Faculty Bibliography

BACKGROUND:Among the alternative solutions being tested to improve access to genetic services, chatbots (or conversational agents) are being increasingly used for service delivery. Despite the growing number of studies on the accessibility and feasibility of chatbot genetic service delivery, limited attention has been paid to user interactions with chatbots in a real-world health care context. OBJECTIVE:We examined users' interaction patterns with a pretest cancer genetics education chatbot as well as the associations between users' clinical and sociodemographic characteristics, chatbot interaction patterns, and genetic testing decisions. METHODS:We analyzed data from the experimental arm of Broadening the Reach, Impact, and Delivery of Genetic Services, a multisite genetic services pragmatic trial in which participants eligible for hereditary cancer genetic testing based on family history were randomized to receive a chatbot intervention or standard care. In the experimental chatbot arm, participants were offered access to core educational content delivered by the chatbot with the option to select up to 9 supplementary informational prompts and ask open-ended questions. We computed descriptive statistics for the following interaction patterns: prompt selections, open-ended questions, completion status, dropout points, and postchat decisions regarding genetic testing. Logistic regression models were used to examine the relationships between clinical and sociodemographic factors and chatbot interaction variables, examining how these factors affected genetic testing decisions. RESULTS:Of the 468 participants who initiated a chat, 391 (83.5%) completed it, with 315 (80.6%) of the completers expressing a willingness to pursue genetic testing. Of the 391 completers, 336 (85.9%) selected at least one informational prompt, 41 (10.5%) asked open-ended questions, and 3 (0.8%) opted for extra examples of risk information. Of the 77 noncompleters, 57 (74%) dropped out before accessing any informational content. Interaction patterns were not associated with clinical and sociodemographic factors except for prompt selection (varied by study site) and completion status (varied by family cancer history type). Participants who selected ≥3 prompts (odds ratio 0.33, 95% CI 0.12-0.91; P=.03) or asked open-ended questions (odds ratio 0.46, 95% CI 0.22-0.96; P=.04) were less likely to opt for genetic testing. CONCLUSIONS:Findings highlight the chatbot's effectiveness in engaging users and its high acceptability, with most participants completing the chat, opting for additional information, and showing a high willingness to pursue genetic testing. Sociodemographic factors were not associated with interaction patterns, potentially indicating the chatbot's scalability across diverse populations provided they have internet access. Future efforts should address the concerns of users with high information needs and integrate them into chatbot design to better support informed genetic decision-making.

PURPOSE/OBJECTIVE:XPO1 functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome, however no monogenic XPO1-related disorder has been described to date. MATERIALS AND METHODS/METHODS:We collected clinical data of individuals with de novo XPO1 variants through online matchmaking. We employed Drosophila to study XPO1 function in development and habituation learning. RESULTS:A total of 22 individuals met the criteria to be included in the main study cohort. Of these, half have putative loss-of-function variants and half have coding variants (10 missense and 1 in-frame deletion variant). We find an overlapping phenotype, consistent with a monogenic neurodevelopmental disorder (NDD). We demonstrate XPO1 functions in development by ubiquitous and neuron-specific knockdown in Drosophila. GABAergic neuron specific knockdown flies demonstrated impaired habituation. CONCLUSION/CONCLUSIONS:Our results establish XPO1 as a novel dominant monogenic NDD gene and demonstrate a central role for XPO1 in development.

