title: Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability.
abstract: BACKGROUND
  Inherited peripheral neuropathy (IPN) 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 IPN. We report our findings following NGS panel testing of 448 patients with different types of clinically-suspected IPN.
  
  
  RESULTS
  Genetic diagnosis was achieved in 137 patients (31%) and involved 195 pathogenic variants in 31 genes. 93 patients 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 X-linked disease. Almost half of the diagnosed patients (64) had a pathogenic variant either in genes not previously available for routine diagnostic testing in a UK laboratory (50 patients) or in genes whose primary clinical association was not IPN (14). Seven patients had a pathogenic variant in a gene not hitherto indicated from their phenotype and three patients 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 IPN.
authors.affiliation: Bristol Genetics Laboratory, North Bristol NHS Trust, Southmead Hospital, Bristol, BS10 5NB, UK. thalia.antoniadi@nhs.net.
authors.forename: Thalia
authors.initials: T
authors.lastname: Antoniadi
authors.affiliation: Bristol Genetics Laboratory, North Bristol NHS Trust, Southmead Hospital, Bristol, BS10 5NB, UK. chris.buxton@nhs.net.
authors.forename: Chris
authors.initials: C
authors.lastname: Buxton
authors.affiliation: Bristol Genetics Laboratory, North Bristol NHS Trust, Southmead Hospital, Bristol, BS10 5NB, UK. gemma.dennis@nbt.nhs.uk.
authors.forename: Gemma
authors.initials: G
authors.lastname: Dennis
authors.affiliation: Bristol Genetics Laboratory, North Bristol NHS Trust, Southmead Hospital, Bristol, BS10 5NB, UK. natalie.forrester@nbt.nhs.uk.
authors.forename: Natalie
authors.initials: N
authors.lastname: Forrester
authors.affiliation: Bristol Genetics Laboratory, North Bristol NHS Trust, Southmead Hospital, Bristol, BS10 5NB, UK. debbie.smith@nbt.nhs.uk.
authors.forename: Debbie
authors.initials: D
authors.lastname: Smith
authors.affiliation: Department of Social & Community Medicine, University of Bristol, Oakfield House, Bristol, BS8 2BN, UK. peter.lunt@bristol.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Lunt
authors.affiliation: Bristol Genetics Laboratory, North Bristol NHS Trust, Southmead Hospital, Bristol, BS10 5NB, UK. sarah.burton-jones@nbt.nhs.uk.
authors.forename: Sarah
authors.initials: S
authors.lastname: Burton-Jones
mesh_terms: D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA / Q000191:economics / Q000379:methods