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.
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Communicated by: Robert Steiner
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Synopsis
Whole exome sequencing is a powerful tool for diagnosing inherited metabolic disorders with complex neurologic phenotypes such as NP-C, but results obtained through commercial laboratories must be interpreted carefully and always in the appropriate clinical context.
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Author Contributions
William Zeiger – Conceptualization of the study; interpretation of the data; and drafting and revising the manuscript for intellectual content.
Nasheed I. Jamal – Conceptualization of the study; interpretation of the data; and revising the manuscript for intellectual content.
Maren T. Scheuner – Analysis and interpretation of the data; and revising the manuscript for intellectual content.
Patricia Pittman – Conceptualization of the study.
Kimiyo M. Raymond – Analysis and interpretation of the data; and revising the manuscript for intellectual content.
Massimo Morra – Analysis and interpretation of the data; and revising the manuscript for intellectual content.
Shri K. Mishra – Conceptualization of the study; analysis and interpretation of the data; and revising the manuscript for intellectual content.
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William Zeiger.
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Dr. Zeiger declares that he has no conflict of interest.
Dr. Jamal declares that she has no conflict of interest.
Dr. Scheuner declares that she has no conflict of interest.
Ms. Pittman declares that she has no conflict of interest.
Dr. Raymond declares that she has no conflict of interest.
Dr. Morra is an employee of Personalis, Inc.
Dr. Mishra declares that he has no conflict of interest.
The authors confirm independence from any sponsors and the content of the article has not been influenced by any sponsors.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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This case report was carried out in accordance with the guidance of the office of research and development of the Veterans Health Administration. No identifiable patient information is included in this report.
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© 2018 Society for the Study of Inborn Errors of Metabolism (SSIEM)
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Zeiger, W.A. et al. (2018). Probable Diagnosis of a Patient with Niemann–Pick Disease Type C: Managing Pitfalls of Exome Sequencing. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 41. JIMD Reports, vol 41. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_90
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DOI: https://doi.org/10.1007/8904_2018_90
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