Abstract
ObjectivesThe objective of the study was to explore the added value of whole-exome sequencing (WES) in abnormal fetuses with detailed prenatal ultrasound and postnatal phenotype with normal karyotype and chromosomal microarray analysis (CMA).MethodsParents of fetuses with structural abnormalities by prenatal ultrasound who consented to provide fetal samples were prospectively recruited from January 2017 to December 2019. With aneuploidies or cases with copy number variations (CNVs) excluded, WES was performed for cases with normal karyotype and CMA results. Detailed prenatal ultrasound and postnatal imaging or pathology features were recommended for further interpretation of genetic variants.ResultsWES was performed for 94 eligible fetuses, DNA samples of which were extracted from 53 parent–fetus trios and 41 proband-only fetal tissues. A diagnostic genetic variant was identified in 37 (39.4%) of 94 fetuses, and 34 (64.2%) were detected in 53 trios, which was significantly greater than 3 (7.3%) in 41 proband-only cases (p < 0.001). In 34 trios with diagnostic genetic variants, 23 (67.6%) were de novo and 11 (32.4%) were inherited with two homozygous and nine heterozygous variants. Fourteen (14.9%) of 94 fetuses had a variant of uncertain significance (VUS). Among 94 cases, six affected pregnancies continued and 88 terminated, and 57 of 88 terminated cases underwent postmortem examinations. With accurate phenotypes demonstrated by prenatal ultrasound and postnatal autopsies, the clinical phenotypes were correlated in 33 (89.2%) of 37 cases with specific genotypes, with the highest matching ratio in skeletal diseases (20/33, 60.6%).ConclusionWES has added value in the genetic diagnosis of abnormal fetuses with normal karyotypes and CMA, particularly in skeletal diseases. Using WES in various anomalous fetuses can broaden the understanding of prenatal phenotypes and genetic variants.
Highlights
Congenital anomalies affect 2–4% of all infants and are responsible for 21% of perinatal deaths (Ely and Driscoll, 2019)
The underlying etiology has been identified in many fetal abnormalities by the use of whole-exome sequencing (WES), including anomalies of the kidney and urinary tract (13%) (Lei et al, 2017), skeletal disease (88.9%) (Han et al, 2020), and non-immune hydrops fetalis (29%) (Sparks et al, 2020); the limited prenatal phenotype information, difficulties in variant interpretation of secondary findings, and the time-consuming nature of this costly technology have put off the widespread clinical implementation of WES
To expand the prenatal phenotype– genotype spectrum and facilitate the utility of prenatal WES, we analyze the diagnostic yield of WES in fetuses with different kinds of abnormalities with detailed ultrasound and postnatal phenotypes
Summary
Congenital anomalies affect 2–4% of all infants and are responsible for 21% of perinatal deaths (Ely and Driscoll, 2019). Using ultrasound, these abnormalities can be identified in the first and second trimesters, ranging from fetal hydrops to major lethal disorders. The underlying etiology has been identified in many fetal abnormalities by the use of WES, including anomalies of the kidney and urinary tract (13%) (Lei et al, 2017), skeletal disease (88.9%) (Han et al, 2020), and non-immune hydrops fetalis (29%) (Sparks et al, 2020); the limited prenatal phenotype information, difficulties in variant interpretation of secondary findings, and the time-consuming nature of this costly technology have put off the widespread clinical implementation of WES. To expand the prenatal phenotype– genotype spectrum and facilitate the utility of prenatal WES, we analyze the diagnostic yield of WES in fetuses with different kinds of abnormalities with detailed ultrasound and postnatal phenotypes
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