Application of targeted multi-gene panel testing for the diagnosis of XXXX provides a high diagnostic yield with unexpected phenotype-genotype variability.

@entity1 @entity1897 @entity1112
BACKGROUND: @entity1897 ( @entity1897 ) is a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with the different subtypes. Sequential gene screening is gradually being replaced by next generation sequencing (NGS) applications. METHODS: We designed and validated a targeted NGS panel assay including 56 genes associated with known causes of @entity1897 . We report our findings following NGS panel testing of 448 @entity1 with different types of clinically-suspected @entity1897 . RESULTS: Genetic diagnosis was achieved in 137 @entity1 (31  %) and involved 195 pathogenic variants in 31 genes. 93 @entity1 had pathogenic variants in genes where a resulting phenotype follows dominant inheritance, 32 in genes where this would follow recessive inheritance, and 12 presented with @entity1112 . Almost half of the diagnosed @entity1 (64) had a pathogenic variant either in genes not previously available for routine diagnostic testing in a UK laboratory (50 @entity1 ) or in genes whose primary clinical association was not @entity1897 (14). Seven @entity1 had a pathogenic variant in a gene not hitherto indicated from their phenotype and three @entity1 had more than one pathogenic variant, explaining their complex phenotype and providing information essential for accurate prediction of recurrence risks. CONCLUSIONS: Our results demonstrate that targeted gene panel testing is an unbiased approach which overcomes the limitations imposed by limited existing knowledge for rare genes, reveals high heterogeneity, and provides high diagnostic yield. It is therefore a highly efficient and cost effective tool for achieving a genetic diagnosis for @entity1897 .
