aCGH Analysis Reveals Novel Mutations Associated with Congenital Diaphragmatic Hernia Plus (CDH+)
Yannick Schreiner1, Teresa Stoll1, Oliver Nowak2
1Department of Neonatology, University Children's Hospital Mannheim, University of Heidelberg, 69117 Mannheim, Germany.
Insights
Genetic analysis of congenital diaphragmatic hernia with other malformations (CDH+) identified novel mutations. Array-based comparative genomic hybridization (aCGH) revealed deletions and duplications, including two candidate genes, PTPRD and GATA4.
Area of Science:
- Medical Genetics
- Developmental Biology
- Genomics
Background:
- Congenital diaphragmatic hernia (CDH) is a significant birth defect.
- CDH often presents with additional malformations (CDH+).
- Genetic factors are implicated in CDH+, typically identified by array-based comparative genomic hybridization (aCGH).
Purpose of the Study:
- To identify novel genetic mutations associated with CDH+ using aCGH.
- To investigate the relationship between genetic alterations and CDH+ outcomes.
- To discover new candidate genes for CDH+.
Main Methods:
- Analysis of 43 CDH+ patients from 2012-2021.
- Utilized array-based comparative genomic hybridization (aCGH) for mutation detection.
- Classified detected deletions and duplications as pathological or variants of unknown significance (VUS).
Main Results:
- Detected 32 deletions and 29 duplications in CDH+ patients.
- Identified a pathological heterozygous deletion at 8p23.1 involving GATA4, NEIL2, SOX7, and MSRA.
- Found a heterozygous deletion at 9p23 encompassing PTPRD in two patients.
Conclusions:
- Expands the understanding of genetic alterations in CDH+.
- Proposes GATA4 and PTPRD as novel candidate genes for CDH+.
- Highlights the utility of aCGH in identifying genetic causes of complex congenital anomalies.
Abstract:
Congenital diaphragmatic hernia (CDH) is a major birth anomaly that often occurs with additional non-hernia-related malformations, and is then referred to as CDH+. While the impact of genetic alterations does not play a major role in isolated CDH, patients with CDH+ display mutations that are usually determined via array-based comparative genomic hybridization (aCGH). We analyzed 43 patients with CDH+ between 2012 and 2021 to identify novel specific mutations via aCGH associated with CDH+ and its outcome. Deletions (n = 32) and duplications (n = 29) classified as either pathological or variants of unknown significance (VUS) could be detected. We determined a heterozygous deletion of approximately 3.75 Mb located at 8p23.1 involving several genes including GATA4, NEIL2, SOX7, and MSRA, which was consequently evaluated as pathological. Another heterozygous deletion within the region of 9p23 (9,972,017-10,034,230 kb) encompassing the Protein Tyrosine Phosphatase Receptor Type Delta gene (PTPRD) was identified in 2 patients. This work expands the knowledge of genetic alterations associated with CDH+ and proposes two novel candidate genes discovered via aCGH.
