Improved sensitivity for detection of pathogenic variants in familialNF2-related schwannomatosis

Abstract

PurposeTo determine the impact of additional genetic screening techniques on the rate of detection of pathogenic variants leading to familialNF2-related schwannomatosis.MethodsWe conducted genetic screening of a cohort of 168 second-generation individuals meeting the clinical criteria forNF2-related schwannomatosis. In addition to the current clinical screening techniques, targeted next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification analysis, we applied additional genetic screening techniques, including karyotype and RNA analysis. For characterisation of a complex structural variant, we also performed long-read sequencing analysis.ResultsAdditional genetic analysis resulted in increased sensitivity of detection of pathogenic variants from 87% to 95% in our second-generationNF2-related schwannomatosis cohort. A number of pathogenic variants identified through extended analysis had been previously observed after NGS analysis but had been overlooked or classified as variants of uncertain significance.ConclusionOur study indicates there is added value in performing additional genetic analysis for detection of pathogenic variants that are difficult to identify with current clinical genetic screening methods. In particular, RNA analysis is valuable for accurate classification of non-canonical splicing variants. Karyotype analysis and whole genome sequencing analysis are of particular value for identification of large and/or complex structural variants, with additional advantages in the use of long-read sequencing techniques.