G005 Tackling ‘too short’ HTT CAG repeat expansions from scientific and patient perspectives

<h3>Background</h3> Cases of Huntington disease (HD) phenotypes with reduced penetrance or intermediate HTT CAG repeats are well reported. Recent data on HTT gene structure and disease modifying genetic risk variants provide only partial explanations. There are no clear guidelines for clinicians including further genetic testing, and limited counseling information for patients. Cases are excluded from research studies (ex: Enroll-HD). Our goal is to improve generation and comprehension of diagnostic information for families, as a first step towards better understanding mechanisms behind HD phenotype penetrance in lower CAG repeat ranges. <h3>Aims</h3> Pilot a stepwise clinical assessment pathway acceptable to all stakeholders including patients; develop a genetic counseling protocol to better communicate these results. <h3>Methods</h3> We use commercial genetic testing pathways to clarify ‘too short’ CAG repeats HD diagnoses. Testing captures HD phenocopies, and genetic variants that could impact HD phenotype penetrance. We refer families to large ongoing research studies on HTT long read sequencing and HD genetic risk factors. We use clinical encounters and patient interviews to adapt genetic counseling. <h3>Results</h3> We report commercial genetic testing outcomes including barriers to obtaining testing; pros and cons of non-local research-based testing; and draft updated genetic counseling guidelines. <h3>Conclusions</h3> We propose specific clinical plus research genetic testing pathway, with results return using an updated approach to convey uncertainty and elements of rapidly advancing genetic research in lower CAG repeat length cases. We hope to provide HD clinics and families with tools that improve rates of clinical genetic testing, research engagement, and consistent genetic counseling.