Deep whole-genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias
Eric L. Bogenschutz,
Zac D. Fox,
Andrew Farrell,
Julia Wynn,
Barry Moore,
Lan Yu,
Gudrun Aspelund,
Gabor Marth,
Mark Yandell,
Yufeng Shen,
Wendy K. Chung,
Gabrielle Kardon
Affiliations
Eric L. Bogenschutz
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Zac D. Fox
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Andrew Farrell
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Julia Wynn
Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA
Barry Moore
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Lan Yu
Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA
Gudrun Aspelund
Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
Gabor Marth
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Mark Yandell
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Yufeng Shen
Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA; JP Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY 10032, USA
Wendy K. Chung
Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
Gabrielle Kardon
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Corresponding author
Summary: The diaphragm is critical for respiration and separation of the thoracic and abdominal cavities, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The genetic etiology of CDH is complex. Single-nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs) in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple individuals and mutated genes are incompletely penetrant. This suggests that multiple genetic variants in combination, other not-yet-investigated classes of variants, and/or nongenetic factors contribute to CDH etiology. However, no studies have comprehensively investigated in affected individuals the contribution of all possible classes of variants throughout the genome to CDH etiology. In our study, we used a unique cohort of four individuals with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood and deep whole-genome sequencing to assess germline and somatic de novo and inherited SNVs, indels, and SVs. In each individual we found a different mutational landscape that included germline de novo and inherited SNVs and indels in multiple genes. We also found in two individuals a 343 bp deletion interrupting an annotated enhancer of the CDH-associated gene GATA4, and we hypothesize that this common SV (found in 1%–2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial.
