches in Fetal Malformations, Dynamic Anomalies and Soft Markers: Diagnostic Rates and Challenges—Systematic Review of the Literature and Meta-Analysis

“…For the quantitative analysis, 40 articles [121, were secondarily excluded. Of these, three papers focused on fetal demises or stillbirths [256][257][258], three papers focused on information postmortem [242,250,254], three were case reports [238,246,252], five focused on a single specific phenotype [240,241,248,261,274], three presented inhomogeneity in inclusion criteria and chromosomal anomalies/CNV assessment [239,251,262], six included both fetuses and postnatal cases [244,249,253,259,260,269], three focused on candidate genes [243,247,263], three focused on recurrent phenotypes or previously described cohorts [245,255,272], five were excluded for the lack of inclusion or eligibility criteria [264,265,268,271,276], two were excluded for the higher a priori risk for consanguinity and recurrence [266,270], one because parents were tested for recessive disorders [267], two because they focused on gene panels [273,275], and one due to the postnatal diagnosis [121].…”