A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

Kathie J. Ngo, Jessica E. Rexach, Hane Lee, Lauren E. Petty, Susan Perlman, Juliana M. Valera, Joshua L. Deignan, Yuanming Mao, Mamdouh Aker, Jennifer E. Posey, Shalini N. Jhangiani, Zeynep H. Coban-Akdemir, Eric Boerwinkle, Donna Muzny, Alexandra B. Nelson, Sharon Hassin-Baer, Gemma Poke, Katherine Neas, Michael D. Geschwind, Wayne W. GrodyRichard Gibbs, Daniel H. Geschwind, James R. Lupski, Jennifer E. Below, Stanley F. Nelson, Brent L. Fogel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.

Original languageEnglish
Pages (from-to)487-501
Number of pages15
JournalHuman Mutation
Issue number2
StatePublished - 1 Feb 2020


FundersFunder number
Baylor Hopkins Center for Mendelian Genomics
Rochester Ataxia Foundation
National Heart, Lung, and Blood Institute
National Human Genome Research Institute
National Institute of Neurological Disorders and StrokeU54HG003273, K08HG008986, K08NS105916, R01NS082094, R25NS065723, R35NS105078, R01NS058529
University of California
National Center for Advancing Translational Sciences
Asian American Studies Center, University of California Los Angeles
Atlanta Clinical and Translational Science Institute
Wellcome Trust
Clinical and Translational Science Institute, University of California, San FranciscoUL1TR000124, UM1HG006542


    • ataxia
    • cerebellar ataxia
    • cerebellum
    • diagnostic testing
    • exome
    • gait disorders
    • genetics
    • genomics
    • neurogenetics
    • spastic paraparesis
    • spastic paraplegia
    • spinocerebellar ataxia


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