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Profiling the genome-wide landscape of tandem repeat expansions.

ABSTRACT: Tandem repeat (TR) expansions have been implicated in dozens of genetic diseases, including Huntington's Disease, Fragile X Syndrome, and hereditary ataxias. Furthermore, TRs have recently been implicated in a range of complex traits, including gene expression and cancer risk. While the human genome harbors hundreds of thousands of TRs, analysis of TR expansions has been mainly limited to known pathogenic loci. A major challenge is that expanded repeats are beyond the read length of most next-generation sequencing (NGS) datasets and are not profiled by existing genome-wide tools. We present GangSTR, a novel algorithm for genome-wide genotyping of both short and expanded TRs. GangSTR extracts information from paired-end reads into a unified model to estimate maximum likelihood TR lengths. We validate GangSTR on real and simulated data and show that GangSTR outperforms alternative methods in both accuracy and speed. We apply GangSTR to a deeply sequenced trio to profile the landscape of TR expansions in a healthy family and validate novel expansions using orthogonal technologies. Our analysis reveals that healthy individuals harbor dozens of long TR alleles not captured by current genome-wide methods. GangSTR will likely enable discovery of novel disease-associated variants not currently accessible from NGS.

SUBMITTER: Mousavi N

PROVIDER: S-EPMC6735967 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Profiling the genome-wide landscape of tandem repeat expansions.

Mousavi Nima N Shleizer-Burko Sharona S Yanicky Richard R Gymrek Melissa M

Nucleic acids research 20190901 15

Tandem repeat (TR) expansions have been implicated in dozens of genetic diseases, including Huntington's Disease, Fragile X Syndrome, and hereditary ataxias. Furthermore, TRs have recently been implicated in a range of complex traits, including gene expression and cancer risk. While the human genome harbors hundreds of thousands of TRs, analysis of TR expansions has been mainly limited to known pathogenic loci. A major challenge is that expanded repeats are beyond the read length of most next-ge ...[more]

PMID: 31194863

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Project description:BackgroundScreening for short tandem repeat (STR) expansions in next-generation sequencing data can enable diagnosis, optimal clinical management/treatment, and accurate genetic counseling of patients with repeat expansion disorders. We aimed to develop an efficient computational workflow for reliable detection of STR expansions in next-generation sequencing data and demonstrate its clinical utility.MethodsWe characterized the performance of eight STR analysis methods (lobSTR, HipSTR, RepeatSeq, ExpansionHunter, TREDPARSE, GangSTR, STRetch, and exSTRa) on next-generation sequencing datasets of samples with known disease-causing full-mutation STR expansions and genomes simulated to harbor repeat expansions at selected loci and optimized their sensitivity. We then used a machine learning decision tree classifier to identify an optimal combination of methods for full-mutation detection. In Burrows-Wheeler Aligner (BWA)-aligned genomes, the ensemble approach of using ExpansionHunter, STRetch, and exSTRa performed the best (precision = 82%, recall = 100%, F1-score = 90%). We applied this pipeline to screen 301 families of children with suspected genetic disorders.ResultsWe identified 10 individuals with full-mutations in the AR, ATXN1, ATXN8, DMPK, FXN, or HTT disease STR locus in the analyzed families. Additional candidates identified in our analysis include two probands with borderline ATXN2 expansions between the established repeat size range for reduced-penetrance and full-penetrance full-mutation and seven individuals with FMR1 CGG repeats in the intermediate/premutation repeat size range. In 67 probands with a prior negative clinical PCR test for the FMR1, FXN, or DMPK disease STR locus, or the spinocerebellar ataxia disease STR panel, our pipeline did not falsely identify aberrant expansion. We performed clinical PCR tests on seven (out of 10) full-mutation samples identified by our pipeline and confirmed the expansion status in all, showing absolute concordance between our bioinformatics and molecular findings.ConclusionsWe have successfully demonstrated the application of a well-optimized bioinformatics pipeline that promotes the utility of genome-wide sequencing as a first-tier screening test to detect expansions of known disease STRs. Interrogating clinical next-generation sequencing data for pathogenic STR expansions using our ensemble pipeline can improve diagnostic yield and enhance clinical outcomes for patients with repeat expansion disorders.

Project description:Epilepsies are a group of common neurological disorders with a substantial genetic basis. Despite this, the molecular diagnosis of epilepsies remains challenging due to its heterogeneity. Studies utilizing whole-genome sequencing may provide additional insights into genetic causes of epilepsies of unknown aetiology. Whole-genome sequencing was used to evaluate a cohort of adults with unexplained developmental and epileptic encephalopathies (n = 30), for whom prior genetic tests, including whole-exome sequencing in some cases, were negative or inconclusive. Rare single nucleotide variants, insertions/deletions, copy number variants and tandem repeat expansions were analysed. Seven pathogenic or likely pathogenic single nucleotide variants, and two pathogenic deleterious copy number variants were identified in nine patients (32.1% of the cohort). One of the copy number variants, identified in a patient with Lennox-Gastaut syndrome, was too small to be detected by chromosomal microarray techniques. We also identified two tandem repeat expansions with clinical implications in two other patients with Lennox-Gastaut syndrome: a CGG repeat expansion in the 5'untranslated region of DIP2B, and a CTG expansion in ATXN8OS (previously implicated in spinocerebellar ataxia type 8). Three patients had KCNA2 pathogenic variants. One of them died of sudden unexpected death in epilepsy. The other two patients had, in addition to a KCNA2 variant, a second de novo variant impacting potential epilepsy-relevant genes (KCNIP4 and UBR5). Overall, whole-genome sequencing provided a genetic explanation in 32.1% of the total cohort. This is also the first report of coding and non-coding tandem repeat expansions identified in patients with Lennox-Gastaut syndrome. This study demonstrates that using whole-genome sequencing, the examination of multiple types of rare genetic variation, including those found in the non-coding region of the genome, can help resolve unexplained epilepsies.

Dataset Information

Profiling the genome-wide landscape of tandem repeat expansions.

Publications

Profiling the genome-wide landscape of tandem repeat expansions.

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