Exploring perceptions of genetic counseling student-run free clinics as an innovative service delivery model to increase access to genetic counseling services.

Underrepresented groups lack access to genetics services, heightening health disparities among those who benefit from advancements in precision medicine. An innovative approach to addressing this gap in care and increasing health equity in the context of genetic counseling is student-run free clinics (SRFCs). While only one recently established SRFC for genetic counseling is reported in the literature, SRFCs have a long-standing presence in other health professional schools, such as nursing, pharmacy and physical therapy, and research supports the benefits for patients and students. This qualitative study aims to explore the perspectives of certified genetic counselors (CGCs) and genetic counseling  students (GC students) regarding SRFCs as an innovative service delivery model to increase access to genetic counseling services. Semi-structured Zoom interviews were conducted with 10 CGCs and 10 GC students across the United States. Participants were asked open-ended questions about how SRFCs could meet needs of the field, potential challenges in creating and maintaining these clinics, and anticipated outcomes. Through abductive thematic analysis of interview transcripts, three main themes were identified: (1) SRFCs can be mutually beneficial as alignment with profession goals potentially leads to positive outcomes for patients and students; (2) student scope of duties will vary depending on student ability corresponding with their training timeline and level of required supervision; and (3) successful SRFC implementation and sustainability will require thoughtful planning regarding collaboration, infrastructure support, clinic operations, visibility, and protections for vulnerable groups. Participants recognized SRFCs' potential to reduce health disparities by expanding access to genetic counseling for uninsured and underinsured populations. Implementing SRFCs could enhance the quality of GC student training, providing opportunities to apply skills and gain experience working with diverse patient populations. A key subtheme was the need to foster support from the CGC community in transitioning from a traditional supervision model. This research provides a baseline framework from which to further develop and implement SRFCs for genetic counseling.

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease. METHODS: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. CONCLUSION: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.

Cultural, demographic, and other non-demographic factors associated with cancer genetic counseling patients' appointment accompaniment preferences in the United States.

Although the presence of companion(s) in a genetic counseling session can positively influence session dynamics, research has found that some patients prefer to attend their appointments alone. To date, no studies have examined patient accompaniment preferences across different cultural groups in the context of genetic counseling. This quantitative study aimed to identify factors associated with individual preferences in accompaniment at cancer genetic counseling appointments in a sample (N = 130) of Hispanic/Latine (n = 29) and non-Hispanic/Latine White (n = 101) participants at a large academic medical institution. Variables examined included demographics, horizontal and vertical collectivism, and Hispanic and American acculturation. A link to an online questionnaire was emailed to patients who met four criteria: (1) identified as either Hispanic/Latine or non-Hispanic/Latine White; (2) had attended a cancer genetic counseling appointment at UCLA Health to discuss genetic testing options between October 2020 and December 2022; (3) were at least 18 years of age at the time of their appointment; and (4) indicated they were comfortable reading in Spanish or English; responses were anonymous. Logistic regression analyses identified four significant variables in the model associated with accompaniment preferences: individuals with at least one parent born outside of the US, those who attended their appointment in-person, and those with a higher horizontal collectivism score were less likely to want to attend their cancer genetic counseling appointment alone, while the converse was true among those with a higher American acculturation score. These findings highlight cultural and demographic factors that are associated with patient accompaniment preferences unrelated to ethnicity, indicating genetic counselors should not make assumptions regarding accompaniment preferences based solely on cultural or racial/ethnic background. Genetic counselors should incorporate this understanding when assessing patients' accompaniment preferences.

Exploring the role of digital tools in rare disease management: An interview-based study.

