Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes

Lu Qiao, Julia Wynn, Lan Yu, Rebecca Hernan, Xueya Zhou, Vincent Duron, Gudrun Aspelund, Christiana Farkouh-Karoleski, Annette Zygumunt, Usha S. Krishnan, Shannon Nees, Julie Khlevner, Foong Yen Lim, Timothy Crombleholme, Robert Cusick, Kenneth Azarow, Melissa Ellen Danko, Dai Chung, Brad W. Warner, George B. MychaliskaDouglas Potoka, Amy J. Wagner, Samuel Soffer, David Schindel, David J. McCulley, Yufeng Shen, Wendy K. Chung

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Purpose: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes. Methods: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify de novo variants. We grouped cases into those with and without likely damaging (LD) variants and systematically assessed CDH clinical outcomes between the genetic groups. Results: Complex cases with additional congenital anomalies had higher mortality than isolated cases (P = 8 × 10−6). Isolated cases with LD variants had similar mortality to complex cases and much higher mortality than isolated cases without LD (P = 3 × 10−3). The trend was similar with pulmonary hypertension at 1 month. Cases with LD variants had an estimated 12–17 points lower scores on neurodevelopmental assessments at 2 years compared with cases without LD variants, and this difference is similar in isolated and complex cases. Conclusion: We found that the LD genetic variants are associated with higher mortality, worse pulmonary hypertension, and worse neurodevelopment outcomes compared with non-LD variants. Our results have important implications for prognosis, potential intervention and long-term follow up for children with CDH.

Original languageEnglish (US)
Pages (from-to)2020-2028
Number of pages9
JournalGenetics in Medicine
Issue number12
StatePublished - Dec 2020


  • congenital diaphragmatic hernia
  • de novo variants
  • mortality of birth defects
  • neurodevelopmental outcome
  • pleiotropic

ASJC Scopus subject areas

  • Genetics(clinical)


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