Expansions of a subset of short tandem repeats (STRs) have been implicated in approximately 30 different human genetic disorders. Despite extensive application of exome sequencing (ES) in routine diagnostic genetic testing, STRs are not routinely identified from these data.
We assessed diagnostic utility of STR analysis in exome sequencing by applying ExpansionHunter to 2,867 exomes from movement disorder patients and 35,228 other clinical exomes.
We identified 38 movement disorder patients with a possible aberrant STR length. Validation by polymerase chain reaction (PCR) and/or repeat-primed PCR technologies confirmed the presence of aberrant expansion alleles for 13 (34%). For seven of these patients the genotype was compatible with the phenotypic description, resulting in a molecular diagnosis. We subsequently tested the remainder of our diagnostic ES cohort, including over 30 clinically and genetically heterogeneous disorders. Optimized manual curation yielded 167 samples with a likely aberrant STR length. Validations confirmed 93/167 (56%) aberrant expansion alleles, of which 48 were in the pathogenic range and 45 in the premutation range.
Our work provides guidance for the implementation of STR analysis in clinical ES. Our results show that systematic STR evaluation may increase diagnostic ES yield by 0.2%, and recommend making STR evaluation a routine part of ES interpretation in genetic testing laboratories.
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We thank Michael Eberle and Egor Dolzhenko for kindly providing the Python code for the swimlane plots. We thank Ingrid Siegelaer and Monique Gerrits for helping with the molecular confirmations of the HTT allele sizes. This project was financially supported by an Aspasia grant of the Dutch Research Council (015.014.066 to L.E.L.M.V.), a VIDI grant (917-17-353 to CG) and the NWO X-omics project (184.034.019 to CG). The aims of this study contribute to the Solve-RD project (to C.G. and L.E.L.M.V.) which has received funding from the European Union’s Horizon 2020 research and innovation program (number 779257).
The authors declare no competing interests.
Patient samples, together with a basic phenotype description were anonymized. Study was approved by the institutional review board “Commissie Mensgebonden Onderzoek Regio Arnhem-Nijmegen” under number 2011/188. We received and archived consent for participation/publication from every individual whose data is included in this manuscript.
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van der Sanden, B.P.G.H., Corominas, J., de Groot, M. et al. Systematic analysis of short tandem repeats in 38,095 exomes provides an additional diagnostic yield. Genet Med (2021). https://doi.org/10.1038/s41436-021-01174-1