D.P.9 Whole exome sequencing filtered by novel candidate genes as tool for gene discovery in a recessive family with Parkinson and ataxia

Abstract We studied a family of four with a form of juvenile Parkinson, cognitive impairment, ataxia, and obesity, with variable clinical severity. Many genes associated to these diseases were excluded with conventional sequencing: SCA1, SCA2, SCA3, SCA6 and DRPLA for the spinocerebellar ataxias, GM1 and GM2 for the adrenoleukodystrophy, GCH1 for dopa-responsive dystonia and the linkage analysis excluded the Parkinson genes PARK2, PARK3 and PARK7. For both affected patients we hypothesized a neurological disease with multisystem involvement that was genetically determined. We performed the whole exome sequencing analysis by Illumina GAIIe platform on all family members except the affected sister. We identified a mean of 30,000 SNPs or DIPs passing a quality filters (coverage >10, ambigously mapped reads per variant 50, variant confidence/consensus quality >1.5). We elaborated a list of 143 genes that are frankly or putatively associated to Parkinson, obesity or spinocerebellar ataxia and adopted this list as a filter applied to the WES analysis, considering SNPs only in homozygosity or in compound heterozygosity (dbSNPs not excluded). This analysis allowed us to detect 82 variations within 41 genes in homozygosity and 134 variations in compound heterozygosity within 39 genes. We filtered these identified variations in family’s members or in other samples present in the same run; this investigation greatly reduced the numbers of variations, being now 12 homozygous and 54 the compound heterozygous. The variations identified are in course of technical validation as possible mutations in novel genes causing the peculiar phenotype in this family.