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

Utility of rapid whole exome sequencing in the diagnosis of neonatal Niemann Pick disease type C presenting with fetal hydrops and liver failure.
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Rohanizadegan M, El-Almery S, O'Donnell-Luria A, Mihalek I, Chen P, Sanders M, Leeman K, Cho M, Hung C, Bodamer O,


Rohanizadegan M, El-Almery S, O'Donnell-Luria A, Mihalek I, Chen P, Sanders M, Leeman K, Cho M, Hung C, Bodamer O, (click to view)

Rohanizadegan M, El-Almery S, O'Donnell-Luria A, Mihalek I, Chen P, Sanders M, Leeman K, Cho M, Hung C, Bodamer O,

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Cold Spring Harbor molecular case studies 2017 08 11() pii mcs.a002147
Abstract

Rapid whole exome sequencing (rWES) is increasingly 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 employed rWES in the proband and both parents with a turn-around 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 weeks. 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.

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