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

TitleA diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders.
Publication TypeJournal Article
Year of Publication2020
AuthorsNgo, KJ, Rexach, JE, Lee, H, Petty, LE, Perlman, S, Valera, JM, Deignan, JL, Mao, Y, Aker, M, Posey, JE, Jhangiani, SN, Coban-Akdemir, ZH, Boerwinkle, E, Muzny, DM, Nelson, AB, Hassin-Baer, S, Poke, G, Neas, K, Geschwind, MD, Grody, WW, Gibbs, RA, Geschwind, DH, Lupski, JR, Below, JE, Nelson, SF, Fogel, BL
JournalHum Mutat
Volume41
Issue2
Pagination487-501
Date Published2020 02
ISSN1098-1004
Abstract

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.

DOI10.1002/humu.23946
Alternate JournalHum Mutat
PubMed ID31692161
PubMed Central IDPMC7182470
Grant ListR01 NS082094 / NS / NINDS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
R01NS058529 / NS / NINDS NIH HHS / United States
K08 NS105916 / NS / NINDS NIH HHS / United States
R25NS065723 / NS / NINDS NIH HHS / United States
U54HG003273 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom