Genet Med

. 2020 Jul 28. doi: 10.1038/s41436-020-0908-0. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32719394/

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

Lu Qiao ^1 2, Julia Wynn ¹, Lan Yu ¹, Rebecca Hernan ¹, Xueya Zhou ^1 2, Vincent Duron ³, Gudrun Aspelund ³, Christiana Farkouh-Karoleski ¹, Annette Zygumunt ¹, Usha S Krishnan ¹, Shannon Nees ¹, Julie Khlevner ¹, Foong Yen Lim ⁴, Timothy Crombleholme ⁴, Robert Cusick ⁵, Kenneth Azarow ⁶, Melissa Ellen Danko ⁷, Dai Chung ⁷, Brad W Warner ⁸, George B Mychaliska ⁹, Douglas Potoka ¹⁰, Amy J Wagner ¹¹, Samuel Soffer ¹², David Schindel ¹³, David J McCulley ¹⁴, Yufeng Shen ^15 16 17, Wendy K Chung ^18 19 20Affiliations expand

• PMID: 32719394
• DOI: 10.1038/s41436-020-0908-0

Abstract

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.

Keywords: congenital diaphragmatic hernia; de novo variants; mortality of birth defects; neurodevelopmental outcome; pleiotropic.