Exploring relatives' perceptions of participation, ethics, and communication in a patient-driven study for hereditary cancer variant reclassification.

Effective communication of genetic information within families depends on several factors. Few studies explore intra-familial communication of variant of uncertain significance (VUS) results or active collaboration between family members to classify VUS. Our qualitative study aimed to describe the experiences of individuals asked by family members to participate in the FindMyVariant study, a patient-driven family study which aimed to reclassify a clinically identified familial VUS in a hereditary cancer gene. We collected feedback from 56 individuals from 21 different families through phone interviews and written correspondence, transcribed the interviews, and performed thematic analysis on all text. We describe themes from three main topics: participation, ethical considerations, and study impacts. Participation in the FindMyVariant study, defined as returning a sample for targeted genotyping, was motivated by convenience and a desire to help the family, oneself, and science. Relatives were generally responsive to invitations to participate in FindMyVariant from another family member. Those who declined to participate did so due to concerns about research program confidentiality rather than family dynamics. No major ethical issues arose in response to the patient-driven study structure, and no major changes in stress and anxiety, medical care, or behavior occurred. Participation in patient-driven familial VUS classification studies has a neutral or positive impact on family health communication. While it is important to design studies to minimize familial coercion, intra-familial confidentiality breaches, and misinterpretation of genetic results, these were not major concerns among relatives in this study. Clinicians and laboratories may consider encouraging familial communication about genetic variants using family members as liaisons.

Family Studies for Classification of Variants of Uncertain Classification: Current Laboratory Clinical Practice and a New Web-Based Educational Tool.

Multi-gene cancer panels often identify variants of uncertain clinical significance (VUS) that pose a challenge to health care providers in managing a patient's cancer risk. Family segregation analysis can yield powerful data to re-classify a VUS (as either benign or pathogenic). However, financial and personnel resources to coordinate these studies are limited. In an informal assessment we found that family studies for variant classification are done by most clinical genetics laboratories that offer hereditary cancer panel testing. The process for family studies differs substantially across laboratories. One near universal limitation is that families usually have too few individuals for an informative co-segregation analysis. A unique and potential resource-saving approach is to engage patients and their families in expanding their own pedigrees for segregation analysis of their VUS. We describe a novel public educational tool ( FindMyVariant.org ) designed to inform patients and genetic counselors about strategies to improve the probability of variant classification using familial segregation. While the web tool is designed to be useful for any gene, the project was primarily focused on VUS's returned in cancer risk genes. FindMyVariant.org is a resource for genetic providers to offer motivated families who are willing to gather information about their family relationships and history. Working alongside clinical or research genetic laboratories, the information they collect may help reclassify their VUS using segregation analysis.

Detecting the effects of Fabry disease in the adult human brain with diffusion tensor imaging and fast bound-pool fraction imaging.

BACKGROUND: To identify quantitative MRI parameters associated with diffusion tensor imaging (DTI) and fast bound-pool fraction imaging (FBFI) that may detect alterations in gray matter and/or white matter in adults with Fabry disease, a lysosomal storage disorder. MATERIALS AND METHODS: Twelve healthy controls (mean age ± standard deviation: 48.0 ± 12.4 years) and 10 participants with Fabry disease (46.7 ± 12.9 years) were imaged at 3.0 Tesla. Whole-brain parametric maps of diffusion tensor metrics (apparent diffusion coefficient [ADC] and fractional anisotropy [FA]) and the bound-pool fraction (f) were acquired. Mean voxel values of parametric maps from regions-of-interest within gray and white matter structures were compared between cases and controls using the independent t-test. Spearman's rho was used to identify associations between parametric maps and age. RESULTS: Compared with controls, the left thalamus of Fabry participants had an increase in FA (0.29 ± 0.02 versus 0.33 ± 0.05, respectively; P = 0.030) and a trend toward an increase in ADC (0.73 ± 00.02 versus 0.76 ± 0.03 µm(2) /s, respectively; P = 0.082). The left posterior white matter demonstrated a reduction in f (10.45 ± 0.37 versus 9.00 ± 1.84%, respectively; P = 0.035), an increase in ADC (0.78 ± 0.04 versus 0.94 ± 0.19 µm(2) /s, respectively; P = 0.024), and a trend toward a reduction in FA (0.42 ± 0.07 versus 0.36 ± 0.08, respectively; P = 0.052). Among all parameters, only f measured in the left posterior white matter was significantly associated with age in Fabry participants (rho = -0.71; P = 0.022). CONCLUSION: Parameters derived from DTI and FBFI detect Fabry-related changes in the adult human brain, particularly in the posterior white matter where reductions in myelin density as measured by FBFI appear age related.