Evidence for an association between Coffin-Siris syndrome and congenital diaphragmatic hernia

Am J Med Genet A. 2022 Sep;188(9):2718-2723. doi: 10.1002/ajmg.a.62889. Epub 2022 Jul 7.


Coffin-Siris syndrome (CSS) is an autosomal dominant neurodevelopmental syndrome that can present with a variety of structural birth defects. Pathogenic variants in 12 genes have been shown to cause CSS. Most of these genes encode proteins that are a part of the mammalian switch/sucrose non-fermentable (mSWI/SNF; BAF) complex. An association between genes that cause CSS and congenital diaphragmatic hernia (CDH) has been suggested based on case reports and the analysis of CSS and CDH cohorts. Here, we describe an unpublished individual with CSS and CDH, and we report additional clinical information on four published cases. Data from these individuals, and a review of the literature, provide evidence that deleterious variants in ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2, DPF2, and SMARCC2, which are associated with CSS types 1-8, respectively, are associated with the development of CDH. This suggests that additional genetic testing to identify a separate cause of CDH in an individual with CSS may be unwarranted, and that comprehensive genetic testing for individuals with non-isolated CDH should include an evaluation of CSS-related genes. These data also suggest that the mSWI/SNF (BAF) complex may play an important role in diaphragm development.

Keywords: CDH; Coffin-Siris syndrome; congenital diaphragmatic hernia; exome sequencing.

Publication types

  • Case Reports
  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Multiple* / diagnosis
  • Abnormalities, Multiple* / genetics
  • Chromosomal Proteins, Non-Histone
  • DNA Helicases / genetics
  • DNA-Binding Proteins / genetics
  • Face / abnormalities
  • Hand Deformities, Congenital* / complications
  • Hand Deformities, Congenital* / diagnosis
  • Hand Deformities, Congenital* / genetics
  • Hernias, Diaphragmatic, Congenital* / genetics
  • Hernias, Diaphragmatic, Congenital* / pathology
  • Humans
  • Intellectual Disability* / pathology
  • Micrognathism* / genetics
  • Micrognathism* / pathology
  • Neck / abnormalities
  • Nuclear Proteins / genetics
  • Transcription Factors / genetics


  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • DPF2 protein, human
  • Nuclear Proteins
  • SMARCC2 protein, human
  • SMARCE1 protein, human
  • Transcription Factors
  • SMARCA4 protein, human
  • DNA Helicases

Supplementary concepts

  • Coffin-Siris syndrome