Dataset Information

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.

SUBMITTER: Qiao L

PROVIDER: S-EPMC7710626 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Qiao Lu L Wynn Julia J Yu Lan L Hernan Rebecca R Zhou Xueya X Duron Vincent V Aspelund Gudrun G Farkouh-Karoleski Christiana C Zygumunt Annette A Krishnan Usha S US Nees Shannon S Khlevner Julie J Lim Foong Yen FY Crombleholme Timothy T Cusick Robert R Azarow Kenneth K Danko Melissa Ellen ME Chung Dai D Warner Brad W BW Mychaliska George B GB Potoka Douglas D Wagner Amy J AJ Soffer Samuel S Schindel David D McCulley David J DJ Shen Yufeng Y Chung Wendy K WK

Genetics in medicine : official journal of the American College of Medical Genetics 20200728 12

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 32719394

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Project description:BackgroundDe novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.MethodsWe studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).ResultsTwo hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10-12). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10-04) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10-05) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.ConclusionsIn patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

Similar Datasets

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