Familial Studies in Whole Exome and Genome Sequencing

Abstract

Population genetics has been revolutionized by the advent of high-throughput sequencing (HTS) methods in the 21st century. Modern day sequencers are now capable of sequencing entire exomes and genomes at unprecedented speed and accuracy. An explosion of bioinformatics software and data analysis tools now makes sequencing accessible for gene discovery in both rare Mendelian and complex disease. Family-based sequencing studies in particular have great potential for elucidating the genetic basis for many more diseases.

We apply both whole exome and genome sequencing to three different cases of familial disease: intracranial aneurysm (IA), Parkinson disease (PD), and X-linked ataxia dementia (XLAD). IA and PD are both common, complex traits that inflict a devastating disease burden worldwide, mostly due to few effective therapeutic interventions. Little of the heritability of both IA and PD has been explained to date, especially as it relates to the impact of rare variation on disease. XLAD is an extremely rare neurological disease described thus far in one kindred. Although promising results have been achieved through previous genetic study designs, the causative gene has not yet been identified. For all three diseases, HTS offers an opportunity to explore the role of rare variation in disease pathogenesis. In each study, we explore the opportunities and challenges of family-based HTS for different disease models. The work presented herein contributes effective practices for study design, analysis, and interpretation in a rapidly growing field still replete with questions about how best to implement HTS in studying familial disease.