Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH

J Med Genet. 2022 Mar;59(3):270-278. doi: 10.1136/jmedgenet-2020-107317. Epub 2021 Jan 18.


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.

Keywords: and neonatal diseases and abnormalities; congenital; genetic testing; genetics; hereditary; human genetics; medical; respiratory tract diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • DNA Copy Number Variations / genetics
  • DNA Helicases / genetics
  • Exome / genetics
  • Exome Sequencing
  • Forkhead Transcription Factors / genetics
  • Frameshift Mutation
  • Hernias, Diaphragmatic, Congenital* / diagnosis
  • Hernias, Diaphragmatic, Congenital* / genetics
  • Humans
  • Mice
  • Nuclear Proteins / genetics
  • Repressor Proteins / genetics
  • Transcription Factors / genetics


  • FOXP1 protein, human
  • Forkhead Transcription Factors
  • Nuclear Proteins
  • Repressor Proteins
  • Transcription Factors
  • SMARCA4 protein, human
  • DNA Helicases