Evaluation of Diagnostic Yield in Fetal Whole-Exome Sequencing: A Report on 45 Consecutive Families

Abstract

Prenatal ultrasound (US) abnormalities often pose a clinical dilemma and necessitate facilitated investigations in the search of diagnosis. The strategy of pursuing fetal whole-exome sequencing (WES) for pregnancies complicated by abnormal US findings is gaining attention, but the reported diagnostic yield is variable. In this study, we describe a tertiary center’s experience with fetal WES from both terminated and ongoing pregnancies, and examine the clinical factors affecting the diagnostic rate. A total of 45 consecutive families of Jewish descent were included in the analysis, for which clinical fetal WES was performed under either single (fetus only), trio (fetus and parents) or quatro (two fetuses and parents) design. Except one, all families were non-consanguineous. In 41 of the 45 families, WES was sought following abnormal fetal US findings, and 18 of them had positive relevant family history (two or more fetuses with US abnormalities, or single fetus with US abnormalities and an affected parent). The overall diagnostic yield was 28.9% (13/45 families), and 31.7% among families with fetal US abnormalities (13/41). It was significantly higher in families with prenatal US abnormalities and relevant family history (10/18, 55.6%), compared to families with prenatal US abnormal findings and lack of such history (3/23, 13%) ( p = 0.004). WES yield was relatively high (42.9–60%) among families with involvement of brain, renal or musculoskeletal US findings. Taken together, our results in a real-world setting of genetic counseling demonstrates that fetal WES is especially indicated in families with positive family history, as well as in fetuses with specific types of congenital malformation.

Exome sequencing for perinatal phenotypes: The significance of deep phenotyping

“…A pathogenic/likely pathogenic variant was identified in 18/32 (56%) cases in our cohort. This diagnostic yield is higher than the average yield of the fourteen fetal ES studies subjected to review here but is comparable with the reports, which have used stringent inclusion criteria and comprehensive bio‐informatics analysis similar to us . The two largest prenatal exome studies published recently report low diagnostic yields, which is partly due to the wide spectrum of cases included, many of which could be multifactorial in origin …”

“…In four cases with previously known Mendelian disorders, findings leading to phenotype expansion were observed. This has been reported in other studies in literature and indicates that prenatal presentations of the same disorder can differ significantly from postnatal phenotypes, and this may pose challenges during bio‐informatics analysis …”

“…Review of available fetal exome studies revealed 14 research articles satisfying inclusion criteria . The number of exomes performed ranged from 15 to 610, with an overall 1601 fetal exomes including all the studies.…”

A report on the impact of rapid prenatal exome sequencing on the clinical management of 52 ongoing pregnancies: a retrospective review

“…As many single-gene disorders can present in-utero, it was postulated that exome sequencing could provide additional diagnosis, owing to its greater resolution and demonstrated utility in diagnosing postnatal cases such as developmental disorders [1]. Initial studies focused on highly selected and phenotypically homogenous cohorts which showed high diagnostic yield, up to 80% for select phenotypes such as skeletal anomalies [2][3][4][5]. When broader inclusion criteria are applied, diagnosis is made in ~10% [6,7].…”

Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives—A Systematic Review

“… 20-case study because it combined prenatal and postnatal phenotyping to interpret WES variants [ 67 ]. 45-case study, Jewish descent, excluded due to the different inclusion criteria and the ethnicity at high risk for recessive disorders [ 68 ]. 19-case study, for inhomogeneity in inclusion criteria and chromosomal anomalies/CNV assessment [ 69 ].…”