Implementation of Exome Sequencing in Prenatal Diagnosis and Impact on Genetic Counseling: The Polish Experience

Abstract

Background: Despite advances in routine prenatal cytogenetic testing, most anomalous fetuses remain without a genetic diagnosis. Exome sequencing (ES) is a molecular technique that identifies sequence variants across protein-coding regions and is now increasingly used in clinical practice. Fetal phenotypes differ from postnatal and, therefore, prenatal ES interpretation requires a large amount of data deriving from prenatal testing. The aim of our study was to present initial results of the implementation of ES to prenatal diagnosis in Polish patients and to discuss its possible clinical impact on genetic counseling. Methods: In this study we performed a retrospective review of all fetal samples referred to our laboratory for ES from cooperating centers between January 2017 and June 2021. Results: During the study period 122 fetuses were subjected to ES at our institution. There were 52 abnormal ES results: 31 in the group of fetuses with a single organ system anomaly and 21 in the group of fetuses with multisystem anomalies. The difference between groups was not statistically significant. There were 57 different pathogenic or likely pathogenic variants reported in 33 different genes. The most common were missense variants. In 17 cases the molecular diagnosis had an actual clinical impact on subsequent pregnancies or other family members. Conclusions: Exome sequencing increases the detection rate in fetuses with structural anomalies and improves genetic counseling for both the affected couple and their relatives.

When should we offer antenatal sequencing for urinary tract malformations? A systematic review, cohort study and meta‐analysis

“…In addition to the two extended cohorts, 12 studies were deemed fit for inclusion, [30][31][32][33][34][35][36][37][38][39][40][41] giving a total of 409 cases of prenatally diagnosed UTM (174 isolated and 235 associated with additional extra-UTMs).…”

“…In addition to the two extended cohorts, 12 studies were deemed fit for inclusion, 30–41 giving a total of 409 cases of prenatally diagnosed UTM (174 isolated and 235 associated with additional extra‐UTMs). The screening process and studies used are detailed in the PRISMA chart in Figure 1.…”

RASopathies are the most common set of monogenic syndromes identified by exome sequencing for nonimmune hydrops fetalis: A systematic review and meta‐analysis

“…Forest plot demonstrating proportion of RASopathies among all NIHF cases with positive ES diagnosis. Studies with zero RASopathy cases were included in the primary systematic review (Al‐Kouatly et al, 2023) in addition to our updated search as a part of our meta‐analysis calculations (Aggarwal et al, 2020; Correa et al, 2021; Daum et al, 2019; Dempsey et al, 2021; Deng et al, 2020; Greenbaum et al, 2019; Jelin et al, 2020; Kucińska‐Chahwan et al, 2022; Qi et al, 2020; Shamseldin et al, 2015, 2018; Sun et al, 2020; Tolusso et al, 2021; J. Zhou, Yang, et al, 2021). Study by Greenbaum et al (2019) is excluded in this figure as all three NIHF cases did not yield a positive result on ES.…”

Prenatal whole‐exome sequencing in fetuses with increased nuchal translucency

“…With decreases in costs and increases in the speed of bioinformatics analytical pipelines, exome sequencing has been increasingly used in the prenatal diagnosis of Mendelian diseases. Many studies on prenatal exome sequencing have successfully identified genetic diagnoses in fetuses with structural abnormalities, but diagnostic rates differed greatly in different phenotypic subgroups (Chen et al, 2020; Drury et al, 2015; Kucińska‐Chahwan et al, 2022; Lord et al, 2019; Petrovski et al, 2019; Sparks et al, 2020; Vora et al, 2017; Zhang et al, 2021). Exome sequencing studies focused on isolated increased NT obtained diagnostic rates ranging from 0% to 21% (Chen et al, 2020; Daum et al, 2019; Drury et al, 2015; Lord et al, 2019; Mellis et al, 2022; Petrovski et al, 2019; Sparks et al, 2020; Xue et al, 2020; Yang et al, 2020).…”