2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Evaluating the Impact of Long Read Genomes in Rare Disease: A systematic analysis of 1000 HiFi Genomes

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The document discusses the implementation of long read HiFi genome sequencing (lrGS) in a rare disease cohort called Genomic Answers for Kids (GA4K) in order to increase the diagnostic rate in rare diseases. The lrGS was applied to individuals with suspected genetic disorders who remained undiagnosed after exome or genome sequencing. The genome sequences were analyzed for copy number, structural variation, single nucleotide variation, repeat expansion, and 5-methyl C detection. Alignment metrics were evaluated, showing that the assembly size of the HiFi genomes was 3.02x109 and the mean N50 was 2.3x107. The implementation of HiFi GS resulted in an approximate 10% increase in diagnostic yield in the cohort. Previously reported variants were also recapitulated, indicating the usability of HiFi GS as a first-tier genome test. The document also mentions the detection of additional variation, such as SNVs and SVs/CNVs, by HiFi sequencing compared to short-read sequencing. HiFi sequencing was able to resolve known pseudogene regions, such as GBA, and detect pathogenic deletions. The use of the tandem repeat genotype tool (TGRT) allowed for the identification of pathological expansions in genes associated with repeat expansion disorders. Clinical confirmation through genotyping and PCR was done for special cases. The document further discusses the use of direct 5-methyl-C detection, which resulted in functional validation of detected expansions and the identification of novel hypermethylation events. Overall, the implementation of lrGS in the GA4K program shows promise in increasing diagnostic rates in rare diseases and simplifying genetic testing algorithms.

Asset Subtitle

Presenting Author - Emily G. Farrow, PhD, CGC; Co-Author - Isabelle Thiffault, PhD, MsC, FABMGG; Co-Author - Ana SA. Cohen, PhD; Co-Author - Tricia N. Zion, MS,CGC; Co-Author - Adam M. Walter, MB(ASCP); Co-Author - Margaret Gibson, MB(ASCP); Co-Author - Chengpeng Bi, PhD; Co-Author - Warren A. Cheung, PhD; Co-Author - Jeffrey J. Johnston, PhD; Co-Author - Tomi Pastinen, MD, PhD;

Meta Tag

Genetic Testing

Genome sequencing

Genomic Methodologies

NextGen Sequencing

Sequencing

Triplet and Other Repeats

Variant Detection

Co-Author Isabelle Thiffault, PhD, MsC, FABMGG

Co-Author Ana SA. Cohen, PhD

Co-Author Tricia N. Zion, MS,CGC

Co-Author Adam M. Walter, MB(ASCP)

Co-Author Margaret Gibson, MB(ASCP)

Co-Author Chengpeng Bi, PhD

Co-Author Warren A. Cheung, PhD

Co-Author Jeffrey J. Johnston, PhD

Co-Author Tomi Pastinen, MD, PhD

Presenting Author Emily G. Farrow, PhD, CGC

Keywords

long read HiFi genome sequencing

rare disease cohort

diagnostic rate

genome sequencing

copy number variation

structural variation

repeat expansion

5-methyl C detection

diagnostic yield

first-tier genome test