Orphanet J Rare Dis. 2024 Sep 27;19(1):354. doi: 10.1186/s13023-024-03264-0.

ABSTRACT

INTRODUCTION: Rare genetic neurodevelopmental disorders and intellectual disability (ID), collectively called genetic ID (GID), can profoundly impact daily functioning and overall well-being of affected individuals. To improve our understanding of the impact of GID and advancing both care and research, measuring relevant patient reported outcomes (PROs) is crucial. Currently, various PROs are measured for GID. Given the shared comorbidities across disorders, we aim to develop a generic core PRO set for children and adults with GID.

METHODS AND RESULTS: Developing the generic core PRO set entails the following steps: 1) providing an overview of potentially relevant PROs by scoping reviews and qualitative research; 2) integrating and conceptualizing these PROs (i.e., describing the content of the PROs in detail) into a pilot generic core PRO set; and 3) prioritizing relevant PROs by a European Delphi survey and consensus meetings.

CONCLUSIONS: This protocol presents the steps for developing a generic core PRO set for children and adults with GID. The next step involves selecting suitable patient reported outcome measures (PROMs) to adequately measure these PROs: the generic core PROM set. This generic core PROM set needs validation in the GID population, and eventually implementation in care and research, facilitating the aggregation and analysis of PRO data and guaranteeing continuous integration of the patient perspective in both care and research.

PMID:39334201 | PMC:PMC11428331 | DOI:10.1186/s13023-024-03264-0

Nat Commun. 2024 Sep 27;15(1):8268. doi: 10.1038/s41467-024-52463-7.

ABSTRACT

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.

PMID:39333082 | PMC:PMC11436875 | DOI:10.1038/s41467-024-52463-7

Medicina (B Aires). 2024 Sep;84 Suppl 3:9-14.

ABSTRACT

Rare diseases are characterized by low prevalence and high complexity, affecting millions globally. Although technologies like massive sequencing improve diagnose, therapeutic options remain largely symptomatic or palliative, with few curative treatments approved. In the context of rare diseases, especially genetic neurodevelopmental disorders, therapy development faces obstacles such as phenotypic variability, diverse molecular mechanisms, and complexities in assessing neurodevelopment in natural history and clinical trials. Current strategies include drug repositioning, biomarker development, and a multilateral approach in seeking solutions, offering hope. This work reviews various strategies in developing therapies, from gene therapy and epigenetic therapies to identifying biological targets.

PMID:39331769

Zhonghua Er Ke Za Zhi. 2024 Oct 2;62(10):989-994. doi: 10.3760/cma.j.cn112140-20240312-00173.

ABSTRACT

Objective: To analyze the diagnosis and treatment of children with rare diseases in the pediatric intensive care unit (PICU), the distribution of disease types and populations, clinical characteristics, and the use of orphan drugs. Methods: A retrospective case summary was conducted. Data were collected from 105 children aged 29 days to <18 years with a confirmed diagnosis of rare diseases according to the "First Batch of Rare Disease Catalogue in China" who were admitted to the PICU of Beijing Children's Hospital, Capital Medical University from January 2020 to December 2022. Data including general information, auxiliary examinations, and treatment details for each patient were collected from the hospital's electronic medical record system. Patients were divided into age groups: infancy (29 days to<1 year), early childhood (1 to <3 years), preschool age (3 to<7 years), school age (7 to<13 years), and adolescence (13 to<18 years). The chi-square test was used to compare gender distribution differences among various rare diseases. Results: A total of 105 patients with 130 cases meeting the diagnostic criteria were included, accounting for 4.7% (130/2 754) of the total admissions to the PICU. The age at PICU admission was 5.3 (0.8, 9.5) years and there were 81 cases in male. The 3 most common types of diseases were endocrine, nutritional, and metabolic diseases (37 cases); followed by neurological disorders(32 cases); and congenital malformations, deformities, and chromosomal abnormalities(17 cases). The 5 most common rare diseases were methylmalonic acidemia (14 cases), mitochondrial encephalomyopathy (14 cases), atypical hemolytic uremic syndrome (12 cases), autoimmune encephalitis (12 cases), and idiopathic cardiomyopathy (9 cases). The distributions of common rare diseases varied among different age groups. In infants, atypical hemolytic uremic syndrome was most common (6 children). There was no statistically significant difference regarding gender among children with mitochondrial encephalomyopathy (13.6% (11/81) vs. 6.1% (3/49), χ2=1.77, P=0.184). Respiratory failure (36 cases) was the primary reason for rare diseases children to be admitted to the PICU. A total of 95 cases underwent mechanical ventilation, 39 cases received multidisciplinary collaborative diagnosis and treatment, and only 6 children received orphan drug therapy during their stay in the PICU. Conclusions: Rare diseases are not uncommon in PICU. Endocrine, nutritional and metabolic disorders, neurological disorders, congenital malformations, deformities, and chromosomal abnormalities were common. Methylmalonic acidemia, mitochondrial encephalomyopathy, atypical hemolytic uremic syndrome and autoimmune encephalitis have higher cases. Many children with rare diseases in the PICU have complex conditions those are challenging to treat, requiring multidisciplinary collaboration. The utilization rate of orphan drugs among children with rare diseases in PICU needs to be improved.

PMID:39327967 | DOI:10.3760/cma.j.cn112140-20240312-00173

Vaccine. 2024 Sep 23:126324. doi: 10.1016/j.vaccine.2024.126324. Online ahead of print.

