Phenotypic Description Research Articles

Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer’s disease: a neuropsychological data-driven approach

BackgroundThe clinical presentations of early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort.MethodsNeuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of “predominant” impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes.ResultsWe identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia.ConclusionA neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations.

P0276 Psoriasis is more frequently induced and displays a distinct phenotype in patients with Inflammatory Bowel Disease.

Abstract Background Specific psoriasis (Pso) phenotypes seem to emerge in inflammatory bowel disease (IBD) patients. Our study explored Pso phenotypes under and outside biologic therapy in IBD, comparing them to those in chronic inflammatory rheumatism (IRD). Methods From a prospective university hospital cohort of patients with IBD, IRD, and Pso, we selected those with IBD and/or IRD (axial and peripheral spondyloarthritis or rheumatoid arthritis) associated with Pso, excluding psoriatic arthritis cases. Each case was reviewed to classify psoriasis as therapy-induced or not, define prevalence with phenotype description, examine treatments responsible for induced Pso, and assess risk factors for therapy-induced Pso in IBD. Results Among 2,412 patients in the database, 237 (9.8%) had psoriasis associated with IBD and/or IRD: 98 with IBD, 110 with IRD, and 29 with both IBD and IRD. Pso prevalence was 12.1% in IBD vs. 8.5% in IRD (p=0.0056). After analysis, 92 (93.9%) IBD and 86 (78.2%) IRD patients had been exposed to systemic therapy (p=0.0013). The mean age for IBD+Pso and IRD+Pso was 46.4 (±15.8) and 52.8 (±15.5) years, respectively (p=0.0034); 62 (63.3%) and 49 (45%) were women (p=0.0083). Phenotypic details of Pso were available in 97/98 IBD and 90/110 IRD cases: 70 (71.4%) vs. 33 (30%) were therapy-induced Pso, respectively (p<0.0001). The main systemic therapy linked to induced Pso was biologics: adalimumab in 44 (62.9%) IBD and 15 (45.5%) IRD patients (p=0.0957). Plaque and inverse psoriasis were noted in 72 (73.5%) and 39 (39.8%) IBD vs. 53 (48.2%) and 6 (5.4%) IRD patients (p=0.0002 and p<0.0001). Lesions appeared on the face in 26 (26.5%) IBD vs. 6 (5.4%) IRD (p<0.0001), on the scalp in 40 (40.8%) IBD vs. 30 (27.3%) IRD (p=0.0391), and on nasal wings in 13 (13.3%) IBD patients only (p<0.0001), suggesting this as a specific site. In IBD, inverse and scalp Pso were more frequent in therapy-induced cases. Regarding Pso treatments, biologic therapy was discontinued in 13 (13.3%) IBD patients vs. 2 (1.8%) IRD patients (p=0.0014), and a swap out of biologic class was made in 32 (32.7%) IBD patients vs. 5 (4.5%) IRD patients (p<0.0001). Factors associated to therapy-induced Pso in IBD were active smoking (OR= 2.02, 95% CI [1.14–3.56], p=0.0193), inflammatory phenotype in Crohn’s disease (OR=1.94, 95% CI [1.21;3.10], p=0.0047), and female sex (OR=2.04 [1.25–3.31], p=0.0041). Conclusion In this large cohort, Pso prevalence in IBD was high, with therapy-induced Pso being more frequent among women and smokers. Specific phenotypes were observed (induced, inverse, scalp, nasal wings), suggesting a common pathophysiology with the underlying inflammatory disease.

Evaluation of PCORnet as an Approach to Accessing Electronic Health Record (EHR) Data for Cleft Outcomes Research: Advantages and Limitations.

Objective: To evaluate the feasibility of using the National Patient-Centered Clinical Research Network (PCORnet®) as a source of electronic health record (EHR) data for cleft outcomes research. Design: Exploratory retrospective analysis of multi-year, administrative and clinical, structured data stored in PCORnet. Setting: Academic institution with an ACPA-approved cleft and craniofacial team. Patients/Participants: Encounter-level data pertaining to patients with orofacial clefts treated at this center between 2010 and 2018. Outcome Measures: (1) Ability of PCORnet to report metrics such as the following: number of new and returning patients per year; demographics; phenotype; procedures; readmission or reoperation within 30 days; etc. (2) Accuracy of selected metrics, compared with manual chart review. Results: PCORnet is useful for the calculation of simple process metrics such as patient demographics, phenotype mix, case mix, and number of readmissions. However, as it lacks access to clinical notes, PCORnet alone cannot provide more detailed information. Phenotypic classification (based on ICD codes) and procedural description (based on CPT®) are subject to inaccuracy. A 1-2 year delay in data upload to PCORnet may be rate-limiting for certain applications. Multi-institutional queries were feasible. Conclusions: PCORnet does not include all necessary data elements from the EHR. While very convenient for the tabulation of simple process metrics, especially from multiple institutions, supplemental data collection will be required for meaningful cleft outcomes research. Cleft teams whose institutions participate in PCORnet might choose to store the supplemental data as "sidecars" alongside the standard PCORnet database tables, which would allow for future PCORnet queries to be more informative and impactful.

