TY  - JOUR
A1  - Rafehi, Haloom
A1  - Fearnley, Liam G.
A1  - Read, Justin
A1  - Snell, Penny
A1  - Davies, Kayli C.
A1  - Scott, Liam
A1  - Gillies, Greta
A1  - Thompson, Genevieve C.
A1  - Field, Tess A.
A1  - Eldo, Aleena
A1  - Bodek, Simon
A1  - Butler, Ernest
A1  - Chen, Luke
A1  - Drago, John
A1  - Goel, Himanshu
A1  - Hackett, Anna
A1  - Halmagyi, G. Michael
A1  - Hannaford, Andrew
A1  - Kotschet, Katya
A1  - Kumar, Kishore R.
A1  - Kumble, Smitha
A1  - Lee-Archer, Matthew
A1  - Malhotra, Abhishek
A1  - Paine, Mark
A1  - Poon, Michael
A1  - Pope, Kate
A1  - Reardon, Katrina
A1  - Ring, Steven
A1  - Ronan, Anne
A1  - Silsby, Matthew
A1  - Smyth, Renee
A1  - Stutterd, Chloe
A1  - Wallis, Mathew
A1  - Waterston, John
A1  - Wellings, Thomas
A1  - West, Kirsty
A1  - Wools, Christine
A1  - Wu, Kathy H.C.
A1  - Szmulewicz, David J.
A1  - Delatycki, Martin B.
A1  - Bahlo, Melanie
A1  - Lockhart, Paul J.
T1  - A prospective trial comparing programmable targeted long-read sequencing and short-read genome sequencing for genetic diagnosis of cerebellar ataxia
Y1  - 2025/04/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 769 
EP  - 785 
DO  - 10.1101/gr.279634.124 
VL  - 35 
IS  - 4 
UR  - http://genome.cshlp.org/content/35/4/769.abstract 
N2  - The cerebellar ataxias (CAs) are a heterogeneous group of disorders characterized by progressive incoordination. Seventeen repeat expansion (RE) loci have been identified as the primary genetic cause and account for >80% of genetic diagnoses. Despite this, diagnostic testing is limited and inefficient, often utilizing single gene assays. This study evaluates the effectiveness of long- and short-read sequencing as diagnostic tools for CA. We recruited 110 individuals (48 females, 62 males) with a clinical diagnosis of CA. Short-read genome sequencing (SR-GS) was performed to identify pathogenic RE and also non-RE variants in 356 genes associated with CA. Independently, long-read sequencing with adaptive sampling (LR-AS) was performed to identify pathogenic RE. SR-GS provided a genetic diagnosis for 38% of the cohort (40/110) including seven non-RE pathogenic variants. RE causes disease in 33 individuals, with the most common condition being SCA27B (n = 24). In comparison, LR-AS identified pathogenic RE in 29 individuals. RE identification for the two methods was concordant apart from four SCA27B cases not detected by LR-AS due to low read depth. For both technologies manual review of the RE alignment enhances diagnostic outcomes. Orthogonal testing for SCA27B revealed a 15% and 0% false positive rate for SR-GS and LR-AS, respectively. In conclusion, both technologies are powerful screening tools for CA. SR-GS is a mature technology currently used by diagnostic providers, requiring only minor changes in bioinformatic workflows to enable CA diagnostics. LR-AS offers considerable advantages in the context of RE detection and characterization but requires optimization before clinical implementation. 
ER  -