1. Sanger Tests The test involves more than one disorder/gene – how many forms should I complete?  Forms should be completed for each single inherited condition (e.g. isolated Fallot’s Tetralogy) with single or multiple genes. If there is more than one disorder ASSOCIATED WITH THE GENE(S) but the disorders have different clinical presentations (ie. pleiotropy), please submit these as separate forms, per disorder (except for panel tests, where pleiotropy should be indicated, but may not necessarily require a separate form). A single form should be submitted if the specific test for a disorder is defined as the analysis of more than one gene e.g. BRCA 1 & 2. If there is more than one disorder ASSOCIATED WITH THE GENE(S) and the disorders have clinical presentations with significant clinical overlap, it may be possible to submit one form for these disorders/genes. If you are unsure whether or not to submit one form or a number of forms, please contact the UKGTN project team who will seek advice from the UKGTN clinical and scientific advisors. The application will be evaluated in the context of the use of the test in a particular disorder and in a specified population. 2. Principles for NGS Submissions Background Next generation sequencing is being widely used in UKGTN member laboratories to diagnose inherited disorders. This technology can be used in a number of ways: Replacement technology for targeted gene testing – to sequence one or a small number of genes that were previously sequenced sequentially by Sanger sequencing to identify mutations for a specific disorder Targeted or virtual panel tests – (from 2 to >100 genes) to interrogate a set of genes associated with a particular phenotype or group of phenotypes to identify variations or mutations that can lead to a genetic disorder Exome sequencing - studying all the genes known to cause genetically inherited diseases (clinical exome) or the whole coding region of the genome (whole exome) to identify variations or mutations that could cause a genetic disorder General principles The Genetic Test Evaluation Working Group will consider NGS Gene Dossiers for introduction into NHS service where they meet the following criteria:- 1. Laboratories submitting gene dossiers or additional provider forms have validated their test pipelines (targeting, sequencing and bioinformatics analysis) and verified their individual panel tests to meet the guidelines specified by the ACGS (www.acgs.uk.com)  this will be assessed from the responses to questions 9, 10, 11 (pipeline validation data) and 20 (panel or sub-panel test verification)  data for the pipeline validation and panel/sub-panel verification should include a summary of the results for the numbers of unique variants in different categories ( eg 1 SNVs, indels with size range detected) for which the lab has investigated the concordance of its results for NGS and another ‘gold standard’ method. 2. Laboratories submitting gene dossiers or additional provider forms have appropriate expertise to report the test results.  this will be assessed from the responses to questions 12 (Are you providing this test already) and 13 ( Is their specialised clinical/research expertise available to the lab?) in the gene dossier  this is also evidenced through the issue of clinical reports using the new NGS test before the gene dossier is submitted 3. A defined panel of genes appropriate to a phenotype/clinical presentation can be described. There is no upper limit on the number of genes than can be interrogated provided that: the dossier clearly lists which genes are being tested for which disorder/phenotype in a panel or sub-panel  there is sufficient evidence that a mutation in one of the genes listed can cause the given phenotype/disease;  all genes where the primary phenotype associated with a gene may not be the phenotype under test are identified and systems are in place to handle reporting of these results (questions 28, 29 and 30)  test referral criteria are defined The GTEWG may refer the list of phenotypes/genes to be tested to an external expert/group of experts for ratification. 4. Gene dossiers submitted for exome sequencing of patients with a specific phenotype, which do not fulfil any diagnostic criteria or for whom routine diagnostic testing has not provided a diagnosis if: referral criteria for the test population can be defined  the rationale for the exome sequencing approach can be described, including the level of evidence required to report a variant as disease causing. This should be included as a separate section in question 9 of the dossier  a strategy is included for handling incidental findings (questions 29, 29 and 30)  where the pipeline is effectively the ‘test’, data for that pipeline validation must be given in sufficient detail for another laboratory to repeat the test; in addition to the information required for panel tests the parameters used to filter the data to identify clinically significant variants must be described in question 11 of the gene dossier If you wish to submit an NGS Gene Dossier that does not fall into the categories described above please contact Professor Sian Ellard, UKGTN Scientific Advisor, [email protected] or Dr Jacqui Hoyle, UKGTN Knowledge & Communications Manager [email protected] to discuss the best approach. 2 3. UKGTN Principles for Evaluation Additional Provision Additional Provider Form Required 1. Full additional provider form for test for conditions that are listed on Directory but the submitting lab doesn’t currently offer any component for test No Additional Provider Form Required Adding genes to a service that the lab already offers and where the genes are listed on the directory (Sanger) or adding genes to an existing Panel test that the lab already provides. 2. Panel/Multigene tests - no proposed change to Testing Criteria (TC) - request validation document (addendum to Gene Dossier if exists). Requires scientific advisor approval 3. If TC requires amendment- scientific advisor to sign off validation docs. TC goes to TC evaluation team (SNM/FS) and then to GTEWG for endorsement 4. If TC requires development- Scientific advisor to sign off validation docs. TC to GTEWG for evaluation 5. Adhoc basis-request clinical and scientific advice from project team New Services Gene Dossier form required 6. New disorder or new group of phenotypes, a full gene dossier is required. 3