Investigating the role of GPR39 in treatment of stress-induced depression and anxiety.

Chronic stress is one of the leading causes of depression. Yet, knowledge of the pathomechanism of this process still eludes us. Chronic unpredictable mild stress (CUMS) model of depression enables researchers to look for a root cause of the disease in mice by mimicking a stressful human environment. Since zinc has already been shown to impact the treatment of depression, in our study we aimed to shed light on the role of the zinc receptor GPR39 in stress-induced depression. We also aimed to highlight the role of GPR39 activation in monoamine-based antidepressant treatment. Using large battery of behavioural tests, we provided a detailed description of CUMS-induced phenotype in both - CD-1 and GPR39 knock-out mice. Our experiments showed that combined treatment with TC-G 1008 (GPR39 agonist) and antidepressants produces stronger antidepressant-like effect of classic antidepressants. We also demonstrated the inter-strain differences in stress response and the greater stress susceptibility of GPR39 knock-out mice. The lack of GPR39 expression also either diminished or completely abolished the response to treatment with different antidepressants combined with TC-G 1008. The results show that GPR39 KO mice are more susceptible to chronic stress and that they are non-responsive to SSRI treatment. Utilizing various behavioural tests gave us much broader understanding not only of the role of GPR39 in depression treatment, but also of the importance of detailed behavioural description in a proper interpretation of the results. Further research with known selective agonists and antagonists of GPR39 will be necessary to understand the full potential of this receptor as a pharmacological target.

Clinical phenotype of COVID-19 vaccine-associated myocarditis in Victoria, 2021-22: a cross-sectional study.

To describe myocarditis as an adverse event after coronavirus disease 2019 (COVID-19) vaccination, including a detailed description of clinical phenotypes and diagnostic test results and differences by age, sex, and degree of troponin level elevation. Retrospective cross-sectional study. Cases of suspected myocarditis following the administration of a COVID-19 vaccine in Victoria during 22February 2021 - 30 September 2022 reported to Surveillance of Adverse Events Following Vaccination In the Community (SAEFVIC), with symptom onset within 14 days of vaccination, and deemed to be confirmed myocarditis according to the Brighton Collaboration Criteria. Demographic (sex, broad age group), vaccine, and clinical presentation characteristics; cardiac investigation results (troponin levels, electrocardiography, echocardiography, cardiac magnetic resonance imaging [cMRI]). Of 454 SAEFVIC reports of suspected COVID-19 vaccine-associated myocarditis, 206 were deemed confirmed cases. The median age of people with confirmed myocarditis was 21 years (interquartile range [IQR], 16-32 years; range, 10-76 years); 129 were aged 24 years or younger (63%), 155 were male (75%). The median time from vaccination to symptom onset was two days (IQR, 1-4 days); 201 cases (98%) followed the administration of mRNA vaccines; five cases followed vaccination with AZD122. Forty-six cases followed first vaccine doses (22%), 138 second doses (67%), and 22 cases third vaccine doses (11.0%). In 201 cases, people initially presented to emergency departments; 129 people were admitted to hospital (63%; median length of stay, two days; IQR, 1-3 days). Five people were admitted to intensive care. Echocardiographic abnormalities were identified in 26 of 200 patients (13%); electrocardiographic abnormalities were identified in 105 of 206 patients (51%; less frequently in female than male patients: adjusted odds ratio, 0.75; 95% confidence interval, 0.64-0.89). Troponin levels were elevated in 205 of 206 patients; the median increase was greater in male (95.3-fold; IQR, 5.8-273-fold) than female patients (9.9-fold; IQR, 4.7-50-fold). No cMRI abnormalities were found in patients for whom the troponin increase was threefold or less. The clinical severity of COVID-19 vaccine-associated myocarditis in Victoria was generally mild. Markers of a more severe phenotype were more frequently recorded for male patients and people aged 24 years or younger. A threefold troponin increase could be used as a threshold for risk stratification of people with COVID-19 vaccine-associated myocarditis, especially in hospitals with limited access to cMRI facilities.

