Reanalysis of Next-Generation Sequencing Data to Detect Tandem Repeat Expansions in 1,106 Czech Probands With Neurologic Disease.

Background and Objectives: Tandem repeats (TRs) are DNA regions of tandemly repeated nucleotide motifs. Their pathogenic expansions cause various, mainly neurologic, diseases. Methods: We analyzed 65 TR loci using ExpansionHunter in individuals who underwent short-read whole-exome sequencing (WES) or whole-genome sequencing (WGS) for the diagnosis of a rare neurologic condition. Results: Of 1,106 proband samples (1,053 WES, 53 WGS), we detected 232 TR expansions in the intermediate or pathogenic range in 18.7% (207/1,106). However, 51 TR expansions were revised as false positives (FPs) and 83 as nondisease-causing. Of the 98 disease-causing TR expansions, 5 were classified as causal hemizygous or heterozygous TR expansions associated with X-linked recessive (XLR) or autosomal dominant (AD) neurologic disorders in 5 probands (0.5%). The low incidence is due to the fact that individuals with typical clinical symptoms (spinocerebellar ataxia) were tested for TR expansion by conventional laboratory methods. Only 1 proband with clinical suspicion of spinal and bulbar muscular atrophy was fully explained by TR expansion in the Discussion: The unexpectedly high detection rate (18.7%) of TR expansions necessitates the filtration of FPs and nondisease-causing expansions, thereby underscoring the necessity of visual inspection of ExpansionHunter results. The study demonstrated that both WES and WGS diagnostics can benefit from TR expansion analysis. The secondary findings indicate that the previously published pathogenic ranges of TR expansions in