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Prenatal Genetic Diagnosis in Three Fetuses With Left Heart Hypoplasia (LHH) From Three Unrelated Families.

ABSTRACT: Background: Congenital heart defects (CHDs) are the most common birth defects, and left heart hypoplasia (LHH) is a severe form of CHD and responsible for more than 20% cardiac deaths during the first week of life, however, its genetic causes remain largely elusive. Methods: Three families with fetal LHH were recruited. Genomic DNA from amniotic fluid or peripheral blood, and trio whole exome sequencing (trio-WES) and copy number variation sequencing (CNV-seq) were performed. Results: All the three couples had no family history, and mid-gestation ultrasound revealed LHH and other variable cardiovascular defects in the fetuses. Trio-WES revealed de novo pathogenic variations in KMT2D (p.Gly3465Aspfs^*37) (NM_003482) and WDFY3 (p.Ser117Xfs^*) (NM_014991), and CNV-seq identified a deletion of 150 kb encompassing NOTCH1. KMT2D and NOTCH1 previously have been reported to be associated with CHDs, however, WDFY3 is reported for the first time to be possibly related to CHD in human. Conclusion: Our study suggested that genetic component is an important risk factor for the development of LHH, and next generation sequencing is a powerful tool for genetic diagnosis in fetuses with CHDs and genetic counseling, however, more studies and data are need to establish the correlation of fetal phenotypes and genotypes.

SUBMITTER: Luo S

PROVIDER: S-EPMC8062744 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe present study aimed to explore the etiological relationship between fetal abnormalities and copy number variations (CNVs) with the aim of intervening and preventing the birth of children with birth defects in time.MethodsSamples of 913 fetuses with puncture indications were collected from January 2017 to December 2019. Karyotype analysis and CNV sequencing (CNV-seq) testing was performed for fetuses with ultrasonic abnormalities, a high risk of Down's syndrome and an adverse birth history. All cases were followed up.ResultsIn total, 123 cases (13.47%) had abnormal karyotypes, including 109 cases with chromosome number abnormalities and 14 cases of chromosomal structural abnormalities. Thirty-seven (4.05%) cases with pathogenic CNVs were detected. The detection rate of pathogenicity CNVs was 12.82% for mixed indications, followed by 7.5% for an adverse birth history, 5.88% at high risk of non-invasive prenatal testing, 5.00% with an abnormal ultrasonic marker, 1.89% at high risk of screening for Down's syndrome and 1.45% with advanced maternal age. There were 12 (1.31%) cases with microduplications and 25 (2.74%) cases with microdeletions. Trisomy 21 (39.02%), trisomy 18 (13.82%) and Turner syndrome (9.76%) were the top three chromosome abnormalities. There were 104, 746 and 63 cases in the 11-13 weeks, 14-27 weeks 28-38 weeks gestational ages, respectively. The abnormal rates of fetal chromosome aneuploidy and the rate of pathogenic CNVs were decreased and increased with the increase of gestational age (p < 0.05), respectively.ConclusionsCompared with karyotype analysis, CNV-seq can improve the detection rate of chromosomal abnormalities. CNV-seq combined karyotype analysis should be performed simultaneously in fetuses with puncture indications.

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