Вариабельность признаков синдрома делеции 2q37 на примере клинических наблюдений

2q37 deletion syndrome is characterized by terminal deletions of the long arm of chromosome 2 and a variable clinical picture that includes type E brachydactyly, obesity, delayed motor and psychomotor development, congenital malformations of internal organs and the facial phenotype particular qualities. Authors present the two clinical case reports of patients with 2q37 deletions demonstrating different clinical manifestations. Proband 1 complained exclusively of brachydactyly while proband 2 had almost the full spectrum of clinical symptoms characterizing the syndrome. The Face2Gene AI-Powered Diagnosis & Care Management Tool suggested the correct diagnosis in both cases based on the features of the facial phenotype that in its turn became the key factors in choosing the tactics for further molecular genetic diagnostics. Conclusion: careful collection of anamnesis data, description of the facial phenotype and the use of artificial intelligence-based tools can become the key factors in choosing the tactics for the molecular genetic diagnostics available for practitioners of various specialties.

Fetal Presentation of MYRF-Related Cardiac Urogenital Syndrome: An Emerging and Challenging Prenatal Diagnosis.

MYRF-related cardiac-urogenital syndrome (MYRF-CUGS) is a rare condition associated with heterozygous MYRF variants. The description of MYRF-CUGS phenotype is mostly based on postnatal cases and 36 affected individuals have been published so far. We aim now to delineate the prenatal phenotype of MYRF-CUGS by reporting clinical data from fetuses and neonates with a pathogenic MYRF variant. Detailed radiographic, pathological, clinical, and molecular data from 12 prenatal cases were collected through an international collaborative study. Adding the five fetuses previously published, we were able to study a cohort of 17 cases. Main ultrasound-accessible manifestations of MYRF-CUGS include congenital heart defects (13/17, 76%), congenital diaphragmatic hernia (10/17, 59%) and disorders of sexual differentiation in 46, XY fetuses (7/14; 50%). Postnatal examination and/or autopsy data highlighted additional birth defects and neurological findings with a large spectrum of severity. Molecular results revealed ten previously unpublished variants, one missense and nine predicted truncating variants (three frameshift, three nonsense and three splice site variants). We report the first prenatal cohort of MYRF-CUGS, allowing us to further characterize the variable expressivity of this rare disorder in fetuses. Severe congenital anomalies with a poor prognosis are more frequent than previously described in postnatal cases. Our data suggest that MYRF-CUGS is characterized by a recurrent recognizable malformative association, accessible to prenatal diagnosis, with a significant intrafamilial phenotypic variability making genetic counseling challenging.

Prenatal diagnosis and genetic analysis: rare familial chromosomal duplications larger than 5 Mb without disease phenotypes.

This study aimed to identify large duplications (>5 Mb) that are harmless through long-term clinical follow-ups of fetuses and phenotype analyses of carrier family members. We retrospectively analyzed fetuses undergoing prenatal diagnosis and who had >5 Mb chromosomal duplications. Routine karyotyping and single-nucleotide polymorphism array analysis were performed to identify the source and location information of the duplicated segments. Genotype-phenotype analyses were conducted based on genetic information and phenotypes during postnatal follow-up. Eight eligible cases were included. All fetuses carried maternal or paternal duplications ranging in length from 5.3 to 12.2 Mb. The locations were as follows: 2q32.3q33.1 (Chr2:192322509-199548704), 4q22.1 (Chr4: 88347368-93602855), 4q34.2q35.2 (Chr4:176956406-189189971), 4q34.3q35.2 (Chr4:180613345-189353740), 5p14.3p14.1 (Chr5:19093749-28557664), 10q22.2q23.2 (Chr10:77448435-88786593), 12q21.31q21.32 (Chr12:81983257-87322734), and 13q14.11q14.2 (Chr13: 40825382-47633710). Karyotyping revealed that these duplications occurred within their respective chromosomal regions, except in pedigrees 6 and 7. In the eight pedigrees, the coordinates and lengths of duplicated segments in family members were matched with those in fetuses. Neither the fetuses nor other carriers were clinically symptomatic. Our findings revealed that the eight pedigrees carrying duplications >5 Mb were asymptomatic, providing new data to inform genetic counseling for the observed segments. We focused on unrelated fetuses among eight pedigrees who carried duplications of different chromosomal segments. These duplications had been stably transmitted through 2 or 3 generations of normal individuals. Importantly, phenotypic abnormalities were lacking, which was unexpected given that the maximum segment size was approximately 12.2 Mb. We found that duplications in these regions were benign in the context of prenatal genetic counseling. These results provide a foundation for addressing genotype-phenotype correlations. To our knowledge, this is the first description of normal phenotypes in individuals with duplications in these regions.

