Erik-Jan Kamsteeg1, Christian Gilissen2,3, Bart P G H van der Sanden4,5, Jordi Corominas4, Michelle de Groot4, Maartje Pennings4, Rowdy P P Meijer4, Nienke Verbeek6, Bart van de Warrenburg7, Meyke Schouten4, Helger G Yntema4, Lisenka E L M Vissers4,5. 1. Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands. erik-jan.kamsteeg@radboudumc.nl. 2. Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands. christian.gilissen@radboudumc.nl. 3. Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. christian.gilissen@radboudumc.nl. 4. Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands. 5. Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands. 6. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 7. Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
Abstract
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.
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.
Authors: Gaby Schobers; Jolanda H Schieving; Michèl A A P Willemsen; Lisenka E L M Vissers; Helger G Yntema; Maartje Pennings; Rolph Pfundt; Ronny Derks; Tom Hofste; Ilse de Wijs; Nienke Wieskamp; Simone van den Heuvel; Jordi Corominas Galbany; Christian Gilissen; Marcel Nelen; Han G Brunner; Tjitske Kleefstra; Erik-Jan Kamsteeg Journal: Genome Med Date: 2022-06-17 Impact factor: 15.266
Authors: Saskia B Wortmann; Machteld M Oud; Mariëlle Alders; Karlien L M Coene; Saskia N van der Crabben; René G Feichtinger; Alejandro Garanto; Alex Hoischen; Mirjam Langeveld; Dirk Lefeber; Johannes A Mayr; Charlotte W Ockeloen; Holger Prokisch; Richard Rodenburg; Hans R Waterham; Ron A Wevers; Bart P C van de Warrenburg; Michel A A P Willemsen; Nicole I Wolf; Lisenka E L M Vissers; Clara D M van Karnebeek Journal: J Inherit Metab Dis Date: 2022-05-22 Impact factor: 4.750