Oral Presentation 9th GeneMappers Conference 2012

Using Genome-Wide Linkage Analysis And Whole-Exome Sequencing To Identify A Locus For Frontotemporal Dementia – Motor Neuron Disease (#26)

Carol Dobson-Stone 1 2 , Agnes A Luty 1 2 , Elizabeth M Thompson 3 4 , Peter Blumbergs 5 , William S Brooks 1 2 , Glenda M Halliday 1 2 , Peter R Schofield 1 2 , John BJ Kwok 1 2
  1. Neuroscience Research Australia, Sydney, NSW, Australia
  2. University of New South Wales, Sydney, NSW, Australia
  3. SA Clinical Genetics Service, Women’s and Children’s Hospital, Adelaide, SA, Australia
  4. University of Adelaide, Adelaide, SA, Australia
  5. Institute of Medical and Veterinary Science, Adelaide, SA, Australia
The recent advances in sequencing technology make it a relatively simple prospect to sequence the entire exome of any given individual with an inherited disorder. What is significantly less straightforward is how to filter this huge amount of data to find the causative variant. One approach is to use linkage analysis in large families affected with the disorder to hone the search for the disease variant. We describe a unique pedigree (Aus-12) that presents with dementia and motor deficits most consistent with frontotemporal dementia-motor neuron disease (FTD-MND), but with additional corticobasal pathology. DNA from affected Aus-12 individuals was screened and found to be negative for mutations in all known dementia and MND genes (APP, PSEN1, PSEN2, MAPT, GRN, VCP, CHMP2B, SOD1, TARDBP, FUS, TAF15, C9ORF72, OPTN). We performed genome-wide linkage analysis on 13 pedigree members, five of whom were classed as affected. Linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1-16q12.2. Haplotype construction of chromosome 16 revealed a shared haplotype in all affecteds flanked by D16S3103 and D16S489 and spanning a maximum of 37.9 Mb. A smaller suggestive disease haplotype, flanked by D16S753 and D16S3112 and spanning 24.4 Mb, is defined by recombination in an elderly unaffected individual. The Aus-12 critical region overlaps with a separate locus on 16q12.1-q12.2 reported in two independent MND families, indicating that this region may harbour a major locus for neurodegeneration. We performed whole-exome sequencing of five Aus-12 individuals (four affected and one elderly unaffected). From 16,384 non-dbSNP variants identified initially we have identified four variants present in the maximal critical region that segregate with disease. Our study highlights the effectiveness of combining both traditional and next-generation genetic techniques for positional cloning of Mendelian disorders.