Hidradenitis Suppurativa from a Multi-Omic Scope.

Hidradenitis suppurativa (HS) is recognized as a systemic immune-mediated disease (IMID), sharing genetic and environmental risk factors with other IMIDs such as inflammatory bowel disease and psoriasis. Over time, correlating clinical findings with genetic, proteomic, and metabolomic results has been challenging due to diverse sampling methods, analysis techniques, and the use of variable clinical phenotype descriptions across studies. This review aims to summarize the results from various omics fields to explore the etiopathology of HS. Genetic studies highlight defects in Notch and γ-secretase signaling and inflammasome function. Syndromic HS involves specific mutations in autoinflammatory syndromes such as pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) and pyoderma gangrenosum, acne, and HS (PASH). Proteomic analyses reveal key inflammatory pathways indicating activation of both innate and adaptive immunity. Additionally, microbiome studies show an increased presence of anaerobes like Prevotella in HS lesions and a decreased presence of commensals such as Staphylococcus epidermidis. Gut microbiota dysbiosis, particularly involving Ruminococcus gnavus and Clostridium ramosum, is associated with HS. Moreover, metabolomic profiling indicates dysregulated tryptophan catabolism and lipid metabolism, with increased 5-lipoxygenase-derived metabolites and odd-chain fatty acids suggesting bacterial involvement. In summary, despite advances, robust associations between genetics, proteomics, microbiome, and metabolomics in HS are still lacking. Integrating these datasets could identify new clinical phenotypes, genetic predispositions, microbial signatures, and therapeutic targets, enhancing personalized treatment strategies and biomarker discovery for HS classification, prognosis, and treatment response.

Image-Based Quantitative Analysis of Epidermal Morphology in Wild Potato Leaves.

The epidermal leaf patterns of plants exhibit remarkable diversity in cell shapes, sizes, and arrangements, driven by environmental interactions that lead to significant adaptive changes even among closely related species. The Solanaceae family, known for its high diversity of adaptive epidermal structures, has traditionally been studied using qualitative phenotypic descriptions. To advance this, we developed a workflow combining multi-scale computer vision, image processing, and data analysis to extract digital descriptors for leaf epidermal cell morphology. Applied to nine wild potato species, this workflow quantified key morphological parameters, identifying descriptors for trichomes, stomata, and pavement cells, and revealing interdependencies among these traits. Principal component analysis (PCA) highlighted two main axes, accounting for 45% and 21% of variance, corresponding to features such as guard cell shape, trichome length, stomatal density, and trichome density. These axes aligned well with the historical and geographical origins of the species, separating southern from Central American species, and forming distinct clusters for monophyletic groups. This workflow thus establishes a quantitative foundation for investigating leaf epidermal cell morphology within phylogenetic and geographic contexts.

Discovery of a cryptic founder variant in MYBPC3 associated with hypertrophic cardiomyopathy by promoting the most frequent natural missplicing events

