Systematic analysis of short tandem repeats in 38,095 exomes provides an additional diagnostic yield

Abstract

PurposeThe expansion of specific short tandem repeats (STRs) can lead to 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. MethodsWe assessed diagnostic utility by applying ExpansionHunter to 2,867 exomes from movement disorder patients and 35,228 other clinical exomes. ResultsWe identified 36 movement disorder patients with a possible aberrant STR length. Validation by PCR and/or repeat-primed PCR technologies confirmed the presence of aberrant expansion alleles for 11 (31%). For seven of these patients the genotype was compatible with the phenotypic description, and resulted 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 140 samples with a likely aberrant STR length. Validations confirmed 70/140 (50%) aberrant expansion alleles, of which 48 were in the pathogenic range and 22 in the premutation range. ConclusionsOur 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 to make STR evaluation a routine part of ES interpretation in genetic testing laboratories.