Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.

Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies.

More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed associated clinical features and phenotypic relatedness by using HPO-based semantic similarity analysis for individuals with de novo variants in the same gene. Gene-specific phenotypic signatures included associations of SCN1A with "complex febrile seizures" (HP: 0011172; p = 2.1 × 10-5) and "focal clonic seizures" (HP: 0002266; p = 8.9 × 10-6), STXBP1 with "absent speech" (HP: 0001344; p = 1.3 × 10-11), and SLC6A1 with "EEG with generalized slow activity" (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.

Digital Health Technology for Real-World Clinical Outcome Measurement Using Patient-Generated Data: Systematic Scoping Review.

BACKGROUND: Digital health technologies (DHTs) play an ever-expanding role in health care management and delivery. Beyond their use as interventions, DHTs also serve as a vehicle for real-world data collection to characterize patients, their care journeys, and their responses to other clinical interventions. There is a need to comprehensively map the evidence-across all conditions and technology types-on DHT measurement of patient outcomes in the real world. OBJECTIVE: We aimed to investigate the use of DHTs to measure real-world clinical outcomes using patient-generated data. METHODS: We conducted this systematic scoping review in accordance with the Joanna Briggs Institute methodology. Detailed eligibility criteria documented in a preregistered protocol informed a search strategy for the following databases: MEDLINE (Ovid), CINAHL, Cochrane (CENTRAL), Embase, PsycINFO, ClinicalTrials.gov, and the EU Clinical Trials Register. We considered studies published between 2000 and 2022 wherein digital health data were collected, passively or actively, from patients with any specified health condition outside of clinical visits. Categories for key concepts, such as DHT type and analytical applications, were established where needed. Following screening and full-text review, data were extracted and analyzed using predefined fields, and findings were reported in accordance with established guidelines. RESULTS: The search strategy identified 11,015 publications, with 7308 records after duplicates and reviews were removed. After screening and full-text review, 510 studies were included for extraction. These studies encompassed 169 different conditions in over 20 therapeutic areas and 44 countries. The DHTs used for mental health and addictions research (111/510, 21.8%) were the most prevalent. The most common type of DHT, mobile apps, was observed in approximately half of the studies (250/510, 49%). Most studies used only 1 DHT (346/510, 67.8%); however, the majority of technologies used were able to collect more than 1 type of data, with the most common being physiological data (189/510, 37.1%), clinical symptoms data (188/510, 36.9%), and behavioral data (171/510, 33.5%). Overall, there has been real growth in the depth and breadth of evidence, number of DHT types, and use of artificial intelligence and advanced analytics over time. CONCLUSIONS: This scoping review offers a comprehensive view of the variety of types of technology, data, collection methods, analytical approaches, and therapeutic applications within this growing body of evidence. To unlock the full potential of DHT for measuring health outcomes and capturing digital biomarkers, there is a need for more rigorous research that goes beyond technology validation to demonstrate whether robust real-world data can be reliably captured from patients in their daily life and whether its capture improves patient outcomes. This study provides a valuable repository of DHT studies to inform subsequent research by health care providers, policy makers, and the life sciences industry. TRIAL REGISTRATION: Open Science Framework 5TMKY; https://osf.io/5tmky/.

A longitudinal footprint of genetic epilepsies using automated electronic medical record interpretation.

PURPOSE: Childhood epilepsies have a strong genetic contribution, but the disease trajectory for many genetic etiologies remains unknown. Electronic medical record (EMR) data potentially allow for the analysis of longitudinal clinical information but this has not yet been explored. METHODS: We analyzed provider-entered neurological diagnoses made at 62,104 patient encounters from 658 individuals with known or presumed genetic epilepsies. To harmonize clinical terminology, we mapped clinical descriptors to Human Phenotype Ontology (HPO) terms and inferred higher-level phenotypic concepts. We then binned the resulting 286,085 HPO terms to 100 3-month time intervals and assessed gene-phenotype associations at each interval. RESULTS: We analyzed a median follow-up of 6.9 years per patient and a cumulative 3251 patient years. Correcting for multiple testing, we identified significant associations between "Status epilepticus" with SCN1A at 1.0 years, "Severe intellectual disability" with PURA at 9.75 years, and "Infantile spasms" and "Epileptic spasms" with STXBP1 at 0.5 years. The identified associations reflect known clinical features of these conditions, and manual chart review excluded provider bias. CONCLUSION: Some aspects of the longitudinal disease histories can be reconstructed through EMR data and reveal significant gene-phenotype associations, even within closely related conditions. Gene-specific EMR footprints may enable outcome studies and clinical decision support.

