TY - JOUR
T1 - Systematic analysis of short tandem repeats in 38,095 exomes provides an additional diagnostic yield
AU - van der Sanden, Bart P G H
AU - Corominas, Jordi
AU - de Groot, Michelle
AU - Pennings, Maartje
AU - Meijer, Rowdy P P
AU - Verbeek, Nienke
AU - van de Warrenburg, Bart
AU - Schouten, Meyke
AU - Yntema, Helger G
AU - Vissers, Lisenka E L M
AU - Kamsteeg, Erik-Jan
AU - Gilissen, Christian
N1 - Funding Information:
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).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - PURPOSE: 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.METHODS: 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.RESULTS: 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.CONCLUSION: 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.
AB - PURPOSE: 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.METHODS: 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.RESULTS: 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.CONCLUSION: 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.
UR - http://www.scopus.com/inward/record.url?scp=85104144053&partnerID=8YFLogxK
U2 - 10.1038/s41436-021-01174-1
DO - 10.1038/s41436-021-01174-1
M3 - Article
C2 - 33846582
SN - 1098-3600
VL - 23
SP - 1569
EP - 1573
JO - Genetics in medicine : official journal of the American College of Medical Genetics
JF - Genetics in medicine : official journal of the American College of Medical Genetics
IS - 8
ER -