While digital tools, such as the Internet, smartphones, and social media, are an important part of modern society, little is known about the specific role they play in the healthcare management of individuals and caregivers affected by rare disease. Collectively, rare diseases directly affect up to 10% of the global population, suggesting that a significant number of individuals might benefit from the use of digital tools. The purpose of this qualitative interview-based study was to explore: (a) the ways in which digital tools help the rare disease community; (b) the healthcare gaps not addressed by current digital tools; and (c) recommended digital tool features. Individuals and caregivers affected by rare disease who were comfortable using a smartphone and at least 18 years old were eligible to participate. We recruited from rare disease organizations using purposive sampling in order to achieve a diverse and information rich sample. Interviews took place over Zoom and reflexive thematic analysis was utilized to conceptualize themes. Eight semistructured interviews took place with four individuals and four caregivers. Three themes were conceptualized which elucidated key aspects of how digital tools were utilized in disease management: (1) digital tools should lessen the burden of managing a rare disease condition; (2) digital tools should foster community building and promote trust; and (3) digital tools should provide trusted and personalized information to understand the condition and what the future may hold. These results suggest that digital tools play a central role in the lives of individuals with rare disease and their caregivers. Digital tools that centralize trustworthy information, and that bring the relevant community together to interact and promote trust are needed. Genetic counselors can consider these ideal attributes of digital tools when providing resources to individuals and caretakers of rare disease.

A pioneering EMR-embedded digital health literacy tool reveals healthcare disparities for diverse older adults.

BACKGROUND: The COVID-19 pandemic transformed healthcare delivery with the rapid adoption of telehealth and digital technologies to access healthcare. Interventions are needed to ensure that older people in underserved communities do not face new technology-driven healthcare disparities. This article describes pioneering electronic medical record (EMR) embedded tools to assess and support each diverse patient's digital health literacy. METHODS: We designed and validated a rapid EMR-embedded Digital Health Engagement Tool (DHET) to assess each patient's digital literacy in English and Spanish. We built a separate, EMR-generated auto-scoring function to assess patient use of telehealth and healthcare navigation as recorded within the EMR. Combined, the tools created a complete digital literacy assessment for each patient. We then deployed the tools to conduct a pilot study to elucidate disparities. RESULTS: A total of 112 ethnic/racial diverse older patients were enrolled (mean age was 78, ranging from 57 to 96) years (SD = 8.04). The female participants were 72.3%. Among the participants, non-Hispanic Whites were 47.3%; Hispanic 25.0%; non-Hispanic Asian 19.6%; non-Hispanic others (including multi-race and non-Hispanic Black/African Americans) 8.0%. Digital literacy disparities were revealed for older adults, particularly those over 70 years old, female gender, and those reporting relying on a helper. CONCLUSION: New EMR-embedded tools enable healthcare systems to assess the ability of patients to navigate and utilize EMR capabilities, such as video telehealth appointments, messaging providers, reviewing labs/radiology reports, and requesting prescriptions. The study identified significant challenges for older patients in navigating EMRs and calls for healthcare systems to better support patient learning.

Virtual Care for Behavioral Health Conditions.

The COVID-19 pandemic has highlighted the urgent need for behavioral health care services. A substantial portion of mental health care transitioned to virtual care during the COVID-19 pandemic, remains virtual today, and will continue that way in the future. Mental health needs continue to grow, and there has been growing evidence showing the efficacy of virtual health for behavioral health conditions at the system, provider, and patient level. There is also a growing understanding of the barriers and challenges to virtual behavioral health care.

Clinical application of a scale to assess genomic healthcare empowerment (GEmS): Process and illustrative case examples.

The Genome Empowerment Scale (GEmS), developed as a research tool, assesses perspectives of parents of children with undiagnosed disorders about to undergo exome or genome sequencing related to the process of empowerment. We defined genomic healthcare empowerment as follows: perceived ability to understand and seek new information related to the genomic sequencing, manage emotions related to the diagnostic process and outcomes, and utilize genomic sequencing information to the betterment of the individual/child and family. The GEmS consists of four scales, two are primarily emotion-focused (Meaning of a Diagnosis, and Emotional Management of the Process) and two are action-oriented (Seeking Information and Support, and Implications and Planning). The purpose of this research was to provide a strategy for interpreting results from the GEmS and present illustrative cases. These illustrations should serve to facilitate use of the GEmS in the clinical and research arena, particularly with respect to guiding genetic counseling processes for parents of children with undiagnosed conditions.

Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain.

PURPOSE: We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1ß subunit of the cyclic AMP-dependent protein kinase A (PKA). METHODS: Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. RESULTS: Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. CONCLUSION: Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

Lessons Learned During COVID-19 That Can Move Telehealth in Primary Care Forward.

INTRODUCTION: Our university hospital-based primary care practices transitioned a budding interest in telehealth to a largely telehealth-based approach in the face of the COVID-19 pandemic. INITIAL WORK: Implementation of telehealth began in 2017. Health system barriers, provider and patient reluctance, and inadequate reimbursement prevented widespread adoption at the time. COVID-19 served as the catalyst to accelerate telehealth efforts. IMPLEMENTATION: COVID-19 resulted in the need for patient care with "social distancing." In addition, due to the pandemic, the Centers for Medicare and Medicaid Services and other insurers began expanded reimbursement for telehealth. More than 2000 providers received virtual health training in less than 2 weeks. In March 2020, we provided 2376 virtual visits, and in April 5293, which was more than 75 times the number provided in February; 73% of all visits in April were virtual (up from 0.5% in October 2019). As COVID-19 cases receded in May, June, and July, patient demand for virtual visits decreased, but 28% of visits in July were still virtual. LESSONS LEARNED: Several key lessons are important for future efforts regarding clinical implementation: (1) prepare for innovation, (2) cultivate an innovation mindset, (3) standardize (but not too much), (4) technological innovation is necessary but not sufficient, and (5) communicate widely and often.

Expansion of NEUROD2 phenotypes to include developmental delay without seizures.

De novo heterozygous variants in the brain-specific transcription factor Neuronal Differentiation Factor 2 (NEUROD2) have been recently associated with early-onset epileptic encephalopathy and developmental delay. Here, we report an adolescent with developmental delay without seizures who was found to have a novel de novo heterozygous NEUROD2 missense variant, p.(Leu163Pro). Functional testing using an in vivo assay of neuronal differentiation in Xenopus laevis tadpoles demonstrated that the patient variant of NEUROD2 displays minimal protein activity, strongly suggesting a loss of function effect. In contrast, a second rare NEUROD2 variant, p.(Ala235Thr), identified in an adolescent with developmental delay but lacking parental studies for inheritance, showed normal in vivo NEUROD2 activity. We thus provide clinical, genetic, and functional evidence that NEUROD2 variants can lead to developmental delay without accompanying early-onset seizures, and demonstrate how functional testing can complement genetic data when determining variant pathogenicity.

Family genetic result communication in rare and undiagnosed disease communities: Understanding the practice.

Genetic results have implications not only for the individual, but also for their family members. Research on family communication of genetic results has primarily focused on families affected by adult-onset, dominant conditions as well as more common genetic conditions such as familial hypercholesterolemia, cardiomyopathies, and genetic hearing loss. This study therefore aimed to characterize genetic result communication in families with rare and undiagnosed conditions and identify factors that influence communication. One hundred and forty-two individuals who received a diagnosis from the Undiagnosed Diseases Network (UDN), a study focused on providing diagnoses to individuals with undiagnosed conditions, were eligible to complete a survey assessing genetic results communication. Survey items assessed if communication was discussed with healthcare providers, with whom participants communicated genetic testing, why they chose to communicate with these family members, and what information they communicated. All respondents (5 adult UDN participants, 38 parents/guardians of UDN participants, and 2 identifying as both) shared genetic results with at least one family member. Individuals who identified as both were considered exclusively adult participants for the purpose of these analyses. Adult participants and parents/guardians of participants reported high levels of understanding (96%), utility (96%), and comfort communicating genetic results (89%). Additionally, parents/guardians were more likely to disclose genetic results due to a general desire to share (60% of parents/guardians vs. 14% adult participants), while adult participants reported that they shared results to communicate risk to family members (86% of adult participants vs. 24% of parents/guardians). Many respondents did not recall discussing with a healthcare provider how (64%) or what (42%) to communicate about results. The results of this study provide insight into the practice of result communication by individuals with rare and previously undiagnosed conditions, which can ideally inform development of more effective counseling strategies and guidelines to aid family communication.

