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

TitleLikely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.
Publication TypeJournal Article
Year of Publication2020
AuthorsQiao, L, Wynn, J, Yu, L, Hernan, R, Zhou, X, Duron, V, Aspelund, G, Farkouh-Karoleski, C, Zygumunt, A, Krishnan, US, Nees, S, Khlevner, J, Lim, FYen, Crombleholme, T, Cusick, R, Azarow, K, Danko, MEllen, Chung, D, Warner, BW, Mychaliska, GB, Potoka, D, Wagner, AJ, Soffer, S, Schindel, D, McCulley, DJ, Shen, Y, Chung, WK
JournalGenet Med
Date Published2020 Jul 28

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). Isolated cases with LD variants had similar mortality to complex cases and much higher mortality than isolated cases without LD (P = 3 × 10). 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.

Alternate JournalGenet. Med.
PubMed ID32719394
Grant ListT32 HL007854 / HL / NHLBI NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
5T32HL007854-22 / / Ruth L. Kirschstein National Research Service Award of the NIH /