Extended Family Outreach in Hereditary Cancer Using Web-Based Genealogy, Direct-to-Consumer Ancestry Genetics, and Social Media: Mixed Methods Process Evaluation of the ConnectMyVariant Intervention.

BACKGROUND: Cascade screening, defined as helping at-risk relatives get targeted genetic testing of familial variants for dominant hereditary cancer syndromes, is a proven component of cancer prevention; however, its uptake is low. We developed and conducted a pilot study of the ConnectMyVariant intervention, in which participants received support to contact at-risk relatives that extended beyond first-degree relatives and encourage relatives to obtain genetic testing and connect with others having the same variant through email and social media. The support that participants received included listening to participants' needs, assisting with documentary genealogy to find common ancestors, facilitating direct-to-consumer DNA testing and interpretation, and assisting with database searches. OBJECTIVE: We aimed to assess intervention feasibility, motivations for participating, and engagement among ConnectMyVariant participants and their families. METHODS: We used a mixed methods design including both quantitative and qualitative evaluation methods. First, we considered intervention feasibility by characterizing recruitment and retention using multiple recruitment mechanisms, including web-based advertising, dissemination of invitations with positive test results, provider recruitment, snowball sampling, and recruitment through web-based social networks and research studies. Second, we characterized participants' motivations, concerns, and engagement through project documentation of participant engagement in outreach activities and qualitative analysis of participant communications. We used an inductive qualitative data analysis approach to analyze emails, free-text notes, and other communications generated with participants as part of the ConnectMyVariant intervention. RESULTS: We identified 84 prospective participants using different recruitment mechanisms; 57 participants were ultimately enrolled in the study for varying lengths of time. With respect to motivations for engaging in the intervention, participants were most interested in activities relating to genealogy and communication with others who had their specific variants. Although there was a desire to find others with the same variant and prevent cancer, more participants expressed an interest in learning about their genealogy and family health history, with prevention in relatives considered a natural side effect of outreach. Concerns about participation included whether relatives would be open to communication, how to go about it, and whether others with a specific variant would be motivated to help find common ancestors. We observed that ConnectMyVariant participants engaged in 6 primary activities to identify and communicate with at-risk relatives: sharing family history, family member testing, direct-to-consumer genealogy genetic testing analysis, contacting (distant) relatives, documentary genealogy, and expanding variant groups or outreach. Participants who connected with others who had the same variant were more likely to engage with several extended family outreach activities. CONCLUSIONS: This study demonstrated that there is an interest in extended family outreach as a mechanism to improve cascade screening for hereditary cancer prevention. Additional research to systematically evaluate the outcomes of such outreach may be challenging but is warranted.

Diagnostic yield of genetic screening in a diverse, community-ascertained cohort.

BACKGROUND: Population screening for genetic risk of adult-onset preventable conditions has been proposed as an attractive public health intervention. Screening unselected individuals can identify many individuals who will not be identified through current genetic testing guidelines. METHODS: We sought to evaluate enrollment in and diagnostic yield of population genetic screening in a resource-limited setting among a diverse population. We developed a low-cost, short-read next-generation sequencing panel of 25 genes that had 98.4% sensitivity and 99.98% specificity compared to diagnostic panels. We used email invitations to recruit a diverse cohort of patients in the University of Washington Medical Center system unselected for personal or family history of hereditary disease. Participants were sent a saliva collection kit in the mail with instructions on kit use and return. Results were returned using a secure online portal. Enrollment and diagnostic yield were assessed overall and across race and ethnicity groups. RESULTS: Overall, 40,857 people were invited and 2889 (7.1%) enrolled. Enrollment varied across race and ethnicity groups, with the lowest enrollment among African American individuals (3.3%) and the highest among Multiracial or Other Race individuals (13.0%). Of 2864 enrollees who received screening results, 106 actionable variants were identified in 103 individuals (3.6%). Of those who screened positive, 30.1% already knew about their results from prior genetic testing. The diagnostic yield was 74 new, actionable genetic findings (2.6%). The addition of more recently identified cancer risk genes increased the diagnostic yield of screening. CONCLUSIONS: Population screening can identify additional individuals that could benefit from prevention, but challenges in recruitment and sample collection will reduce actual enrollment and yield. These challenges should not be overlooked in intervention planning or in cost and benefit analysis.

Deletion of FUNDC2 and CMC4 on Chromosome Xq28 Is Sufficient to Cause Hypergonadotropic Hypogonadism in Men.

BACKGROUND: Hypergonadotropic hypogonadism (HH) is characterized by low sex steroid levels and secondarily elevated gonadotropin levels with either congenital or acquired etiology. Genetic factors leading to HH have yet to be fully elucidated. METHODS: Here, we report on genome and transcriptome data analyses from a male patient with HH and history of growth delay who has an inherited deletion of chromosome Xq28. Expression analyses were done for this patient and his unaffected family members and compared to normal controls to identify dysregulated genes due to this deletion. RESULTS: Our patient's Xq28 deletion is 44,806 bp and contains only two genes, FUNDC2 and CMC4. Expression of both FUNDC2 and CMC4 are completely abolished in the patient. Gene ontology analyses of differentially expressed genes (DEGs) in the patient in comparison to controls show that significantly up-regulated genes in the patient are enriched in Sertoli cell barrier (SCB) regulation, apoptosis, inflammatory response, and gonadotropin-releasing regulation. Indeed, our patient has an elevated follicle stimulating hormone (FSH) level, which regulates Sertoli cell proliferation and spermatogenesis. In his mother and sister, who are heterozygous for this deletion, X-chromosome inactivation (XCI) is skewed toward the deleted X, suggesting a mechanism to avoid FSH dysregulation. CONCLUSION: Compared to the previously reported men with variable sized Xq28 deletions, our study suggests that loss of function of FUNDC2 and CMC4 results in dysregulation of apoptosis, inflammation, and FSH, and is sufficient to cause Xq28-associated HH.

Novel Report of Phosphoserine Phosphatase Deficiency in an Adult with Myeloneuropathy and Limb Contractures.

Serine is a nonessential amino acid that plays a vital role in proper development and functioning of the central nervous system (CNS). Serine deficiency leads to microcephaly, intellectual disability, seizures, and psychomotor retardation in children and severe axonal neuropathy in adults. Serine deficiency syndrome is due to a deficiency of one of three enzymes in the endogenous serine biosynthesis pathway: phosphoglycerate dehydrogenase, phosphoserine transaminase, or, most rarely, phosphoserine phosphatase. Of critical importance to clinical care, serine deficiency syndrome is treatable. Herein, we describe the novel presentation of phosphoserine phosphatase deficiency in an adult. The patient had intrauterine growth restriction, lifelong intellectual disability, childhood onset epilepsy, and borderline microcephaly. In adulthood, she developed progressively severe lower extremity hypertonia, axonal neuropathy, and hand contractures. Neuropathy was complicated by non-healing wounds. Fasting plasma amino acids showed low serine and glycine. Molecular analysis revealed compound heterozygous mutations in phosphoserine phosphatase (PSPH). Treatment with oral serine resulted in improvement of plasma serine levels, decreased neuropathic pain, and subjective improvement in energy level. Although the first case of phosphoserine phosphatase deficiency was described nearly 20 years ago, only eight cases have been reported, all in children. This is the first report of phosphoserine phosphatase deficiency in an adult.