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Cold Spring Harb Mol Case Stud. 2018 Jun 1;4(3). pii: a002469. doi: 10.1101/mcs.a002469. Print 2018 Jun.

The case for early use of rapid whole-genome sequencing in management of critically ill infants: late diagnosis of Coffin-Siris syndrome in an infant with left congenital diaphragmatic hernia, congenital heart disease, and recurrent infections.

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Rady Children's Institute for Genomic Medicine, University of California, San Diego, California 92123, USA.
Department of Pediatrics, Division of Neonatology, University of California, San Diego, California 92123, USA.
Department of Pediatrics, Division of Genetics, University of California, San Diego, California 92123, USA.
Department of Pediatrics, Division of Dysmorphology and Teratology, Center for Better Beginnings, University of California, San Diego, California 92123, USA.


Congenital diaphragmatic hernia (CDH) results from incomplete formation of the diaphragm leading to herniation of abdominal organs into the thoracic cavity. CDH is associated with pulmonary hypoplasia, congenital heart disease, and pulmonary hypertension. Genetically, it is associated with aneuploidies, chromosomal copy-number variants, and single gene mutations. CDH is the most expensive noncardiac congenital defect. Management frequently requires implementation of extracorporeal membrane oxygenation (ECMO), which increases management expenditures 2.4-3.5-fold. The cost of management of CDH has been estimated to exceed $250 million per year. Despite in-hospital survival of 80%-90%, current management is imperfect, as a great proportion of surviving children have long-term functional deficits. We report the case of a premature infant prenatally diagnosed with CDH and congenital heart disease, who had a protracted and complicated course in the intensive care unit with multiple surgical interventions, including postcardiac surgery ECMO, gastrostomy tube placement with Nissen fundoplication, tracheostomy for respiratory failure, recurrent infections, and developmental delay. Rapid whole-genome sequencing (rWGS) identified a de novo, likely pathogenic, c.3096_ 3100delCAAAG (p.Lys1033Argfs*32) variant in ARID1B, providing a diagnosis of Coffin-Siris syndrome. Her parents elected palliative care and she died later that day.


anteverted nares; aplasia/hypoplasia of the corpus callosum; central hypotonia; congenital diaphragmatic hernia; congenital mitral stenosis; failure to thrive in infancy; frontal hirsutism; malrotation of small bowel; moderate global developmental delay; perimembranous ventricular septal defect; postductal coarctation of the aorta; recurrent respiratory infections

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