Abstract
PurposeWe describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in the first subjects tested. MethodsWe outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings). ResultsAmong the 207 subjects tested, 57 (27.6%) were positive for a diagnostic episignature including 48/136 (35.3%) in the targeted cohort and 8/71 (11.3%) in the screening cohort, with 4/207 (1.9%) remaining inconclusive after EpiSign analysis. ConclusionThis study describes the implementation of diagnostic clinical genomic DNA methylation testing in patients with rare disorders. It provides strong evidence of clinical utility of EpiSign analysis, including the ability to provide conclusive findings in the majority of subjects tested.
Highlights
Mendelian disorders are estimated to occur at a rate of 40 to 82 per 1,000 live births.[1]
EpiSign analysis was concordant with the previous genetic findings in 207/211 samples
Assessment of exome sequencing data, array comparative genomic hybridization, and multiplex ligationdependent probe amplification (MLPA) analysis showed no evidence of this this duplication
Summary
Mendelian disorders are estimated to occur at a rate of 40 to 82 per 1,000 live births.[1]. Evolution of genetic testing from single-nucleotide assessment to clinical exome and genome sequencing, while increasing the diagnostic yield to an average of 36%,4 has resulted in a significant increase in ambiguous or uncertain genetic findings, referred to as variants of unknown clinical significance (VUS). Despite concerted efforts to standardize guidelines for the interpretation of sequence variants[5] and to define the functional evidence for variant classification,[6] a large proportion of VUS remain without conclusive clinical interpretation. The understanding of the impact of genetic variation outside of proteincoding DNA sequences is very limited, and as such, the majority of genetic testing in clinical laboratories is focused on exonic and short surrounding intronic sequences. In silico prediction algorithms, and gene-specific functional studies may help resolve VUS findings, but in the majority of cases these are not available, feasible, or conclusive
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