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Expanded carrier screening (ECS) is used to identify individuals and couples at risk for having children with recessive or X-linked genetic conditions; however, personal health risks (PHR) can also be identified through this testing. There is limited data on how genetic counseling regarding PHR from ECS is perceived by the individual, or how they use this information. This study quantitatively surveyed individuals identified with these risks between September 2013 and March 2020. The 30-item survey included the validated Genomics Outcome Scale Short Form, the validated Genetic Counseling Satisfaction Scale, and original questions. Survey topics included pre-test knowledge of the possibility of discovering PHR through testing, satisfaction with pre-test education that addresses potential risks, perceived severity of PHR, empowerment by and understanding of information, anxiety levels related to their PHR, perceived genetic counseling support, and satisfaction with telehealth. A total of 416 completed surveys were analyzed using descriptive statistics, and linear and logistic regressions. The majority of participants were satisfied or extremely satisfied with pre-test education (n = 328; 78.8%) and telehealth (n = 329; 79.1%). However, more participants who were aware of the possibility of identifying PHR through ECS prior to testing were satisfied with pre-test education compared to those who were not aware. Additionally, a lack of prior awareness of PHR was associated with lower empowerment scores (p = .004). Those who were highly satisfied with genetic counseling were more likely to feel empowered and understand the information presented (p = .001). The majority of individuals used their PHR information following their results appointment (n = 391; 94.0%). The results of this study suggest that receiving PHR information was useful and was positively influenced by both pre-test education and the genetic counseling process.

JScreen is a national public health initiative based out of Emory University that provides reproductive carrier screening through an online portal and follow-up genetic counseling services. In 2014, JScreen began reporting to patients variants of uncertain significance (VUSs) in the gene that causes Tay-Sachs disease (HEXA). Genetic counseling was provided to discuss the VUS and patients were offered hexosaminidase A (HEXA) blood enzyme testing to assist with VUS reclassification. To identify patient reactions and factors influencing their follow-up testing decisions after receiving these results, we conducted a retrospective quantitative study by administering online surveys to 62 patients with HEXA VUSs. Participants who pursued enzyme testing and those who did not both experienced low levels of distress when receiving the VUS results. Perceptions of HEXA carrier status after genetic counseling, decisional conflict levels, plans to have children in the near future, time available to pursue enzyme testing, and eligibility for research were significant factors influencing decision-making to pursue or not pursue enzyme testing. Genetic counseling played an important role in helping patients understand the VUS and follow-up testing options. When discussing VUSs with patients, it would be beneficial for genetic counselors to focus on the patient's perception of the VUS, anxiety related to the uncertainty of their results, and follow-up options, when available.

Background Pathogenic variants in HEXA that impair β‐hexosaminidase A (Hex A) enzyme activity cause Tay‐Sachs Disease (TSD), a severe autosomal‐recessive neurodegenerative disorder. Hex A enzyme analysis demonstrates near‐zero activity in patients affected with TSD and can also identify carriers, whose single functional copy of HEXA results in reduced enzyme activity relative to noncarriers. Although enzyme testing has been optimized and widely used for carrier screening in Ashkenazi Jewish (AJ) individuals, it has unproven sensitivity and specificity in a pan‐ethnic population. The ability to detect HEXA variants via DNA analysis has evolved from limited targeting of a few ethnicity‐specific variants to next‐generation sequencing (NGS) of the entire coding region coupled with interpretation of any discovered novel variants. Methods We combined results of enzyme testing, retrospective computational analysis, and variant reclassification to estimate the respective clinical performance of TSD screening via enzyme analysis and NGS. We maximized NGS accuracy by reclassifying variants of uncertain significance and compared to the maximum performance of enzyme analysis estimated by calculating ethnicity‐specific frequencies of variants known to yield false‐positive or false‐negative enzyme results (e.g., pseudodeficiency and B1 alleles). Results In both AJ and non‐AJ populations, the estimated clinical sensitivity, specificity, and positive predictive value were higher by NGS than by enzyme testing. The differences were significant for all comparisons except for AJ clinical sensitivity, where NGS exceeded enzyme testing, but not significantly. Conclusions Our results suggest that performance of an NGS‐based TSD carrier screen that interrogates the entire coding region and employs novel variant interpretation exceeds that of Hex A enzyme testing, warranting a reconsideration of existing guidelines.