OBJECTIVE:To examine whether patient sociodemographic and clinical characteristics and prior interactions with the healthcare system were associated with opening patient portal messages related to cancer genetic services and beginning services. STUDY SETTING AND DESIGN/METHODS:The trial was conducted in the University of Utah Health (UHealth) and NYU Langone Health (NYULH) systems. Between 2020 and 2023, 3073 eligible primary care patients aged 25-60 years meeting family history-based criteria for cancer genetic evaluation were randomized 1:1 to receive a patient portal message with a hyperlink to a pretest genetics education chatbot or information about scheduling a pretest standard of care (SOC) appointment. DATA SOURCES AND ANALYTIC SAMPLE/UNASSIGNED:Primary data were collected. Eligible patients had a primary care visit in the previous 3 years, a patient portal account, no prior cancer diagnosis except nonmelanoma skin cancer, no prior cancer genetic services, and English or Spanish as their preferred language. Multivariable models identified predictors of opening patient portal messages by site and beginning pretest genetic services by site and experimental condition. PRINCIPAL FINDINGS/RESULTS:Number of previous patient portal logins (UHealth average marginal effect [AME]: 0.32; 95% CI: 0.27, 0.38; NYULH AME: 0.33; 95% CI: 0.27, 0.39), having a recorded primary care provider (NYULH AME: 0.15; 95% CI: 0.08, 0.22), and more primary care visits in the previous 3 years (NYULH AME: 0.09; 95% CI: 0.02, 0.16) were associated with opening patient portal messages about genetic services. Number of previous patient portal logins (UHealth AME: 0.14; 95% CI: 0.08, 0.21; NYULH AME: 0.18; 95% CI: 0.12, 0.23), having a recorded primary care provider (NYULH AME: 0.08; 95% CI: 0.01, 0.14), and more primary care visits in the previous 3 years (NYULH AME: 0.07; 95% CI: 0.01, 0.13) were associated with beginning pretest genetic services. Patient sociodemographic and clinical characteristics were not significantly associated with either outcome. CONCLUSIONS:As system-level initiatives aim to reach patients eligible for cancer genetic services, patients already interacting with the healthcare system may be most likely to respond. Addressing barriers to accessing healthcare and technology may increase engagement with genetic services.

Fanconi anemia (FA) is a rare genetic disease characterized by loss-of-function variants in any of the 22 previously identified genes (FANCA-FANCW) that encode proteins participating in the repair of DNA interstrand crosslinks (ICLs). Patient phenotypes are variable, but may include developmental abnormalities, early onset pancytopenia, and predisposition to hematologic and solid tumors. Here, we describe two unrelated families with multiple pregnancy losses and offspring presenting with severe developmental and hematologic abnormalities leading to death in utero or in early life. Homozygous loss-of-function variants in FAAP100 were identified in affected children of both families. The FAAP100 protein associates with FANCB and FANCL, the E3 ubiquitin ligase responsible for the monoubiquitination of FANCD2 and FANCI, which is necessary for FA pathway function. Patient-derived cells exhibited phenotypes consistent with FA. Expression of the wild-type FAAP100 cDNA, but not the patient-derived variants, rescued the observed cellular phenotypes. This establishes FAAP100 deficiency as a cause of Fanconi anemia, with FAAP100 gaining an alias as FANCX. The extensive developmental malformations of individuals with FAAP100 loss-of-function variants are among the most severe across previously described FA phenotypes, indicating that the FA pathway is essential for human development.

Pathogenic variants resulting in protein phosphatase 2A (PP2A) dysfunction result in mild to severe neurodevelopmental delay. PP2A is a trimer of a catalytic (C) subunit, scaffolding (A) subunit, and substrate binding/regulatory (B) subunit, encoded by 19 different genes. De novo missense variants in PPP2R5D (B56δ) or PPP2R1A (Aα) and de novo missense and loss-of-function variants in PPP2CA (Cα) lead to syndromes with overlapping phenotypic features, known as Houge-Janssens syndrome (HJS) types 1, 2, and 3, respectively. Here, we describe an additional condition in the HJS spectrum in 26 individuals with variants in PPP2R5C, encoding the regulatory B56γ subunit. Most changes were de novo and of the missense type. The clinical features were well within the HJS spectrum with strongest resemblance to HJS type 1, caused by B56δ variants. Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features. Head circumferences were above average or macrocephalic. The degree of intellectual disability was, on average, milder than in other HJS types. All variants affected either substrate binding (2/19), C-subunit binding (2/19), or both (15/19). Five variants were recurrent. Catalytic activity of the phosphatase was variably affected by the variants. Of note, PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic parent. This implies that a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.

INTRODUCTION/BACKGROUND:Heterozygous pathogenic variants in NTRK2 (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of NTRK2-related disorders and to delineate the clinical presentation METHODS: We report extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported. RESULTS:Our analysis led to splitting the cohort into two entities. DISCUSSION/CONCLUSIONS:One group had variants in the cholesterol binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A>G p.(Tyr434Cys). These variants probably lead to upregulation of TRKB activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variants that presumably disturb the 3D structure of the protein leading to loss of function. These individuals had a remarkably milder phenotype of developmental delay, obesity and hyperphagia.

