NINDS Family-Based Whole-Genome Sequencing to Find HD Modifiers

The goal of our studies is to identify genetic modifiers of neurodegeneration in Huntington's disease (HD). HD is caused by expansion of CAG repeats in the huntingtin (Htt) gene, with longer stretches often leading to more rapid disease onset and progression. Yet, for a given number of repeats, the age of symptom onset can be variable, differing by up to decades. Thus, the age of onset of motor symptoms in HD is only partly explained by the length of the CAG expansion. Available evidence suggests that genetic modifiers contribute to the variation in HD onset. Identifying genetic modifiers is important because they may provide critical insights into HD pathogenesis and reveal key pathways that could be targeted by novel HD therapeutics. This is important since there are no disease-modifying therapies for HD, and mHtt is an unattractive small-molecule drug target. We recruited 21 HD families with varying characteristics of disease progression and age of onset and obtained medical histories, clinical records and DNA samples that were subjected to whole-genome sequencing (WGS). These WGS data describe families of 104 subjects, including HD patients and their unaffected family members. These individuals were selected based on individual clinical histories and family structures that best fit our criteria for expressing potential genetic modifiers. We are testing the hypothesis that novel, rare genetic variants contribute to HD and those genetic modifiers can be identified by WGS.]]>
Inclusion criteria: Subjects are able to provide informed consent Index subjects with the HD gene previously identified, with or without clinical symptoms of the disease. Spouses, adult children, siblings, and parents of the index subject, regardless of previous HD test status or desire to obtain HD diagnostic testing. Subjects over age 21 of either gender. Exclusion criteria: Subjects with wound healing or immunodeficiency disorders will be excluded to further minimize risk of skin biopsy. Subjects with allergy to the local anesthetic agents used in skin biopsy. Subjects who, in the opinion of the study PI, should not participate in this research study. ]]>
August 2014 - Study was announced to HD families by HD Roster October 2014 - Study opens for enrollment of new patients and families November 2014 - Initiated contact with first round of interested patients and family members and sent consent forms February 2015 - Received first round of DNA samples from HD Roster March 2015 - Began receiving samples from other sources June 2015 - Enrolled ~60 new participants and began receiving clinical data and medical records September 2015 - Submitted 39 samples to CIDR for WGS December 2015 - Enrolled ~50 new participants January 201 - Enrolled 130 participants in total ]]>