Utility of rapid whole-exome sequencing in the diagnosis of Niemann-Pick disease type C presenting with fetal hydrops and acute liver failure

Cold Spring Harb Mol Case Stud. 2017 Nov 21;3(6):a002147. doi: 10.1101/mcs.a002147. Print 2017 Nov.


Rapid whole-exome sequencing (rWES) is used in critically ill newborn infants to inform about diagnosis, clinical management, and prognosis. Here we report a male newborn infant with hydrops, pancytopenia, and acute liver failure who was listed for liver transplantation. Given the acuity of the presentation, the procedure-related morbidity and mortality, and lack of diagnosis, we used rWES in the proband and both parents with a turnaround time of 10 business days. rWES returned one maternally inherited, likely pathogenic and one paternally inherited, likely pathogenic variant in NPC1, suggestive of a diagnosis of Niemann-Pick disease type C (NPC). Interestingly, a diagnosis of NPC was entertained prior to rWES, but deemed unlikely in light of absent cholesterol storage on liver biopsy and near-normal oxysterol levels in dried blood. The diagnosis of NPC was confirmed on filipin stain in fibroblasts demonstrating defective cholesterol trafficking. NPC is a slowly progressive neurodegenerative disorder that may also affect the liver with overall poor prognosis. It was decided to take the infant off the transplant list and transfer to palliative care, where he died after 4 wk. This case highlights the utility of rWES in an acute clinical setting for several domains of precision medicine including (1) diagnosis, (2) prognosis and outcome, (3) management and therapy, and (4) utilization of resources.

Keywords: fatal liver failure in infancy; fetal ascites; nonimmune hydrops fetalis.

Publication types

  • Case Reports

MeSH terms

  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Exome
  • Exome Sequencing / statistics & numerical data
  • Filipin / analysis
  • Humans
  • Hydrops Fetalis / diagnosis
  • Hydrops Fetalis / genetics
  • Infant, Newborn
  • Intracellular Signaling Peptides and Proteins
  • Liver / pathology
  • Liver Failure, Acute / genetics
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Niemann-Pick C1 Protein
  • Niemann-Pick Disease, Type C / diagnosis*
  • Niemann-Pick Disease, Type C / genetics*


  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • Niemann-Pick C1 Protein
  • Filipin