2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Detecting Short Tandem Repeat Expansions: Three-year Experience with Clinical Whole Genome Sequencing (cWGS) for a Rare and Undiagnosed Population

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This document summarizes a three-year experience with detecting short tandem repeat (STR) expansions using clinical whole-genome sequencing (cWGS) in 929 individuals with rare and undiagnosed diseases. The study aimed to illustrate the STR screening and confirmatory testing process and summarized the findings by age, phenotype, and repeat size.<br /><br />The study reported pathogenic expanded alleles in 13 affected individuals from 10 families, accounting for 1.4% of total cases and 3.7% of positive cases. Five gene targets were found to have STRs, including ATXN7, ATXN8OS, C9orf72, DMPK, and FXN. The genetic disorders identified included hereditary forms of ataxia (61.5%), frontotemporal dementia and/or amyotrophic lateral sclerosis (15.4%), and neuromuscular disease (23.1%).<br /><br />Sequencing was performed using the Illumina TruSeq PCR-free kit, and ExpansionHunter was used to screen 21 gene targets for repeat expansions in clinically relevant short tandem repeats. The study confirmed the original STR expansion results in all samples submitted for orthogonal testing. <br /><br />The findings of the study suggest that testing for STRs improves the sensitivity and clinical utility of cWGS as a first-tier diagnostic test. Expanding the list of gene targets could further enhance the value of incorporating STR testing into cWGS. The study also highlights the importance of developing best practices for reporting STRs in a rare disease population, both in adults and children. The distribution of phenotype by age showed that hereditary ataxias were diagnosed in both pediatric and adult patients, while frontotemporal dementia/amyotrophic lateral sclerosis and neuromuscular conditions were more prevalent in the adult population.<br /><br />Overall, the study demonstrates the potential of cWGS in detecting STR expansions and its clinical utility in diagnosing rare and undiagnosed diseases.

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Presenting Author - Brittany Thomas, MS, CGC; Co-Author - Akanchha Kesari, PhD, FACMG; Co-Author - Aime Lumaka, MD, PhD; Co-Author - Mario Cornejo-Olivas, MD; Co-Author - David Ward, MD; Co-Author - Parul Jayakar, MD, MS; Co-Author - Donald Basel, MBBCh; Co-Author - Marilyn C. Jones, MD; Co-Author - Erin Thorpe, MS,CGC; Co-Author - Denise L. Perry, MS; Co-Author - Ryan J. Taft, PhD;

Meta Tag

Cognitive Disorders

Genetic Testing

Genome sequencing

Genomic Methodologies

Methodology

NextGen Sequencing

Sequencing

Triplet and Other Repeats

Variant Detection

Co-Author Akanchha Kesari, PhD, FACMG

Co-Author Aime Lumaka, MD, PhD

Co-Author Mario Cornejo-Olivas, MD

Co-Author David Ward, MD

Co-Author Parul Jayakar, MD, MS

Co-Author Donald Basel, MBBCh

Co-Author Marilyn C. Jones, MD

Co-Author Erin Thorpe, MS,CGC

Co-Author Denise L. Perry, MS

Co-Author Ryan J. Taft, PhD

Presenting Author Brittany Thomas, MS, CGC

Keywords

short tandem repeat expansions

clinical whole-genome sequencing

rare diseases

phenotype

gene targets

hereditary ataxia

frontotemporal dementia

neuromuscular disease

diagnostic test

phenotype distribution