NEXT-GENERATION SEQUENCING GENE DISCOVERY STUDIES IN EARLY-ONSET DEMENTIA

Background: Major breakthroughs in dementia research were realized in studying large families with an early disease onset. Although early-onset dementia (EOD) is relatively rare, these findings are at the basis of our current understanding of the disease biology of neurodegenerative dementias and at the foundation of current drug development strategies. Methods: To further elucidate the missing heritability in dementia we apply whole exome sequencing (WES) on selected EOD patients with high genetic load. This project builds on an impressive collection of EOD patients (> 5000)/families ascertained within the framework of the European Early-Onset Dementia consortium. Patients of all dementia phenotypes are selected based on onset age < 65 years. We prioritize the WES studies on families with DNA for 2-5 affected relatives and isolated patients with onset age < 55 years and, particularly for Alzheimer patients, APOE E4 minus carriers. Selected patients are profiled for mutations in known genes using a NGS gene panel of 30 genes associated with neurodegenerative dementia and related diseases. Results: At present we selected 11 families with DNA of 2-3 patients. Except for one recessive pedigree all families were consistent with dominant inheritance. Further, we included 272 familial or sporadic isolated patients with disease onset below 55 years. Phenotypes include AD, FTLD, FTLD-ALS, ALS, CBD and ANCL. In one family WES we already identified a genetic variant that most probably explains disease. The pedigree includes a sibship of 5 of whom 4 patients and 2 unaffected parents, consistent with recessive disease. The patients suffer from a mixed phenotype of cognitive deterioration, speech problems, extrapyramidal symptoms and epilepsy presenting at age 50-60 years. The candidate variant is homozygous in the 3 tested patients and heterozygous in the unaffected mother. The unaffected sib is homozygous for the wild-type allele. Conclusions: A better understanding of the genetics and biology of dementia will improve classification of patients based on their molecular profile rather than on clinico-pathological symptomatology, which is expected to drastically improve development of effective diagnostic tools, biomarkers and targeted therapies, both for early- and the more common late-onset forms of dementia.