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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Short tandem repeat expansions in the diagnosis of ...
Short tandem repeat expansions in the diagnosis of rare Mendelian diseases by whole genome sequencing
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Pdf Summary
Novel short tandem repeats (STRs) are repetitive sequences of 1-6 base pairs that make up around 3% of the human genome. These STR loci have been associated with various diseases, but they are often not included in the diagnostic process of whole-genome sequencing due to the difficulty in identifying and interpreting them. Most existing tools for detecting STRs only focus on known reference loci, rather than novel loci where STR expansions may occur.<br /><br />However, an approach called STRling has been developed to identify both established and novel STR expansions. It uses k-mer counts derived from DNA sequencing reads to determine the presence and size of STR expansions. Outlier tests are then used to identify rare variants in an individual compared to controls. This method has been successfully applied to identify pathogenic variants in diseases such as myotonic dystrophy.<br /><br />In a study using data from the 1000 Genomes Project, STRling was applied to identify novel STR expansions in 2,504 individuals. The researchers catalogued expansions in both known and novel STR loci. As the sample size increased, the number of variable STR loci discovered also increased, with more reference loci than novel loci identified.<br /><br />One advantage of STRling is that it does not rely on the repeat unit being present in the reference genome, making it valuable in populations with different allele frequencies. The study also demonstrated that STRling is sensitive to large pathogenic expansions, with high detection rates for individuals with allele size estimates from PCR greater than 150 base pairs.<br /><br />Furthermore, STRling has been used in the Undiagnosed Diseases Network (UDN) to identify previously missed pathogenic STR expansions in rare disease families. This includes cases of Huntington's Disease and Spinocerebellar Ataxia Type 17 where the expansions were not detected in previous tests such as whole-genome sequencing.<br /><br />In summary, STRling is a method for identifying both established and novel STR expansions using k-mer counts derived from DNA sequencing reads. It has been shown to be effective in detecting pathogenic variants and has the potential to improve the diagnostic process for rare Mendelian diseases.
Asset Subtitle
Presenting Author - Harriet Dashnow, PhD; Co-Author - Brent Pedersen, PhD; Co-Author - Laurel Hiatt, BA; Co-Author - Aaron R. Quinlan, PhD;
Meta Tag
Bioinformatics
Genome sequencing
Genomic Methodologies
Triplet and Other Repeats
Co-Author
Brent Pedersen, PhD
Co-Author
Laurel Hiatt, BA
Co-Author
Aaron R. Quinlan, PhD
Presenting Author
Harriet Dashnow, PhD
Keywords
Novel short tandem repeats
STRs
human genome
diseases
diagnostic process
whole-genome sequencing
STRling
k-mer counts
STR expansions
pathogenic variants
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