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PROBING FTD GENETICS WITH NEXT-GENERATION SEQUENCING
  1. Carolin Koriath,
  2. Gary Adamson,
  3. Ron Druyeh,
  4. Janna Kenny,
  5. Martin Rossor,
  6. Jon Schott,
  7. John Collinge,
  8. Nick Fox,
  9. Jon Rohrer,
  10. Simon Mead
  1. University College London

Abstract

In a previous study of the UCL frontotemporal dementia (FTD) cohort, 40% of patients reported some family history of dementia but only 20% carried a mutation in GRN or MAPT. Since then, other genes have been shown to cause FTD and more widespread next-generation sequencing (NGS) offers the potential to simultaneously screen for all known causal genes.

We applied a validated 17-gene NGS dementia panel combined with PCR-based assessments of the C9orf72 and PRNP expansions to the UCL FTD DNA cohort (n=381). We classified mutations by likelihood of pathogenicity and compared with demographic and clinical data.

39% of patients report some family history but only 13% had an autosomal-dominant history. 27.6% of patients carried a deleterious variant; a further 6.0% had potentially deleterious variants. Most deleterious mutations were found in C9orf72, GRN or MAPT, while other genes amounted to 6.8%. Only 26.9% of patients with a strong family history did not have a deleterious mutation.

Custom panel provide affordable high-quality sequencing. With additional C9orf72 testing, they can assess the most FTD genes and mutations in more unusual genes occur at a significant rate. NGS identifies an abundance of novel or uncertain variants; these will require considerable work to classify correctly.

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