Case report: Early use of whole exome sequencing unveils HNRNPU-related neurodevelopmental disorder and answers additional clinical questions through reanalysis.

This case report chronicles the diagnostic odyssey and resolution of a 27-year-old female with a complex neurodevelopmental disorder (NDD) using Whole Exome Sequencing (WES). The patient presented to a precision medicine clinic with multiple diagnoses including intellectual disability, autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), tics, seizures, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although this patient previously had chromosomal microarray and several single-gene tests, the underlying cause of this patient's symptoms remained elusive. WES revealed a pathogenic missense mutation in the HNRNPU gene, associated with HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) and developmental and epileptic encephalopathy-54 (DEE54, OMIM: # 617391). Following this diagnoses, other treating clinicians identified additional indications for genetic testing, however, as the WES data was readily available, the clinical team was able to re-analyze the WES data to address their inquiries without requiring additional tests. This emphasizes the pivotal role of WES in expediting diagnoses, reducing costs, and providing ongoing clinical utility throughout a patient's life. Accessible WES data in primary care settings can enhance patient care by informing future genetic inquiries, enhancing coordination of care, and facilitating precision medicine interventions, thereby mitigating the burden on families and the healthcare system.

From Vaccines to Vitality: The Progression of a Community-Academic Collaboration.

In this practice note, we document the progression of the Community Vaccine Collaborative (CVC), on which we first published in 2021. The CVC convened to address deep COVID-19-related disparities affecting the Black, Latine, immigrant/refugee, and lesbian, gay, bisexual, transgender, queer, (questioning), intersex, asexual, and (agender) (LGBTQIA+) communities. The COVID-19 pandemic is rooted in centuries of oppression and marginalization leading to inequities and required dedicated focus to support marginalized communities in times of crisis. The CVC comprises community members, community-based organizations, health care providers, researchers, health systems leaders, and public health practitioners (among others), all of whom are dedicated to promoting COVID-19 vaccine equity. As the pandemic shifts and changes, so too has our group, to remain relevant to community needs and priorities. This article details Year 2 of the CVC, focusing on how we have grown and sustained this unique partnership. We also share results from an evaluation of the CVC, documenting participation in the collaborative space and alignment with CVC core principles. Finally, we discuss next steps and implications for the CVC including our pivot from vaccines to community vitality as we expand and sustain our collaborative efforts to address the ongoing COVID-19 pandemic and intersecting public health crises.

Documenting Pharmacogenomic Test Results in Electronic Health Records: Practical Considerations for Primary Care Teams.

With increasing patient interest in and access to pharmacogenomic testing, clinicians practicing in primary care are more likely than ever to encounter a patient seeking or presenting with pharmacogenomic test results. Gene-based prescribing recommendations are available to healthcare providers through Food and Drug Administration-approved drug labeling and Clinical Pharmacogenetics Implementation Consortium guidelines. Given the lifelong utility of pharmacogenomic test results to optimize pharmacotherapy for commonly prescribed medications, appropriate documentation of these results in a patient's electronic health record (EHR) is essential. The current "gold standard" for pharmacogenomics implementation includes entering pharmacogenomic test results into EHRs as discrete results with associated clinical decision support (CDS) alerts that will fire at the point of prescribing, similar to drug allergy alerts. However, such infrastructure is limited to the few institutions that have invested in the resources and personnel to develop and maintain it. For the majority of clinicians who do not practice at an institution with a dedicated clinical pharmacogenomics team and integrated pharmacogenomics CDS in the EHR, this report provides practical tips for documenting pharmacogenomic test results in the problem list and allergy field to maximize the visibility and utility of results over time, especially when such results could prevent the occurrence of serious adverse drug reactions or predict therapeutic failure.

A Community Partnered Approach to Promoting COVID-19 Vaccine Equity.

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected communities of color. To dismantle these disparities, it is critical to promote COVID-19 vaccine equity, both through increasing vaccine access and addressing vaccine mistrust. This article describes a community-academic collaboration (the Community Vaccine Collaborative [CVC]), whose mission is to ensure COVID-19 vaccine equity among marginalized communities. Based in Pittsburgh, Pennsylvania, our group has focused on inclusion of marginalized groups into vaccine clinical trials, addressing vaccine mistrust, and building systems to ensuring equitable access to the COVID-19 vaccine. We review formation of the CVC, activities to-date, and recommendations for other communities interested in developing similar collaboratives.

Participatory Genomic Testing Can Effectively Disseminate Cardiovascular Pharmacogenomics Concepts within Federally Qualified Health Centers: A Feasibility Study.

Objective: We assessed feasibility of an educational program designed to enhance stakeholder knowledge and perceptions of pharmacogenomics at a federally qualified health center (FQHC). Design: FQHCs have a rich history of providing care to the underserved, but often are not represented by studies evaluating cutting-edge concepts. We used a novel educational platform to provide participatory genomic testing and classroom education. We assessed participant knowledge and perceptions using questionnaires between May and July 2018. Setting: We partnered with a FQHC affiliated with an academic medical center in Chicago. Participants: Using convenience sampling, we recruited 20 providers and 10 community members for a feasibility study. Providers included physicians, physician extenders, community health workers, and patient health navigators. Community members were patients, supporters, and/or FQHC advisory board members. Intervention: Participants had the option to undergo personal genomic testing. Online educational modules included basic genetics, cardiovascular pharmacogenomics, and personalized medicine. Education concluded in a 2-hour live course with case-based discussions. Main Outcome Measures: Our main outcome was testing pilot feasibility. Baseline knowledge and perceptions were compared with post-intervention assessments using descriptive statistics, t tests (or Wilcoxon rank-sum) for continuous variables and chi-squared (or Fisher's exact) for categorical variables. Results: We found that attitudes toward the intervention were positive and remained so after intervention. Our intervention was both feasible and acceptable. Genomics knowledge increased for nearly all participants. Conclusions: We have determined that a pharmacogenomics educational program tailored for an underrepresented community is feasible and acceptable. Outcomes will advise methodology for larger implementation studies.

