Background Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.
Methods We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.
Results Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other cases (9%; 7/76). Four individuals had a diagnosis of Kabuki syndrome caused by frameshift variants in KMT2D. Putatively deleterious variants in ALG12 and EP300 were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in FOXP1 and SMARCA4, and compound heterozygous pathogenic variants in BRCA2. The role of these genes in CDH development is supported by the expression of their mouse homologs in the developing diaphragm, their high CDH-specific pathogenicity scores generated using a previously validated algorithm for genome-scale knowledge synthesis and previously published case reports.
Conclusion We conclude that ES should be ordered in cases of CDH+ when a specific diagnosis is not suspected and CNV analyses are negative. Our results also provide evidence in favour of phenotypic expansions involving CDH for genes associated with ALG12-congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anaemia, Coffin-Siris syndrome and FOXP1-related disorders.
- and neonatal diseases and abnormalities
- genetic testing
- human genetics
- respiratory tract diseases
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Contributors CAS and DAS conceived and directed the study. SRL, PL and JAR provided molecular and clinical data. IMC and CAS performed the machine learning analysis. PL classified variants. DAS determined the level of diagnostic certainty. TMS, AH-G and DAS analysed the data. TMS and DAS wrote the manuscript. All authors reviewed, revised and approved the manuscript.
Funding This research was funded in part by NIH/NICHD grant HD098458 to DAS.
Competing interests The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the clinical ES performed at Baylor Genetics.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. All variants that have not been previously published have also been submitted to the ClinVar database.
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