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Probable Diagnosis of a Patient with Niemann–Pick Disease Type C: Managing Pitfalls of Exome Sequencing

  • William A. ZeigerEmail author
  • Nasheed I. Jamal
  • Maren T. Scheuner
  • Patricia Pittman
  • Kimiyo M. Raymond
  • Massimo Morra
  • Shri K. Mishra
Research Report
Part of the JIMD Reports book series (JIMD, volume 41)

Abstract

Here, we present a case of a 31-year-old man with progressive cognitive decline, ataxia, and dystonia. Extensive laboratory, radiographic, and targeted genetic studies over the course of several years failed to yield a diagnosis. Initial whole exome sequencing through a commercial laboratory identified several variants of uncertain significance; however, follow-up clinical examination and testing ruled each of these out. Eventually, repeat whole exome sequencing identified a known pathogenic intronic variant in the NPC1 gene (NM_000271.4, c.1554-1009G>A) and an additional heterozygous exonic variant of uncertain significance in the NPC1 gene (NM_000271.4, c.2524T>C). Follow-up biochemical testing was consistent with a diagnosis of probable Niemann–Pick disease Type C (NP-C). This case illustrates the potential of whole exome sequencing for diagnosing rare complex neurologic diseases. It also identifies several potential common pitfalls that must be navigated by clinicians when interpreting commercial whole exome sequencing results.

Keywords

Ataxia Dementia Dystonia Metabolic disease Neurodegeneration Niemann–Pick type C Whole exome sequencing 

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Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • William A. Zeiger
    • 1
    • 2
    Email author
  • Nasheed I. Jamal
    • 1
    • 2
  • Maren T. Scheuner
    • 3
    • 4
  • Patricia Pittman
    • 2
  • Kimiyo M. Raymond
    • 5
  • Massimo Morra
    • 6
  • Shri K. Mishra
    • 1
    • 2
    • 7
    • 8
  1. 1.Department of NeurologyUCLA David Geffen School of MedicineLos AngelesUSA
  2. 2.Department of NeurologyVA Greater Los Angeles Healthcare SystemLos AngelesUSA
  3. 3.Department of MedicineUCLA David Geffen School of MedicineLos AngelesUSA
  4. 4.Department of Medical GeneticsVA Greater Los Angeles Healthcare SystemLos AngelesUSA
  5. 5.Department of Laboratory Medicine and PathologyMayo Clinic College of Medicine and ScienceRochesterUSA
  6. 6.Personalis Inc.Menlo ParkUSA
  7. 7.Department of NeurologyUSC Keck School of MedicineLos AngelesUSA
  8. 8.Department of NeurologyOlive View–UCLA Medical CenterSylmarUSA

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