Novel NUDT2 variant causes intellectual disability and polyneuropathy.

Exome or genome sequencing was performed to identify the genetic etiology for the clinical presentation of global developmental delay, intellectual disability, and sensorimotor neuropathy with associated distal weakness in two unrelated families. A homozygous frameshift variant c.186delA (p.A63Qfs*3) in the NUDT2 gene was identified in cases 1 and 2 from one family and a third case from another family. Variants in NUDT2 were previously shown to cause intellectual disability, but here we expand the phenotype by demonstrating its association with distal upper and lower extremity weakness due to a sensorimotor polyneuropathy with demyelinating and/or axonal features.

Gut microbiome composition and risk factors in a large cross-sectional IBS cohort.

Objective: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is difficult to diagnose and treat due to its inherent heterogeneity and unclear aetiology. Although there is evidence suggesting the importance of the microbiome in IBS, this association remains poorly defined. In the current study, we aimed to characterise a large cross-sectional cohort of patients with self-reported IBS in terms of microbiome composition, demographics, and risk factors. Design: Individuals who had previously submitted a stool sample for 16S microbiome sequencing were sent a comprehensive survey regarding IBS diagnosis, demographics, health history, comorbidities, family history, and symptoms. Log ratio-transformed abundances of microbial taxa were compared between individuals reporting a diagnosis of IBS without any comorbidities and individuals reporting no health conditions. Univariable testing was followed by a multivariable logistic regression model controlling for relevant confounders. Results: Out of 6386 respondents, 1692 reported a diagnosis of IBS without comorbidities and 1124 reported no health conditions. We identified 3 phyla, 15 genera, and 19 species as significantly associated with IBS after adjustment for confounding factors. Demographic risk factors include a family history of gut disorders and reported use of antibiotics in the last year. Conclusion: The results of this study confirm important IBS risk factors in a large cohort and support a connection for microbiome compositional changes in IBS pathogenesis. The results also suggest clinical relevance in monitoring and investigating the microbiome in patients with IBS. Further, the exploratory models described here provide a foundation for future studies.

Myopathy associated with homozygous PYROXD1 pathogenic variants detected by genome sequencing.

Biallelic pathogenic variants in the gene PYROXD1 have recently been described to cause early-onset autosomal recessive myopathy. Myopathy associated with PYROXD1 pathogenic variants is rare and reported in only 17 individuals. Known pathogenic variants in PYROXD1 include missense, insertion and essential splice-site variants. Here we describe a consanguineous family of individuals affected with late-onset myopathy and homozygous PYROXD1 missense variants (NM_024854.5:c.464A>G [p.Asn155Ser]) expanding our understanding of the possible disease phenotypes of PYROXD1-associated myopathy.

Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.

PURPOSE: We investigated the value of transcriptome sequencing (RNAseq) in ascertaining the consequence of DNA variants on RNA transcripts to improve the diagnostic rate from exome or genome sequencing for undiagnosed Mendelian diseases spanning a wide spectrum of clinical indications. METHODS: From 234 subjects referred to the Undiagnosed Diseases Network, University of California-Los Angeles clinical site between July 2014 and August 2018, 113 were enrolled for high likelihood of having rare undiagnosed, suspected genetic conditions despite thorough prior clinical evaluation. Exome or genome sequencing and RNAseq were performed, and RNAseq data was integrated with genome sequencing data for DNA variant interpretation genome-wide. RESULTS: The molecular diagnostic rate by exome or genome sequencing was 31%. Integration of RNAseq with genome sequencing resulted in an additional seven cases with clear diagnosis of a known genetic disease. Thus, the overall molecular diagnostic rate was 38%, and 18% of all genetic diagnoses returned required RNAseq to determine variant causality. CONCLUSION: In this rare disease cohort with a wide spectrum of undiagnosed, suspected genetic conditions, RNAseq analysis increased the molecular diagnostic rate above that possible with genome sequencing analysis alone even without availability of the most appropriate tissue type to assess.

