TY - JOUR
T1 - Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes
AU - Kumar, Kishore R.
AU - Davis, Ryan L.
AU - Tchan, Michel C.
AU - Wali, G. M.
AU - Mahant, Neil
AU - Ng, Karl
AU - Kotschet, Katya
AU - Siow, Sue Faye
AU - Gu, Jason
AU - Walls, Zachary
AU - Kang, Ce
AU - Wali, Gautam
AU - Levy, Stan
AU - Phua, Chung Sen
AU - Yiannikas, Con
AU - Darveniza, Paul
AU - Chang, Florence C. F.
AU - Morales-Briceño, Hugo
AU - Rowe, Dominic B.
AU - Drew, Alex
AU - Gayevskiy, Velimir
AU - Cowley, Mark J.
AU - Minoche, Andre E.
AU - Tisch, Stephen
AU - Hayes, Michael
AU - Kummerfeld, Sarah
AU - Fung, Victor S. C.
AU - Sue, Carolyn M.
N1 - Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Introduction: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. Methods: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. Results: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). Conclusion: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.
AB - Introduction: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. Methods: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. Results: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). Conclusion: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.
KW - Dystonia
KW - Genetic diagnosis
KW - GNAL
KW - KMT2B
KW - Whole genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85074693403&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/nhmrc/1091551
UR - http://purl.org/au-research/grants/nhmrc/1136800
U2 - 10.1016/j.parkreldis.2019.11.004
DO - 10.1016/j.parkreldis.2019.11.004
M3 - Article
C2 - 31731261
AN - SCOPUS:85074693403
VL - 69
SP - 111
EP - 118
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
SN - 1353-8020
ER -