Abstract Introduction MYBPC3 splicing errors are a common cause of hypertrophic cardiomyopathy (HCM). Most known actionable intronic variants are located near exons. However, genetic variants in deep intronic regions are also emerging as casuals factors of HCM. The previously undescribed variant MYBPC3 (NM_000256.3):c.2308+227G>A is not reported in gnomAD or dbSNP but is overrepresented in a cohort of probands with HCM from the same geographical area. This led us to suspect its clinical relevance despite the very low probability of being splice-altering as assigned by SpliceAI (Δ score = 0.03). Purpose To conduct a phenotypic and clinical description of the cohort, ascertain the pathogenicity of the variant, and investigate the existence of a common ancestor. Methods (1) Observational analysis of clinical data and familial evaluation results, (2) Functional study involving mRNA expression analysis in peripheral blood, along with in silico analysis of the splicing disruption mechanism, and (3) Haplotype analysis to evaluate the founder effect and assess the age of the mutation. Results MYBPC3:c.2308+227G>A was identified in 26 probands with HCM (69% male; mean age at diagnosis 53±10 years). Eighty relatives from 20 families were screened resulting in 17 cases diagnosed (mean age 49±19 years; 53% males), 19 positive genotype/negative phenotype and 38 non-carriers. The greatest cosegregation involved three cases carrying the variant, confirmed in four different families. Males were diagnosed at a younger age but without significant differences in clinical features or events during follow-up (table). RT-PCR expression analysis in patients' blood revealed that this variant disrupts pre-mRNA splicing by promoting the use of cryptic donor and acceptor splice sites, located downstream and upstream of the variant, respectively, which are already present in the intron 23 reference sequence. Strikingly, these cryptic splice sites represent one of the most frequent natural unannotated missplicing events in MYBPC3, as evidenced by SpliceVault analysis of high-throughput RNA sequencing databases. The direct primary event induced by the variant is expected to disrupt a regulatory RNA-protein binding site, thereby unblocking the use of preexisting cryptic splice sites and amplifying natural exonification missplicing events within intron 23 (figure). Finally, the haplotype analysis, based on the copy number of nine STRs covering a total of 29.2 Mb surrounding MYBPC3:c.2308+227G>A, revealed that 17 unrelated carriers shared a DNA segment of 10 Mb (10,067,150 bp). The origin of this mutation is estimated to be at least 82 generations ago and roughly 1649 years in the past (IC95%:1180-2300). Conclusions MYBPC3:c.2308+227G>A is an elusive novel deep intronic variant causing HCM by a molecular mechanism not previously described in this context. The founder effect of this variant is confirmed in our geographical area.Phenotypic and clinical characteristics

Exploring the Phenotype and Possible Mechanisms of Palinopsia in Visual Snow Syndrome.

Palinopsia (persistent afterimages and/or trailing) is a common but poorly understood symptom of the neurological condition visual snow syndrome. This study aimed to collect a phenotypical description of palinopsia in visual snow syndrome and probe for abnormalities in temporal visual processing, hypothesizing that palinopsia could arise from increased visibility of normal afterimage signals or prolonged visible persistence. Thirty controls and 31 participants with visual snow syndrome (18 with migraine) took part. Participants completed a palinopsia symptom questionnaire. Contrast detection thresholds were measured before and after brief exposure to a spatial grating because deficient contrast adaptation could increase afterimage visibility. Temporal integration and segregation were assessed using missing-element and odd-element tasks, respectively, because prolonged persistence would promote integration at wide temporal offsets. To distinguish the effects of visual snow syndrome from comorbid migraine, 25 people with migraine alone participated in an additional experiment. Palinopsia was common in visual snow syndrome, typically presenting as unformed images that were frequently noticed. Contrary to our hypotheses, we found neither reduced contrast adaptation (F(3.22, 190.21) = 0.71, P = 0.56) nor significantly prolonged temporal integration thresholds (F(1, 59) = 2.35, P = 0.13) in visual snow syndrome. Instead, participants with visual snow syndrome could segregate stimuli in closer succession than controls (F(1, 59) = 4.62, P = 0.04, ηp2 = 0.073) regardless of co-occurring migraine (F(2, 53) = 1.22, P = 0.30). In contrast, individuals with migraine alone exhibited impaired integration (F(2, 53) = 4.44, P = 0.017, ηp2 = 0.14). Although neither deficient contrast adaptation nor prolonged visible persistence explains palinopsia, temporal resolution of spatial cues is enhanced and potentially more flexible in visual snow syndrome.

Chromosome 8p Syndromes Clinical Presentation and Management Guidelines.

Rearrangements of the p-arm of Chromosome 8 can result in a spectrum of neurodevelopmental challenges, along with increased risk of epilepsy, structural brain and cardiac malformations, persisting developmental delays, and other health challenges. The majority of patients reported on in this sample are characterized by an inverted-duplication deletion rearrangement, but deletions, duplications, and mosaic ring changes in 8p result in similar phenotype. In this report, we add to the phenotypic and functional description of these patients according to their specific chromosomal rearrangement, share neuro-psychometric values, and propose surveillance care guidelines for caregivers and medical providers of patients with Chromosome 8p Syndromes. Observations from clinical experience with 24 patients seen at our 8p-dedicated Multi-Disciplinary Neurogenetics program are shared.

