Abstract Details

Title Long Read Genome Sequencing for Cerebellar Ataxia

Topic Movement Disorders

Presentation(s) P4 - Poster Session 4 (8:00 AM-9:00 AM)

Poster/Presentation
Number 16-009

Objective To assess the diagnostic yield of long-read genome sequencing (LR-GS) in ataxia patients with prior non-diagnostic genetic testing.

Background Hereditary cerebellar ataxias are genetically diverse disorders characterized by progressive cerebellar atrophy. Despite advances in conventional methods of genetic testing, such as exome sequencing, repeat-expansion testing, and targeted gene panels, many ataxia cases remain genetically undiagnosed. The diagnostic yield of next-generation sequencing and repeat-expansion panels remains limited, and multiple tests are often needed. LR-GS can detect structural variants, including tandem repeats, more robustly than short-read approaches and may consolidate testing and increase diagnostic yield.

Design/Methods We attempted to perform LR-GS on 100 previously extracted DNA samples from patients with negative prior clinical testing for cerebellar ataxia. Of these, 59 samples had adequate quality for LR-GS. Inclusion was not limited by prior test type. The standard PacBio pipeline was used for variant calling and annotation.

Results All 59 patients had negative ataxia repeat-expansion analysis, and a subset had prior exome testing. Six yielded a diagnostic or likely diagnostic finding, and one candidate variant was identified that requires further validation. In one case, LR-GS assisted in the interpretation of two previously identified variants by establishing their phase as in trans.

Conclusions LR-GS can accurately identify disease-causing variants in ataxia. While high-molecular-weight DNA extraction is recommended for LR-GS, over half of previously extracted DNA samples were of sufficient quality, suggesting the feasibility of reanalyzing previously stored specimens. In 8 cases (14%) a potentially diagnostic finding was identified; however, in seven of these eight cases, the finding would likely have been detected by short-read genome sequencing.

Authors/Disclosures
Niki Maki, MD (Harbor UCLA) PRESENTER	An immediate family member of Dr. Maki has received personal compensation for serving as an employee of J &J. An immediate family member of Dr. Maki has received intellectual property interests from a discovery or technology relating to health care.
Kirsten Blanco, MS, LCGC	Ms. Blanco has nothing to disclose.
Rebekah Barrick, MS	Mrs. Barrick has nothing to disclose.
Erica Smith (UC Irvine)	No disclosure on file
Ivan De Dios	Mr. De Dios has nothing to disclose.
Seth Berger (Ambry Genetics)	No disclosure on file
Emmanuele Delot, PhD	Dr. Delot has nothing to disclose.
Krista Bluske, PhD	Dr. Bluske has received personal compensation for serving as an employee of Ambry Genetics.
Georgia Pitsava, MD	Dr. Pitsava has nothing to disclose.
Ravi Das, MD, MBBS	Dr. Das has nothing to disclose.
Christopher Gomez, MD, PhD (University of Chicago)	Dr. Gomez has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Gomez has received research support from Nih.
Eric Vilain, MD, PhD (UCLA)	Eric Vilain, MD, PhD has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Children's National Hospital . Eric Vilain, MD, PhD has received intellectual property interests from a discovery or technology relating to health care.
Changrui Xiao, MD (UC Irvine)	Dr. Xiao has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for WIley. The institution of Dr. Xiao has received research support from NIH.

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