Often with rare genetic diseases, families must endure a frustrating, expensive, and exceptionally lengthy course to find an etiology for the clinical symptoms found in a patient - the diagnostic odyssey. This study examines the impact of exome sequencing on finding the cause of two siblings' global delay and ataxia and the treatments and research resulting from the diagnosis. Included is a glimpse at how pipelines can influence diagnosis.

For this study, the medical history of two affected siblings was used to consider the exome sequence results with regard to clinical symptoms and mitochondrial respiratory chain enzyme analysis. Due to the differing phenotypes of the siblings, the exome data was scoured for possible modifier genes to explain this variation. Finally, the FASTQ files were processed through an alternate pipeline to determine if filtering can play a role in discordant variant calling.

Exome testing diagnosed Complex I deficiency. Each girl had one allele with a common mutation in the NUBPL gene and a novel mutation in trans. Neither sibling had a polymorphism in cis with the common mutation. These are the first reported symptomatic patients with compound heterozygous mutations lacking the polymorphism in cis with the common mutation. The siblings were started on treatment, and clinical trials have been appropriately examined for qualifications. In the more affected sibling, both pipelines found two mutations in the SYNE1 gene, a gene associated with spinocerebellar ataxia. A second pipeline found only one mutation in each sibling's NUBPL gene, therefore missing this diagnosis.

Genetic counseling is a rapidly growing profession that is constantly evolving. However, the field is significantly lacking in awareness and diversity. To increase awareness about genetic counseling and subsequently diversity within the field, new recruitment strategies must be put in place. Reaching students when they are searching for a career in an undergraduate setting, potentially different from the one they originally intended to pursue, could help attain this goal. Previous studies indicated that most college career advisors felt not at all confident in discussing genetic counseling with their students. An additional study noted that undergraduate students who had heard of genetic counseling through their undergraduate advisors were reportedly very unfamiliar with the profession. In the present study, undergraduate advisors were surveyed to assess their comfort level advising on genetic counseling and how that comfort level was impacted by an informational video intervention. Sixty-seven participants were asked demographic questions, about pre-survey confidence level and 12 knowledge questions before and after the viewing of an information video intervention regarding the genetic counseling profession and graduate program requirements. Ninety percent of participants reported hearing of genetic counseling prior to the study and 75% had experience advising students regarding the field. There was a positive mean difference in scores based on correctness of response to the knowledge questions from the pre- to post-survey among all participants regarding the genetic counseling profession and graduate program requirements (1.3 point and 1.2 point increase respectively, p<0.0001 and p=0.02 respectively). While some questions, particularly those related to the profession, were answered correctly by most participants in the pre-survey indicating generalized prior knowledge, many other questions, particularly those related to the graduate program requirements, were greatly impacted by the information in the video based on improvement in correct responses in the post-survey. More than 65% of participants that opened the survey completed the full pre- and post-survey illustrating their interest in learning more about the genetic counseling profession and how best to advise their students. The data indicates the importance of mass distribution of information regarding the profession to various types of undergraduate advisors. Future studies may focus the knowledge questions more on the genetic counseling graduate program requirements and consider extending the length of the video intervention to extend further knowledge to this population.

An important benefit of cancer genetic testing is the potential for detection of an actionable mutation in genes conferring an increased lifetime risk for hereditary cancer. Individuals with a suggestive personal or family history may seek genetic counseling to assess their risk and pursue genetic testing. Genetic counselors review detected pathogenic variants, in combination with personal and family history, to make recommendations for cancer risk management. Two major recommendations include clinical screening (such as imaging) and surgical methodologies designed to prevent or detect cancer at an early and more treatable stage. Uptake of recommendations can vary significantly across patient populations with diverse medical histories, family histories, socioeconomic factors, and institutional factors. Previous studies have identified trends in risk management behavior for high-risk patients after genetic counseling, including facilitators and barriers to uptake. Cancer genetics clinics can apply this knowledge to improve outcomes for low-uptake groups through enhanced service delivery models, provider education, and community engagement. This study aimed to characterize a population of mutation-positive patients (n=149) who have received genetic counseling at UCI from 2018-2020 in order to evaluate uptake of risk management recommendations. In general, uptake of recommended screening and suggested surgery was high for this group of patients; 74% of those who were provided with screening recommendations were documented as having completed screening, and 36% of those who had discussed surgery with a genetic counselor were documented as having completed a subsequent surgery. Patient demographics, personal medical history, family history, and genetic counseling visit details were analyzed as possible predictors of uptake, and were ultimately not determined to be strong predictors. However, for a subset of the population (n=22, 14.8%), the charts which may have documented risk management behavior were not available, perhaps because these patients had on-going healthcare outside of the medical system. Whether patients initiated genetic testing outside of UCI, and whether they received only post-test counseling were predictors for availability of charts. The lack of complete information on all study participants limited the statistical power to identify significant predictors of risk management behavior. Overall, this study revealed high uptake for risk management recommended in the genetic counseling clinic, though significant predictors for uptake were not identified. The findings of this study underscore the importance of accessible, thorough documentation available between care sites to improve longitudinal research on genetic counseling outcomes and achieve comprehensive continuity of care.