Diagnostic uplift through the implementation of short tandem repeat analysis using exome sequencing

Abstract

To date, approximately 50 short tandem repeat (STR) disorders have been identified; yet, clinical laboratories rarely conduct STR analysis on exomes. To assess its diagnostic value, we analyzed STRs in 6099 exomes from 2510 families with mostly suspected neurogenetic disorders. We employed ExpansionHunter and REViewer to detect pathogenic repeat expansions, confirming them using orthogonal methods. Genotype-phenotype correlations led to the diagnosis of thirteen individuals in seven previously undiagnosed families, identifying three autosomal dominant disorders: dentatorubral-pallidoluysian atrophy (n = 3), spinocerebellar ataxia type 7 (n = 2), and myotonic dystrophy type 1 (n = 2), resulting in a diagnostic gain of 0.28% (7/2510). Additionally, we found expanded ATXN1 alleles (≥39 repeats) with varying patterns of CAT interruptions in twelve individuals, accounting for approximately 0.19% in the Korean population. Our study underscores the importance of integrating STR analysis into exome sequencing pipeline, broadening the application of exome sequencing for STR assessments.

Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing

“…They underwent chromosomal microarray and exome sequencing in a quartet for genetic diagnosis. However, previous genetic tests had yielded negative results including copynumber variation (CNV) and STR analysis [15]. Informed consent was appropriately obtained from their parents, and this study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No.1406-081-588).…”