Dataset Information

The Added Value of Whole-Exome Sequencing for Anomalous Fetuses With Detailed Prenatal Ultrasound and Postnatal Phenotype.

ABSTRACT:

Objectives

The 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).

Methods

Parents 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.

Results

WES 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%).

Conclusion

WES 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.

SUBMITTER: He M

PROVIDER: S-EPMC8340955 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background Xp22.31 deletion and duplication have been described in various studies, but different laboratories interpret pathogenicity differently. Objectives Our study aimed to refine the genotype–phenotype associations between Xp22.31 copy number variants in fetuses, with the aim of providing data support to genetic counseling. Methods We retrospectively analyzed karyotyping and single nucleotide polymorphism array results from 87 fetuses and their family members. Phenotypic data were obtained through follow-up visits. Results The percentage of fetuses carrying the Xp22.31 deletions (9 females, 12 males) was 24.1% (n = 21), while duplications (38 females, 28 males) accounted for 75.9% (n = 66). Here, we noted that the typical region (from 6.4 to 8.1 Mb, hg19) was detected in the highest ratio, either in the fetuses with deletions (76.2%, 16 of 21) or duplications (69.7%, 46 of 66). In female deletion carriers, termination of pregnancy was chosen for two fetuses, and the remaining seven were born without distinct phenotypic abnormalities. In male deletion carriers, termination of pregnancy was chosen for four fetuses, and the remaining eight of them displayed ichthyosis without neurodevelopmental anomalies. In two of these cases, the chromosomal imbalance was inherited from the maternal grandfathers, who also only had ichthyosis phenotypes. Among the 66 duplication carriers, two cases were lost at follow-up, and pregnancy was terminated for eight cases. There were no other clinical findings in the rest of the 56 fetuses, including two with Xp22.31 tetrasomy, for either male or female carriers. Conclusion Our observations provide support for genetic counseling in male and female carriers of Xp22.31 copy number variants. Most of them are asymptomatic in male deletion carriers, except for skin findings. Our study is consistent with the view that the Xp22.31 duplication may be a benign variant in both sexes. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-023-01493-z.