Abstract Details

Title Interrogating Whole Genome Sequences for Repeat Expansion Diseases in the NIH Undiagnosed Diseases Program

Topic Movement Disorders

Presentation(s) P3 - Poster Session 3 (12:00 PM-1:00 PM)

Poster/Presentation
Number 3-006

Objective

To search bioinformatically for repeat expansion disorders (REDs) in patients from the NIH Undiagnosed Diseases Program (UDP) who had undergone Whole Genome Sequencing (WGS).

Background REDs represent over 40 inherited diseases, mostly manifesting as neurodegenerative or neuromuscular phenotypes. Fragile-X, myotonic dystrophies, C9orf72 associated ALS-FTD, Huntington’s disease (HD) and many spinocerebellar ataxias (SCAs) are representative examples. Repetitive unstable (tri, tetra, penta, hexa, dodeca) nucleotide sequences, often involving 100s-to-1000s of repeats, lead to diseases by disruption of multiple cell biological processes. Recent advances in PCR-free WGS, longer read-length and improved bioinformatics tools have greatly improved the ability to explore these regions.

Design/Methods We interrogated RED loci in 456 WGS studies including singletons and small nuclear families from the NIH UDP using the bioinformatic tool ExpansionHunter (Illumina Corporation). A loci catalog indicating repeat nucleotide composition and boundaries was carefully curated through inspection of the Human Genome Reference (Hg19) and according to the published literature. Individuals with loci representing suspiciously elevated repeat counts were validated by further bioinformatic means and considered for orthogonal validation by DNA fragment-size measurements and Repeat-Primed PCR.

Results In this pilot study, we identified and subsequently validated four previously undiagnosed patients with REDs. These included two patients with the recently reported RFC1 AAGGG recessive RED associated with cerebellar ataxia, sensory neuropathy and vestibular areflexia syndrome (CANVAS), one patient with glutaminase deficiency due to a GCA expansion in the promoter region of the gene GLS presenting with developmental delay, ataxia and seizures and one patient with a mild presentation of Myotonic Dystrophy Type 1.

Conclusions Next generation sequencing and improved bioinformatic tools are beginning to allow for the exploration of low complexity genomic regions, providing alternative approaches in the genome-wide search for known REDs and the discovery of novel ones.

Authors/Disclosures
Camilo Toro, MD, FAAN (NIH) PRESENTER	Dr. Toro has received personal compensation in the range of $100,000-$499,999 for serving as a TORO with NIH/IRP.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file

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