Correction: A longitudinal footprint of genetic epilepsies using automated electronic medical record interpretation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Striving for affordable medicine: Lessons in price negotiation learned from the United Kingdom.

In August 2022, the Centers for Medicare & Medicaid Services were granted unprecedented power to negotiate the price of some pharmaceuticals covered under Medicare Part D of the Inflation Reduction Act. Price negotiation was previously banned by Medicare Part D legislation but is not a new idea globally. For decades, nations like the United Kingdom have price set or negotiated the cost of medicine with manufacturers, fine-tuning their methodologies, with mixed success. The United States can learn from other countries' work to develop a methodology capable of achieving increased affordability and patient access to medicine. Secretary Xavier Becerra should consider the United Kingdom's policy approach, which facilitates early and transparent collaboration with key stakeholders like patient groups and industry but limits flexibility in evidence submission, to help the United States minimize unintended damage to patient access to new medicines and achieve the Inflation Reduction Act's goals.

Availability, affordability and access to essential medications for asthma and chronic obstructive pulmonary disease in three low- and middle-income country settings.

INTRODUCTION: Despite the rising burden of chronic respiratory disease globally, and although many respiratory medications are included in the World Health Organization Essential Medications List (WHO-EML), there is limited information concerning the availability and affordability of treatment drugs for respiratory conditions in low- and middle-income countries (LMICs). METHODS: All public and private pharmacies in catchment areas of the Global Excellence in COPD outcomes (GECo) study sites in Bhaktapur, Nepal, Lima, Peru, and Nakaseke, Uganda, were approached in 2017-2019 to assess pricing and availability of medications for the management of asthma and COPD. RESULTS: We surveyed all 63 pharmacies in respective study areas in Nepal (95.2% private), 104 pharmacies in Peru (94.2% private) and 53 pharmacies in Uganda (98.1% private). The availability of any medication for respiratory disease was higher in private (93.3%) compared to public (73.3%) pharmacies. Salbutamol (WHO-EML) monotherapy in any formulation was the most commonly available respiratory medication among the three sites (93.7% Nepal, 86.5% Peru and 79.2% Uganda) while beclomethasone (WHO-EML) was only available in Peru (33.7%) and Nepal (22%). LABA-LAMA combination therapy was only available in Nepal (14.3% of pharmacies surveyed). The monthly treatment cost of respiratory medications was lowest in Nepal according to several cost metrics: the overall monthly cost, the median price ratio comparing medication costs to international reference prices at time of survey in dollars, and in terms of days' wages of the lowest-paid government worker. For the treatment of intermittent asthma, defined as 100 mcg Salbutamol/Albuterol inhaler, days' wages ranged from 0.47 days in Nepal and Peru to 3.33 days in Uganda. CONCLUSION: The availability and pricing of respiratory medications varied across LMIC settings, with medications for acute care of respiratory diseases being more widely available than those for long-term management.

Phenotypic homogeneity in childhood epilepsies evolves in gene-specific patterns across 3251 patient-years of clinical data.

While genetic studies of epilepsies can be performed in thousands of individuals, phenotyping remains a manual, non-scalable task. A particular challenge is capturing the evolution of complex phenotypes with age. Here, we present a novel approach, applying phenotypic similarity analysis to a total of 3251 patient-years of longitudinal electronic medical record data from a previously reported cohort of 658 individuals with genetic epilepsies. After mapping clinical data to the Human Phenotype Ontology, we determined the phenotypic similarity of individuals sharing each genetic etiology within each 3-month age interval from birth up to a maximum age of 25 years. 140 of 600 (23%) of all 27 genes and 3-month age intervals with sufficient data for calculation of phenotypic similarity were significantly higher than expect by chance. 11 of 27 genetic etiologies had significant overall phenotypic similarity trajectories. These do not simply reflect strong statistical associations with single phenotypic features but appear to emerge from complex clinical constellations of features that may not be strongly associated individually. As an attempt to reconstruct the cognitive framework of syndrome recognition in clinical practice, longitudinal phenotypic similarity analysis extends the traditional phenotyping approach by utilizing data from electronic medical records at a scale that is far beyond the capabilities of manual phenotyping. Delineation of how the phenotypic homogeneity of genetic epilepsies varies with age could improve the phenotypic classification of these disorders, the accuracy of prognostic counseling, and by providing historical control data, the design and interpretation of precision clinical trials in rare diseases.

Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

SPTBN1 encodes ßII-spectrin, the ubiquitously expressed ß-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal ßII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect ßII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of ßII-spectrin in the central nervous system.