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 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.

Figure 1.. Study design and number of patients.

PH: pulmonary hypertension; 2yr: 2 years of age; BSID-III: Bayley Scales of Infant Development third edition; VABS-II: Vineland Adaptive Behavior Scales second edition.

Figure 2.. Association analyses for genetic groups with mortality and pulmonary hypertension.

(A) Mortality prior to initial discharge. (B) Pulmonary hypertension at 1 month. (C) Pulmonary hypertension at 3 months. P value is given by Fisher’s exact test after correcting multiple tests (P<5×10⁻³). **: P<0.001; *: P<0.005”.

Figure 3.. Association analyses for genetic groups with neurodevelopmental outcomes at 2 years of age.

(A) BSID-III language, (B) BSID-III cognition, (C) BSID-III motor, (D) VABS-II composite adaptive behavior. The black line in the middle of the box is the mean value for each group. The vertical size of the box is the interquartile range (IQR). The whisker is 1.5xIQR. P value is given by Student’s t-test with bold as significant after correcting multiple tests (P<5×10⁻³).

Figure 4.. Effect size for likely damaging variants on neurodevelopmental outcomes at 2yr comparing to non-LD variants.

(A) BSID-III language, (B) BSID-III cognitive, (C) BSID-III motor, (D) VABS-II composite adaptive behavior. Effect size is the coefficient/beta, which aligns with outcome on the y-axis, with the vertical dashed line (v=0) separating positive and negative direction of association. Significant P value after correcting multiple tests (P<5×10⁻³) is noted. LD: likely damaging variants; SES: socioeconomic status; PH: pulmonary hypertension; ECMO: extracorporeal membrane oxygenation.