Pharmacogenomics and Personalized Medicine (Mar 2023)

Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects

  • Cai R,
  • Tan Y,
  • Wang M,
  • Yu H,
  • Wang J,
  • Ren Z,
  • Dong Z,
  • He Y,
  • Li Z,
  • Lin L,
  • Gu Y

Journal volume & issue
Vol. Volume 16
pp. 173 – 181

Abstract

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Rongqin Cai,1,* Ya Tan,1,* Mingming Wang,2 Huijun Yu,1 Jing Wang,1 Zhuo Ren,1 Zhe Dong,1 Yiwen He,1 Zhi Li,1 Li Lin,1 Ying Gu1,3 1Department of Obstetrics and Gynecology, Peking University International Hospital, Beijing, 102206, People’s Republic of China; 2Be Creative Lab (Beijing) Co. Ltd, Beijing, 101111, People’s Republic of China; 3Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, 222000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Lin; Ying Gu, Department of Obstetrics and Gynecology, Peking University International Hospital, Beijing, People’s Republic of China, Tel +86-13683047582 ; +86-18705130302, Email [email protected]; [email protected]: Congenital heart disease (CHD) is the most common birth defect with strong genetic heterogeneity. To date, about 400 genes have been linked to CHD, including cell signaling molecules, transcription factors, and structural proteins that are important for heart development. Genetic analysis of CHD cases is crucial for clinical management and etiological analysis.Methods: Whole-exome sequencing (WES) was performed to identify the genetic variants in two independent CHD cases with DNA samples from fetuses and their parents, followed by the exclusion of aneuploidy and large copy number variations (CNVs). The WES results were verified by Sanger sequencing.Results: In family A, a compound heterozygous variation in PLD1 gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p.R391C) was identified in the fetus. The two variants were inherited from the father (c.1132dupA) and the mother (c.1171C>T), respectively. In family B, a hemizygous variant ZIC3: c.861delG (p.G289Afs*119) was identified in the fetus, which was inherited from the heterozygous mother. We further confirmed that these variants PLD1: c.1132dupA and ZIC3: c.861delG were novel.Conclusion: The findings in our study identified novel variants to the mutation spectrum of CHD and provided reliable evidence for the recurrent risk and reproductive care options to the affected families. Our study also demonstrates that WES has considerable prospects of clinical application in prenatal diagnosis.Keywords: congenital heart disease, whole-exome sequencing, PLD1, ZIC3, prenatal diagnosis

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