Abstract
Complex neurologic phenotypes are inherently difficult to diagnose. Whole-exome sequencing
(WES) is a new tool in the neurologist’s diagnostic armamentarium. Whole-exome sequencing
can be applied to investigate the “diagnostic odyssey” cases. These cases involve
patients with rare diseases that likely have a genetic etiology but have failed to
be diagnosed by clinical evaluation and targeted gene testing. We describe such a
case, a 22-year-old man who had mild intellectual developmental disability and episodes
of jerking ataxic movements that affected his whole body. He underwent numerous multidisciplinary
and multicentric evaluations throughout his life that failed to establish a clear
diagnosis. Following his visit to Mayo Clinic in Jacksonville, Florida, WES was applied
for genetic determination of the unknown disorder in the proband and his biological
parents and sister. Additional clinical evaluation, magnetic resonance neuroimaging,
electromyography, and electroencephalography of the proband were performed to verify
the phenotype after the WES results were available. To our knowledge, this is the
first report of the application of WES to facilitate the diagnosis of episodic ataxia
type 1. This case illustrates that WES supported by clinical data is a useful and
time-saving tool in the evaluation of patients with rare and complex hereditary disorders.
Abbreviations and Acronyms:
DMPK (myotonic dystrophy protein kinase gene), EA1 (episodic ataxia type 1), EEG (electroencephalography), EMG (electromyography), HTT (huntingtin gene), MRI (magnetic resonance imaging), WES (whole-exome sequencing)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Mayo Clinic ProceedingsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Targeted capture and massively parallel sequencing of 12 human exomes.Nature. 2009; 461: 272-276
- Exome sequencing identifies the cause of a mendelian disorder.Nat Genet. 2010; 42: 30-35
- Exome sequencing: an efficient diagnostic tool for complex neurodegenerative disorders.Eur J Neurol. 2013; 20: 486-492
- Implementing individualized medicine into the medical practice.Am J Med Genet C Semin Med Genet. 2014; 166C: 15-23
Farwell KD, Shahmirzadi L, El-Khechen D, et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions [published online ahead of print November 6, 2014]. Genet Med. http://dx.doi.org/10.1038/gim.2014.154.
- Cerebellar ataxias.Curr Opin Neurol. 2009; 22: 419-429
- Episodic ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation.Brain. 2014; 137: 1009-1018
- Hereditary myokymia and periodic ataxia.J Neurol Sci. 1975; 25: 109-118
- Episodic ataxia type 1: a neuronal potassium channelopathy.Neurotherapeutics. 2007; 4: 258-266
- Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability.Ann Neurol. 2000; 48: 647-656
- Episodic ataxia type 1 with distal weakness: a novel manifestation of a potassium channelopathy.Neuropediatrics. 2004; 35: 147-149
- Episodic ataxia type 1 without episodic ataxia: the diagnostic utility of nerve excitability studies in individuals with KCNA1 mutations.Dev Med Child Neurol. 2013; 55: 959-962
- Characterization of the Kv1.1 I262T and S342I mutations associated with episodic ataxia 1 with distinct phenotypes.Arch Biochem Biophys. 2012; 524: 99-105
- A novel KCNA1 mutation associated with global delay and persistent cerebellar dysfunction.Mov Disord. 2009; 24: 778-782
- Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia.JAMA Neurol. 2014; 71: 1237-1246
- Three novel KCNA1 mutations in episodic ataxia type I families.Hum Genet. 1998; 102: 464-466
- Novel mutation in KCNA1 causes episodic ataxia with paroxysmal dyspnea.Muscle Nerve. 2008; 37: 399-402
Article Info
Publication History
Published online: February 02, 2015
Footnotes
Grant Support: This work was supported in part by the Max Kade Foundation (P.T.), grants P50 NS072187 (O.A.R., Z.K.W.) and R01 NS078086 (O.A.R.) from the National Institutes of Health/National Institute of Neurological Disorders and Stroke , a gift from Carl Edward Bolch, Jr, and Susan Bass Bolch (Z.K.W.), and funding from the Mayo Clinic Center for Individualized Medicine.
Potential Competing Interests: Dr Tang and Ms El-Khechen are employed by and receive a salary from Ambry Genetics Corp. Exome sequencing is among its commercially available tests.
Identification
Copyright
© 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