Alternative option labeling impacts decision-making in noninvasive prenatal screening.

Prenatal genetic screening should be an informed, autonomous patient choice. Extrinsic factors which influence patient decision-making threaten the ethical basis of prenatal genetic screening. Prior research in the area of medical decision-making has identified that labeling may have unanticipated effects on patient perceptions and decision-making processes. This Internet-administered study explored the impact of option labeling on the noninvasive prenatal screening (NIPS) selections of US adults. A total of 1,062 participants were recruited through Amazon Mechanical Turk (MTurk) and randomly assigned to one of three possible label sets reflecting provider-derived and industry-derived option labels used in prenatal screening. Multinomial logistic regression analysis showed option labeling had a statistically significant impact on the NIPS selections of study participants (p = .0288). Outcomes of the Satisfaction with Decision Scale (SWD) indicated option labels did not play a role in participant satisfaction with screening selection. The results of this study indicate a need for further evaluation of the impact NIPS option labeling has on patient screening decisions in real-world clinical interactions. Clinical providers and testing laboratories offering NIPS should give careful consideration to the option labels used with prenatal screening so as to minimize influence on patient screening selection and decision-making processes.

Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing.

BACKGROUND: Despite growing evidence of diagnostic yield and clinical utility of whole exome sequencing (WES) in patients with undiagnosed diseases, there remain significant cost and reimbursement barriers limiting access to such testing. The diagnostic yield and resulting clinical actions of WES for patients who previously faced insurance coverage barriers have not yet been explored. METHODS: We performed a retrospective descriptive analysis of clinical WES outcomes for patients facing insurance coverage barriers prior to clinical WES and who subsequently enrolled in the Undiagnosed Diseases Network (UDN). Clinical WES was completed as a result of participation in the UDN. Payer type, molecular diagnostic yield, and resulting clinical actions were evaluated. RESULTS: Sixty-six patients in the UDN faced insurance coverage barriers to WES at the time of enrollment (67% public payer, 26% private payer). Forty-two of 66 (64%) received insurance denial for clinician-ordered WES, 19/66 (29%) had health insurance through a payer known not to cover WES, and 5/66 (8%) had previous payer denial of other genetic tests. Clinical WES results yielded a molecular diagnosis in 23 of 66 patients (35% [78% pediatric, 65% neurologic indication]). Molecular diagnosis resulted in clinical actions in 14 of 23 patients (61%). CONCLUSIONS: These data demonstrate that a substantial proportion of patients who encountered insurance coverage barriers to WES had a clinically actionable molecular diagnosis, supporting the notion that WES has value as a covered benefit for patients who remain undiagnosed despite objective clinical findings.

The genome empowerment scale: An assessment of parental empowerment in families with undiagnosed disease.

While genomic sequencing (ES/GS) has the potential to diagnose children with difficult to diagnose phenotypes, the goal should be not only a diagnosis, but also to empower parents to seek next steps for their children and to emotionally manage the outcome, whether or not a diagnosis is secured. To help achieve this goal, objective measures are needed to assess the process of parental empowerment related to genome sequencing. We present the validity and reliability of the Genome Empowerment Scale (GEmS), developed using a healthcare empowerment theoretical model. To evaluate its psychometric properties, 158 parents of 117 children with an undiagnosed condition undergoing genomic sequencing completed the GEmS, measures for criterion validity and for depression and anxiety. Factor analysis resulted in a four factor solution: (a) meaning of a diagnosis; (b) emotional management of the process; (c) seeking information and support and (d) implications and planning. Reliability and validity analyses show that the GEmS has good psychometric properties. The inter-relationships among the factors revealed a profile that may identify parents at risk for a poorer outcome who may benefit from targeted genetic counseling. The GEmS, an objective measure of parental genomic empowerment, can be utilized for future research and translational applications.

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.