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The Genomics of Congenital Diaphragmatic Hernia: A 10-Year Retrospective Review
K Taylor Wild1, Erica Schindewolf2, Holly L Hedrick3
1Division of Neonatology, The Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA; Division of Human Genetics, The Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA; Roberts Individualized Medical Genetics Center, The Children's Hospital of Philadelphia, Philadelphia, PA.
Insights
Genetic testing is valuable for infants with congenital diaphragmatic hernia (CDH), especially complex cases. Further genomic studies are needed to improve diagnosis and management for all CDH infants.
Area of Science:
- Genetics
- Pediatrics
- Medical Diagnostics
Background:
- Congenital diaphragmatic hernia (CDH) is a complex birth defect.
- Genetic factors play a significant role in CDH, influencing prognosis and management.
- Understanding genetic testing utility is crucial for optimizing care in infants with CDH.
Purpose of the Study:
- To evaluate the utilization and diagnostic yield of genetic testing in infants with CDH over a 10-year period.
- To inform future practices and personalize prognostication and management strategies for CDH patients.
- To assess the effectiveness of different genetic testing modalities in identifying etiologies.
Main Methods:
- Retrospective cohort study of infants with CDH.
- Analysis of demographic, prenatal, and postnatal data.
- Review of genetic testing results, including microarray and exome sequencing.
Main Results:
- Genetic testing was diagnostic in 14% of all infants with CDH.
- Diagnostic rates were significantly higher in complex/syndromic (57%) versus isolated/nonsyndromic (2%) CDH cases.
- Mortality was higher in complex/syndromic infants and those who underwent genetic testing.
Conclusions:
- Comprehensive genetic testing demonstrates utility in infants with CDH, particularly complex cases.
- A significant proportion of CDH cases, especially isolated ones, lack identified genetic etiologies.
- Further genomic research is essential to enhance diagnostic rates and enable individualized management for CDH.
Objective:
To evaluate genetic testing use in infants with congenital diaphragmatic hernia (CDH) over the past decade to better inform future practices and individualize prognostication and management.
Study Design:
A retrospective cohort study was performed of all infants with CDH enrolled in the Pulmonary Hypoplasia Program at Children's Hospital of Philadelphia, born between January 2011 and February 2021. For each infant, demographic information, prenatal and postnatal history, and genetic testing were reviewed.
Results:
The charts of 411 infants were analyzed. Overall, 22% (n = 89) were complex/syndromic and 78% (n = 322) were isolated/nonsyndromic. Mortality was significantly higher in complex/syndromic infants (P < .001) and in infants with diagnostic genetic testing (P < .001). Microarray was diagnostic in 9% (n = 34/399) and exome sequencing was diagnostic in 38% (n = 15/39). Genetic testing was diagnostic in 57% (n = 51/89) of complex/syndromic infants, but in only 2% of isolated/nonsyndromic infants (n = 8/322). Overall, genetic testing was diagnostic in 14% (n = 56).
Conclusions:
The high diagnostic rate in this cohort highlights the utility of comprehensive genetic testing in infants with CDH. However, 43% of complex/syndromic and 98% of isolated/nonsyndromic infants do not have a genetic etiology identified. This finding underscores the need for additional genetic and genomic studies (eg, whole genome, RNA sequencing) to identify novel genes and mutational mechanisms (single genes, regulatory elements, complex traits) that will allow for improved diagnostic rates and ultimately individualized management of infants with CDH.
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