Weight/height2: Mathematical overview of the world's most widely used adiposity index.

A footnote in Adolphe Quetelet's classic 1835 Treatise on Man described his algebraic analysis of how body weight ( ) varies with height ( ) in adult males and females. Using data on 12 short and 12 tall subjects of each sex, Quetelet established the rule that is approximately proportional ( ) to H2 in adults; that is, when for some constant . Quetelet's Rule ( ), transformed and renamed in the twentieth century to body mass index ( ), is now a globally applied phenotypic descriptor of adiposity at the individual and population level. The journey from footnote to ubiquitous adiposity measure traveled through hundreds of scientific reports and many more lay publications. The recent introduction of highly effective pharmacologic weight loss treatments has heightened scrutiny of BMI's origins and appropriateness as a gateway marker for diagnosing and monitoring people with obesity. This contemporary context prompted the current report that delves into the biological and mathematical paradigms that underlie the simple index . Students and practitioners can improve or gain new insights into their understanding of BMI's historical origins and quantitative underpinning from the provided overview, facilitating informed use of BMI and related indices in research and clinical settings.

A corpus of GA4GH phenopackets: Case-level phenotyping for genomic diagnostics and discovery

The Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema was released in 2022 and approved by ISO as a standard for sharing clinical and genomic information about an individual, including phenotypic descriptions, numerical measurements, genetic information, diagnoses, and treatments. A phenopacket can be used as an input file for software that supports phenotype-driven genomic diagnostics and for algorithms that facilitate patient classification and stratification for identifying new diseases and treatments. There has been a great need for a collection of phenopackets to test software pipelines and algorithms. Here, we present Phenopacket Store. Phenopacket Store v.0.1.19 includes 6,668 phenopackets representing 475 Mendelian and chromosomal diseases associated with 423 genes and 3,834 unique pathogenic alleles curated from 959 different publications. This represents the first large-scale collection of case-level, standardized phenotypic information derived from case reports in the literature with detailed descriptions of the clinical data and will be useful for many purposes, including the development and testing of software for prioritizing genes and diseases in diagnostic genomics, machine learning analysis of clinical phenotype data, patient stratification, and genotype-phenotype correlations. This corpus also provides best-practice examples for curating literature-derived data using the GA4GH Phenopacket Schema.

57P Phenotypic description of 40 patients with p.Ser55Phe variant in the MYOT gene: MYOT-MUR study.

57P Phenotypic description of 40 patients with p.Ser55Phe variant in the MYOT gene: MYOT-MUR study.

Talking about diseases; developing a model of patient and public-prioritised disease phenotypes.

Deep phenotyping describes the use of standardised terminologies to create comprehensive phenotypic descriptions of biomedical phenomena. These characterisations facilitate secondary analysis, evidence synthesis, and practitioner awareness, thereby guiding patient care. The vast majority of this knowledge is derived from sources that describe an academic understanding of disease, including academic literature and experimental databases. Previous work indicates a gulf between the priorities, perspectives, and perceptions held by different healthcare stakeholders. Using social media data, we develop a phenotype model that represents a public perspective on disease and compare this with a model derived from a combination of existing academic phenotype databases. We identified 52,198 positive disease-phenotype associations from social media across 311 diseases. We further identified 24,618 novel phenotype associations not shared by the biomedical and literature-derived phenotype model across 304 diseases, of which we considered 14,531 significant. Manifestations of disease affecting quality of life, and concerning endocrine, digestive, and reproductive diseases were over-represented in the social media phenotype model. An expert clinical review found that social media-derived associations were considered similarly well-established to those derived from literature, and were seen significantly more in patient clinical encounters. The phenotype model recovered from social media presents a significantly different perspective than existing resources derived from biomedical databases and literature, providing a large number of associations novel to the latter dataset. We propose that the integration and interrogation of these public perspectives on the disease can inform clinical awareness, improve secondary analysis, and bridge understanding and priorities across healthcare stakeholders.

Research progress of the relationship between phosphoprotein phosphatases (PPPs) and neurodevelopmental disorders.

