Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations

Abstract

PurposeMolecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.MethodsWe performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.ResultssES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).ConclusionsThis method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.

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]…”

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].…”

Retrospective identification of prenatal fetal anomalies associated with diagnostic neonatal genomic sequencing results

“…Two of the largest cohort studies on prenatal WES to date found similar diagnostic yields of approximately 10% in pregnancies complicated by fetal structural anomalies but with normal karyotype and microarray 1,2 . Other studies reported even higher yields 3–5 . Pregnancy complicated by multiple fetal anomalies is associated with the highest yield for diagnostic genetic variants followed by skeletal anomalies and non‐immune hydrops fetalis 1–3,6 .…”

“…1,2 Other studies reported even higher yields. [3][4][5] Pregnancy complicated by multiple fetal anomalies is associated with the highest yield for diagnostic genetic variants followed by skeletal anomalies and non-immune hydrops fetalis. [1][2][3]6 WGS and WES have not been adopted into routine practice in obstetric care due to high cost and suspected low diagnostic yield above karyotype and microarray.…”