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



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.


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.


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.


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.

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Fig. 1: Study design and number of patients.
Fig. 2: Association analyses for genetic groups with mortality and pulmonary hypertension.
Fig. 3: Association analyses for genetic groups with neurodevelopmental outcomes at 2 years of age.
Fig. 4: Effect size for likely damaging (LD) variants on neurodevelopmental outcomes at 2 years comparing to non-LD variants.


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We thank the patients and their families for their generous contribution. We are grateful for the technical assistance provided by Patricia Lanzano, Jiangyuan Hu, Jiancheng Guo, Liyong Deng, Donna Garey, and Anketil Abreu from Columbia University. We thank our clinical coordinators and developmental specialists across the DHREAMS centers: Karen Lukas, Desiree White, and Jessica Conway at Washington University School of Medicine; Patricia Burns, Melissa Spare, and Sarah (Lexie) Price at Cincinnati Children’s Hospital; Sheila Horak and Kelly Miller at Children’s Hospital & Medical Center of Omaha; Jeannie Kreutzman and Jennifer Butcher at CS Mott Children’s Hospital; Tracy Perry at Monroe Carell Jr. Children’s Hospital; Michelle Kallis at Northwell Health, Brandy Gonzales, and Alicia McIntire at Oregon Health and Science University; Gentry Wools and Lorrie Burkhalter at Children’s Medical Center Dallas; Elizabeth Jehle at Hassenfeld Children’s Hospital at NYU Langone Health; Michelle Knezevich and Cheryl Kornberg at Medical College of Wisconsin; and Min Shi at Children’s Hospital of Pittsburgh. The genome sequencing data were generated through National Institutes of Health (NIH) Gabriella Miller Kids First Pediatric Research Program (X01HL132366, X01HL136998, and X01HL140543) and the University of Washington Center for Mendelian Genomics with National Human Genome Research Institute (NHGRI) grant HG006493. This work was supported by NIH grants R01HD057036 (L.Y., J.W., W.K.C.), R03HL138352 (W.K.C., Y.S.), R01GM120609 (Y.S.), UL1 RR024156 (W.K.C.), and 1P01HD068250 (W.K.C., Y.S.). Additional funding support was provided by grants from CHERUBS, CDHUK, and the National Greek Orthodox Ladies Philoptochos Society, Inc. and generous donations from Fore Hadley, the Williams Family, Wheeler Foundation, Vanech Family Foundation, Larsen Family, Wilke Family, and many other families. S.N. received salary support through a Ruth L. Kirschstein National Research Service Award of the NIH under award number 5T32HL007854-22. The genome sequencing data can be obtained from dbGAP through accession phs001110.

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Correspondence to Yufeng Shen PhD or Wendy K. Chung MD, PhD.

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Qiao, L., Wynn, J., Yu, L. et al. Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes. Genet Med (2020).

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