Background/Aims: Access to preconception carrier screening, which provides at-risk couples with more reproductive options, is critically important. To address this need in the Jewish community, genetic counselors at Emory University launched JScreen (www.jscreen.org), a national online genetic disease education and carrier screening program. To reach the preconception demographic, JScreen initiated a study evaluating the impact of marketing and education on knowledge and screening activity on college campuses. Methods: Students at 10 universities were targeted with a marketing campaign designed for this initiative. Those who elected screening were provided pre-test video education designed for the study. Success was assessed through enrollment in testing, comparison of pre- and post-education knowledge quizzes, and patient satisfaction surveys evaluating genetic counseling and the JScreen process. Results: A total of 1,794 participants were enrolled. Over 99% of those screened were not pregnant. Knowledge quiz scores improved significantly post-education, and patient satisfaction was over 98%. Conclusions: Findings suggested that the use of targeted marketing helped promote preconception screening in this population. The study demonstrated that video education was effective in educating participants about benefits and limitations of testing. Also, the use of telehealth technology facilitated access to professional genetic counseling services. This study serves as a model for future public health initiatives.

Purpose: Enzyme replacement therapy (ERT) is a promising therapeutic intervention for lysosomal storage diseases. Posttranslationally engineered human β-glucocerebrosidase (Ceredase®/Cerezyme®) is commercially available and is the standard ERT for Type I Gaucher disease. Cessation of therapy is sometimes necessary for personal or financial reasons, but the consequences of discontinuation are unknown. This study reports results of discontinuing therapy in four patients with Type I Gaucher disease with different genotypes and varying degrees of clinical involvement. Methods: Patient genotypes were as follows: N370S/L444P (Patients 1 and 2), K79N/K79N (Patient 3), and N370S/N370S (Patient 4). All were evaluated before, during, and after withdrawal from ERT. Patients 1, 2, and 3 were studied after reinstituting ERT. The following parameters were documented at 3- to 12-month intervals in all patients: hemoglobin, platelet count, angiotensin-converting enzyme, spleen volume, liver volume, femoral magnetic resonance imaging, bone density, and urinary pyridinium crosslinks. Results: After cessation of therapy, Patients 1, 2, and 3 had more dramatic regression in hematological and visceral parameters than Patient 4 and required reinstitution of ERT within 2 years. All three patients recovered posttreatment status within 4 years of reinstituting ERT. Patient 4 remained stable 6 years after cessation of ERT. Conclusions: Regression of disease status in patients with Type I Gaucher disease after cessation of ERT conformed to the genotype-phenotype relationships of disease onset. Careful monitoring and reinstitution of ERT enabled previously attained treatment status.

Ethnicity-based carrier screening for the Ashkenazi Jewish population has been available and encouraged by advocacy and community groups since the early 1970’s. Both the American College of Medical Genetics and the American Congress of Obstetricians and Gynecologists recommend carrier screening for this population (Obstetrics and Gynecology, 114(4), 950-953, 2009; Genetics in Medicine, 10(1), 55-56, 2008). While many physicians inquire about ethnic background and offer appropriate carrier screening, studies show that a gap remains in implementing recommendations (Genetic testing and molecular biomarkers, 2011). In addition, education and outreach efforts targeting Jewish communities have had limited success in reaching this at-risk population. Despite efforts by the medical and Jewish communities, many Jews of reproductive age are not aware of screening, and remain at risk for having children with preventable diseases. Reaching this population, preferably pre-conception, and facilitating access to screening is critically important. To address this need, genetic counselors at Emory University developed JScreen, a national Jewish genetic disease screening program. The program includes a national marketing and PR campaign, online education, at-home saliva-based screening, post-test genetic counseling via telephone or secure video conferencing, and referrals for face-to-face genetic counseling as needed. Our goals are to create a successful education and screening program for this population and to develop a model that could potentially be used for other at-risk populations.

Gaucher disease, a common lysosomal storage disorder, is associated with mutations at the acid beta-glucosidase (GCase) locus. Two affected individuals are described to share a common mutant allele, but manifest different clinical categorical phenotypes. A 57-year-old female, with Gaucher disease type 1 and Cherokee ancestry, was homozygous for a rare mutant allele encoding Lys79Asn (K79N). A 2-year-old Caucasian male, with Gaucher disease type 3 and Cherokee ancestry, was a heteroallelic homozygote for this same allele (K79N) and a novel complex mutation (null allele). The shared alleles were identical as determined by complete gene sequencing, suggesting a founder effect. The discrepant phenotypes (types 1 and 3) in these two patients provide support for a threshold of residual activity necessary to "protect" the central nervous system (CNS) from the pathogenic effects of Gaucher disease, indicating an allele dose-effect. Designation of genotype associations with specific phenotypes must be assessed with this perspective.