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

Abstract

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.

Figure 1.

NPC1 domains are color coded consistently throughout the panels—blue, cholesterol binding domain; green, NPC1-C; orange, NPC1-I, quasi symmetric partner of NPC1-C; pink, sterol sensing domain; yellow, transmembrane region. (A) Relative exonic distribution of previously published NPC1 mutations. Middle row shows the exonic structure, whereas the height of each bar indicates the relative frequency of disease-causing mutations in each exon. Positions of the mutations described in this work are indicated with arrows. The corresponding structural domains are shown in the bottom row. (B) Structural position of the mutated amino acids Cys516 (blue spheres) and Gly910 (red spheres). A top down view of the putative lipid transport channel shows that Cys516 appears to be closer to the inner surface of the channel. The amino-terminal domain is hidden to not obstruct the view. (C) NPC1 protein domains and affected amino acids. NPC2 is also shown on the same scale (silver). Cholesterol molecules are shown in magenta.

Figure 2.

Cross-species conservation of the NPC1 protein sequence in relation to the two variants p.C516Y and p.G910S, respectively.

Figure 3.

Filipin stain of nonesterified cholesterol in fibroblasts with (A–C) and without (D–F) stimulation of LDL cholesterol uptake. (A,D) Normal control showing 100% esterification. (B,E) Known NPC 1 patient showing 1% esterification. (C,F) Index patient showing 2% esterification. Magnification, 20×.