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

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 to 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 to non-LD variants. Our results have important implications for prognosis, potential intervention and long-term follow up for children with CDH.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 and ALYREF as new candidate risk genes

“…Each participating site also procured approval from their local IRB and signed informed consent A total of 827 cases and their parents had whole genome (WGS) or exome sequencing in the current study. A subset of trios (n=574) has been described in our previous study 3,9 .…”

“…Pulmonary hypoplasia, cardiac displacement and intestinal herniation were considered to be part of the diaphragm defect sequence and were not considered independent malformations. Data on the child's current and past health including family history of congenital anomalies, postoperative pulmonary hypertension, mortality or survival status prior to initial discharge, extracorporeal membrane oxygenation (ECMO) intake were gathered as described previously 3 .…”

“…Congenital diaphragmatic hernia (CDH) affects approximately 3 per 10,000 neonates 1,2 . Approximately 40% of CDH cases occur with additional congenital anomalies besides common secondary anomalies (dextrocardia and lung hypoplasia) 3 . The most common additional anomalies 4,5 are structural heart defects (11-15%), musculoskeletal malformations (15-20%) including limb deficiency, club foot, and omphalocele 6 .…”

“…However, anomalies of almost every organ have been described in association with CDH. Despite advances in care including improved prenatal diagnosis, fetal interventions, extracorporeal membrane oxygenation (ECMO) and gentle ventilation, CDH continues to be associated with at least 20% mortality and significant long-term morbidity including feeding difficulties, pulmonary hypertension and other respiratory complications, and neurocognitive deficits 3,7,8 .…”

“…We also demonstrated a higher burden of de novo likely damaging (LD) variants in females compared to males supporting a "female protective model" 9 . Most recently, in a cohort with long term developmental outcome data 3 , we demonstrated that de novo likely damaging (LD) variants are associated with poorer neurodevelopmental outcomes as well as a higher prevalence of pulmonary hypertension (PH).…”