PURPOSE/OBJECTIVE:Stronger Together is a peer mentoring model that seeks to address the severe lack of mental health and psychosocial support for patients with cancer in many low- and middle-income countries (LMICs). This article presents the results of the Stronger Together pilot study among patients with breast and gynecologic cancer in Viet Nam (VN). METHODS:Eligible participants comprised women age 25 years or older with a diagnosis of breast or gynecologic cancers and receiving treatment at four participating hospitals. Participants were asked whether they wanted to proceed with usual care or be matched with a trained and supervised peer mentor (a cancer survivor). Surveys were administered at baseline (0) and 2, 4, and 6 months and assessed depression, anxiety, stress, mental health and physical health components of quality of life (QOL), self-efficacy, and social support. We computed and compared 2-, 4-, and 6-month changes in scores from baseline and conducted difference-in-difference analyses to estimate the intervention effect at 6 months. RESULTS:The sample size included N = 186 participants. Mentees (n = 91) exhibited improvements in depression, anxiety, stress, and mental health QOL across all time points, whereas usual care participants (n = 95) experienced these improvements at later periods (4 and 6 months). Compared with usual care participants, mentees reported greater improvements in depression at 2 and 4 months, mental health QOL at all time points, and self-efficacy and social support at 4 and 6 months. Greater improvements in stress were also seen in the breast cancer subsample. CONCLUSION/CONCLUSIONS:Stronger Together is a promising model to improve mental health and psychosocial outcomes among patients with breast and gynecologic cancer in VN and can help fill gaps in cancer peer support interventions in many LMICs.

PURPOSE/OBJECTIVE:This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS:We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS:Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing. CONCLUSION/CONCLUSIONS:This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'.

IMPORTANCE/UNASSIGNED:Increasing numbers of unaffected individuals could benefit from genetic evaluation for inherited cancer susceptibility. Automated conversational agents (ie, chatbots) are being developed for cancer genetics contexts; however, randomized comparisons with standard of care (SOC) are needed. OBJECTIVE/UNASSIGNED:To examine whether chatbot and SOC approaches are equivalent in completion of pretest cancer genetic services and genetic testing. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This equivalence trial (Broadening the Reach, Impact, and Delivery of Genetic Services [BRIDGE] randomized clinical trial) was conducted between August 15, 2020, and August 31, 2023, at 2 US health care systems (University of Utah Health and NYU Langone Health). Participants were aged 25 to 60 years, had had a primary care visit in the previous 3 years, were eligible for cancer genetic evaluation, were English or Spanish speaking, had no prior cancer diagnosis other than nonmelanoma skin cancer, had no prior cancer genetic counseling or testing, and had an electronic patient portal account. INTERVENTION/UNASSIGNED:Participants were randomized 1:1 at the patient level to the study groups at each site. In the chatbot intervention group, patients were invited in a patient portal outreach message to complete a pretest genetics education chat. In the enhanced SOC control group, patients were invited to complete an SOC pretest appointment with a certified genetic counselor. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Primary outcomes were completion of pretest cancer genetic services (ie, pretest genetics education chat or pretest genetic counseling appointment) and completion of genetic testing. Equivalence hypothesis testing was used to compare the study groups. RESULTS/UNASSIGNED:This study included 3073 patients (1554 in the chatbot group and 1519 in the enhanced SOC control group). Their mean (SD) age at outreach was 43.8 (9.9) years, and most (2233 of 3063 [72.9%]) were women. A total of 204 patients (7.3%) were Black, 317 (11.4%) were Latinx, and 2094 (75.0%) were White. The estimated percentage point difference for completion of pretest cancer genetic services between groups was 2.0 (95% CI, -1.1 to 5.0). The estimated percentage point difference for completion of genetic testing was -1.3 (95% CI, -3.7 to 1.1). Analyses suggested equivalence in the primary outcomes. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The findings of the BRIDGE equivalence trial support the use of chatbot approaches to offer cancer genetic services. Chatbot tools can be a key component of sustainable and scalable population health management strategies to enhance access to cancer genetic services. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT03985852.