Reversible protein phosphorylation is a ubiquitous phenomenon essential for eukaryotic cellular processes. Recent advancements in research about neurodevelopmental disorders have prompted investigations into the intricate relationship between protein phosphatases, particularly phosphoprotein phosphatases (PPPs), and neurodevelopment. Notably, variants in 10 coding genes spanning four PPP family members have been implicated in neurodevelopmental disorders. Here, we provide a comprehensive overview of the clinical phenotypes, genotypes, and pathogenic mechanisms observed in affected patients. Our analysis reveals challenges in subsequent statistical analyses due to inconsistent clinical phenotypic descriptions and a lack of large multicenter studies, hampering analysis about genotype-phenotype correlations. The scarcity of follow-up data poses a significant obstacle to prognostic counseling for nearly all rare diseases. Presently, symptomatic treatment strategies are employed for patients with variants, as definitive cures remain elusive. Future research may explore protein phosphatase regulators as potential therapeutic targets. Furthermore, it is imperative not to overlook other members of the protein phosphatase family or coding genes with undiscovered variants. Insights gleaned from the temporal and spatial distribution of proteins, along with observations from animal model phenotypes, may provide valuable directions for uncovering novel pathogenic genes.

Influence of COMT (rs4680) and OPRM1 (rs1799971) on Cancer Pain, Opioid Dose, and Adverse Effects.

Background: The influence of pharmacogenomics on opioid response, particularly with COMT (rs4680) and OPRM1 (rs1799971) variants, has been studied individually and in combination. However, most studies are in a noncancer context and not all their possible variant combinations have been examined. Objectives: This study examined COMT (rs4680) and OPRM1 (rs1799971), and their allele combinations, in advanced cancer to examine associations with pain scores, opioid dose, and adverse effects. Setting/Subjects: This multicenter prospective cohort study recruited patients receiving opioids for advanced cancer pain in Melbourne, Australia. Clinical data (demographics, opioids), validated instruments (pain and adverse effects), and blood (DNA) were collected. Descriptive analyses were used. Univariate and multivariate logistic regression analyses were used to evaluate associations between clinical outcomes (opioid dose, pain, adverse effects) and genotypes of interest. Results: Fifty-four participants were recruited to the study. Those with COMT A allele required lower opioid doses [130 mg (interquartile range [IQR] 67.5,230) versus 180 mg (IQR 55,322.5), p = 0.047] and experienced greater adverse effects [sickness response aOR (adjusted odds ratio) 7.1 (95% CI 1.51,33.41), p = 0.01]. Those with the COMT GG/OPRM1 G allele combination required higher opioid doses [322.5 mg (IQR 264,360) versus 125 mg (65,225), (p = 0.04)]. Those with COMT AG/OPRM1 AA experienced higher average pain [aOR 1.55 (95% CI 1.03, 2.33), p = 0.04] and moderate-severe nausea [aOR 5.47 (95% CI 1.35, 22.21), p = 0.02] but reduced drowsiness [aOR 0.25 (95% CI 0.06, 1.02), p = 0.05]. Conclusions: Patients with cancer with the COMT alternate (A) allele have greater sickness response adverse effects, which may be responsible for the lower opioid doses observed. Significant results of two new COMT/OPRM1 genotype combinations are presented that have not previously been studied, with plausible phenotype descriptions suggested.

Calidad de los fenotipos humanos en pacientes con discapacidad intelectual con estudios de secuenciación de exoma en un hospital pediátrico peruano

Introduction. Massive sequencing and the Human Phenotype Ontology have revolutionized genetic diagnosis, allowing for a clearer understanding of diseases. The phenotypes described in medical records can be specific or general, the more detailed and specific the description, the higher the quality of the information. Objectives. To determine the relationship between the quality of human phenotypes in patients with intellectual disability and the findings from massive sequencing test at the Instituto Nacional de Salud del Niño. Methods. We analyzed 124 patients with intellectual disabilities with exome sequencing. The quality of human phenotypes was evaluated using different quality index. Results. A total of 278 human phenotype terms were identified. Phenotypic precision improved after filtering, highlighting the importance of specific phenotypic descriptions (from 103 to 86 unique terms). The specificity index of the dataset was lower in the group with variants of uncertain significance compared to the group with pathogenic variants (0 vs. 0.05). The most frequent phenotypes were psychomotor delay (12.9% - 15.9%) and microcephaly (4.5% - 5.2%). Conclusions. The importance of evaluating the quality of human phenotypes is highlighted. The presence of uncertain variants suggests a genotype-phenotype complexity, emphasizing the need for greater clarity in genetic interpretation. Consistency in confidence intervals and the specificity index of the dataset underscores the competence of local medical-genetic personnel.