Knowledge and opinions regarding BRCA1 and BRCA2 genetic testing among primary care physicians.

BRCA1 and BRCA2 (BRCA1/2) testing is standard for individuals with personal and/or family history suggestive of hereditary breast and ovarian cancer syndrome. The indications for testing have been expanding. To accommodate the need, incorporation of cancer genetic services into the practice of non-genetic healthcare providers should be considered. We carried out a survey to evaluate the knowledge and opinions regarding BRCA1/2 testing among primary care providers. The survey was sent to 245 Obstetrics/Gynecology and 97 Family Medicine physicians in the UPMC network. Eighty-six completed the survey between July 2015 and September 2015. The average correct responses to knowledge questions was 73%. A few respondents reported being completely confident, and ~50% reported being somewhat confident, in providing BRCA1/2-related information. Respondents selected genetic specialists and oncologists as the most qualified to provide cancer genetic services. Several perceived barriers and motivating factors to the implementation of BRCA1/2 testing in primary care were identified. The findings from this study suggested that primary care providers were not uniformly ready to provide BRCA1/2 genetic testing. Availability of professional society guidelines and evidence of testing's usefulness might motivate the incorporation of BRCA1/2 genetic testing into primary care practices. These findings would help guide future educational efforts to promote provision of cancer genetic services by non-genetic professionals.

Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

Alternating hemiplegia of childhood: early characteristics and evolution of a neurodevelopmental syndrome.

OBJECTIVES: Alternating hemiplegia of childhood is a predominantly sporadic neurodevelopmental syndrome of uncertain etiology. In more than 3 decades since its description, little progress has been made in understanding its etiology or in identifying effective treatments. In 1998, in collaboration with the Alternating Hemiplegia of Childhood Foundation, an international registry was established to help document clinical outcomes and promote research efforts. PATIENTS AND METHODS: We present phenotypic data on 103 patients who met existing diagnostic criteria for alternating hemiplegia of childhood. Although some of these subjects may have been included in previously published reviews, our focus was directed toward the earliest manifestations of symptoms and evolution of features over time. Data sources included written questionnaires, face-to-face and telephone interviews, clinical examination, and medical charts. Characteristics of disease onset, medical comorbidities, episode triggers, diagnostic workup, and treatment are presented. RESULTS: Paroxysmal eye movements were the most frequent early symptom, manifesting in the first 3 months of life in 83% of patients. Hemiplegic episodes appeared by 6 months of age in 56% of infants. Background slowing shown by electroencephalography during typical paroxysmal events, including hemiplegic, tonic, or dystonic episodes was frequent (21 of 42 cases). Distinct convulsive episodes with altered consciousness believed to be epileptic in nature were reported in 41% of patients. Ataxia (96%) and cognitive impairment (100%) were frequent nonepisodic symptoms. Empiric pharmacologic treatment approaches offered little benefit in most subjects and resulted in adverse effects in 20% of patients. Prolonged episodes were completely or temporarily aborted during sleep in all subjects. CONCLUSIONS: This descriptive analysis of a large cohort of children indicates that paroxysmal ocular movements are an early, highly suggestive symptom, followed by paroxysmal episodes of focal dystonia or flaccid, alternating hemiplegia in early infancy in the majority of subjects. Current challenges in diagnosis and management contribute to poor outcomes. Early diagnosis and multicenter collaboration are needed to facilitate trials to identify more effective therapies.

Characterization of distinct Stat5b binding sites that mediate growth hormone-stimulated IGF-I gene transcription.

A key agent in the anabolic actions of growth hormone (GH) is insulin-like growth factor-I (IGF-I), a 70-amino acid secreted protein with direct effects on somatic growth and tissue maintenance and repair. GH rapidly and potently stimulates IGF-I gene transcription by mechanisms independent of new protein synthesis, and recent studies have linked the transcription factor Stat5b to a regulatory network connecting the activated GH receptor on the cell membrane to the IGF-I gene in the nucleus. Here we analyze two distinct conserved GH response elements in the rat IGF-I locus that contain paired Stat5b sites. Each response element binds Stat5b in vivo in a GH-dependent way, as assessed by chromatin immunoprecipitation assays, and consists of one high affinity and one lower affinity Stat5b site, as determined by both qualitative and quantitative protein-DNA binding studies. In biochemical reconstitution experiments, both response elements are able to mediate GH-stimulated and Stat5b-dependent transcription when fused to a reporter gene containing either the major IGF-I promoter or a minimal neutral promoter, although the paired Stat5b sites located in the second IGF-I intron were more than twice as effective as the response element that mapped approximately 73 kb 5' to the IGF-I exon 1. Taken together, our results define the initial molecular architecture of a complicated GH-regulated transcriptional pathway, and suggest that apparently redundant hormone response elements provide a mechanism for amplifying GH action at a physiologically important target gene.

Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation.

Alternating hemiplegia of childhood (AHC) is typically distinguished from familial hemiplegic migraine (FHM) by infantile onset of the characteristic symptoms and high prevalence of associated neurological deficits that become increasingly obvious with age. Expansion of the clinical spectrum in FHM recently has begun to blur the distinction between these disorders. We report a novel ATP1A2 mutation in a kindred with features that bridge the phenotypic spectrum between AHC and FHM syndromes, supporting a possible common pathogenesis in a subset of such cases. Mutation analysis in classic sporadic AHC patients and in an additional five kindreds in which linkage to the ATP1A2 locus could not be excluded failed to identify additional mutations.