ABSTRACT

Despite significant public health attention and investment, hundreds of thousands of individuals have suffered fatal opioid overdose since the onset of the opioid crisis. Risk of opioid overdose has been exacerbated by the influx of fentanyl, a powerful synthetic opioid, into the drug supply. The National Institutes of Health Helping End Addiction Long-term (HEAL) Initiative is supporting the development of vaccines targeting fentanyl to protect against overdose. If successful, a vaccine would induce anti-fentanyl antibodies to sequester fentanyl (but not other opioids) in the blood, preventing fentanyl from crossing into the brain and reaching the central nervous system where it can cause overdose. Introduction of an overdose preventing strategy that relies on a vaccine to confer passive protection may be impactful. However, vaccines are poorly understood by the public and politicized. Moreover, the overdose ecosystem is complex and extends across numerous social, economic, medical, and cultural systems. As such, optimal use of a vaccine strategy to address overdose may benefit from multidisciplinary consideration of the social, ethical, and systemic factors that influence substance use and overdose that may also impact the acceptability of a fentanyl vaccine and related implementation strategies. In March 2022, Dr. Elissa Weitzman convened a two-day conference at the Harvard Radcliffe Institute for Advanced Study on the Social Complexity of a Fentanyl Vaccine to Prevent Opioid Overdose. In all, 19 professionals from diverse disciplines (medicine, psychology, history, ethics, immunology, vaccinology, communications, policy) attended the conference and led discussions that centered on population health and epidemiology, history of medicine and frameworks for understanding substance use, ethics, decision-making and attitudes, and operational issues to the question of a novel immunotherapy targeting fentanyl overdose. Participants also debated the risks and benefits of vaccine administration in response to fictional clinical case vignettes. A summary of the conference presentations and discussions follows.

PMID:39317618 | DOI:10.1016/j.vaccine.2024.126324

Mol Genet Metab. 2024 Sep-Oct;143(1-2):108579. doi: 10.1016/j.ymgme.2024.108579. Epub 2024 Sep 14.

ABSTRACT

OBJECTIVES: Patients with inherited metabolic disorders (IMDs) may require emergency hospital care to prevent life-threatening situations such as metabolic decompensation. To date, over one thousand different rare IMDs have been identified, which means that healthcare professionals (HCPs) initiating emergency treatment may not be familiar with these conditions. The objective of this initiative was to provide HCPs with practical guidance for the acute management of children and adults with IMDs who need emergency care, regardless of the underlying reason.

METHODS: We outline how a multidisciplinary working group from the French IMDs Healthcare Network for Rare Diseases, known as G2M, has created concise and standardized protocols _each consisting of a single double-sided A4 sheet _ focused on a specific disease, a group of diseases, or a particular symptom. Prior to validation, these protocols were reviewed by all French reference and competence centres for IMDs, as well as by medical experts from other specialities when necessary, physicians from emergency and intensive care units, and representatives from patient associations.

RESULTS AND CONCLUSION: In total, 51 emergency protocols containing essential information have been developed and provided to affected patients. All the emergency protocols are freely available in both French and English at https://www.filiere-g2m.fr/urgences. These standardized protocols aim to enhance the emergency care of patients without delay, while also assisting HCPs by increasing their confidence and efficiency, minimizing the risk of dosage errors when administering specialized treatments, saving time, and reducing the number of phone calls to metabolic medicine specialists on night duty. The protocols are scheduled for annual review to facilitate further improvements based on feedback from HCPs and patients, as well as to accommodate any changes in management practices as they evolve.

PMID:39305737 | DOI:10.1016/j.ymgme.2024.108579

Health Policy. 2024 Nov;149:105162. doi: 10.1016/j.healthpol.2024.105162. Epub 2024 Sep 13.

ABSTRACT

Newborn screening is a public health measure to diagnose rare diseases at birth, thereby minimising negative effects of late treatment. Genomic technologies promise an unprecedented expansion of screened diseases at low cost and with transformative potential for newborn screening programmes. However, barriers to the public funding of genomic newborn screening are poorly understood, particularly in light of the heterogenous European newborn screening landscape. This study therefore aims to understand whether international newborn screening experts share a common understanding of the barriers to fund genomic newborn screening. For this purpose, we convened 21 European newborn screening experts across a range of professions and national backgrounds in a Delphi study. Stable consensus, determined via the Wilcoxon matched-pairs signed-ranks test, was found via three consecutive survey rounds for all presented barriers. Experts generally judged the scenario of genomic newborn screening being available to every newborn in seven years to be unlikely, identifying treatability and the absence of counselling and a skilled workforce as the most significant barriers to public funding. We identify value re-definition for rare disease treatments, centralisation of genomic expertise, and international research consortia as avenues for pan-European actions which build on the consensus achieved by our Delphi panel.

PMID:39305584 | DOI:10.1016/j.healthpol.2024.105162

Lancet Glob Health. 2024 Oct;12(10):e1587. doi: 10.1016/S2214-109X(24)00341-3.

NO ABSTRACT

PMID:39304232 | DOI:10.1016/S2214-109X(24)00341-3

Gigascience. 2024 Jan 2;13:giae058. doi: 10.1093/gigascience/giae058.

ABSTRACT

The Solve-RD project brings together clinicians, scientists, and patient representatives from 51 institutes spanning 15 countries to collaborate on genetically diagnosing ("solving") rare diseases (RDs). The project aims to significantly increase the diagnostic success rate by co-analyzing data from thousands of RD cases, including phenotypes, pedigrees, exome/genome sequencing, and multiomics data. Here we report on the data infrastructure devised and created to support this co-analysis. This infrastructure enables users to store, find, connect, and analyze data and metadata in a collaborative manner. Pseudonymized phenotypic and raw experimental data are submitted to the RD-Connect Genome-Phenome Analysis Platform and processed through standardized pipelines. Resulting files and novel produced omics data are sent to the European Genome-Phenome Archive, which adds unique file identifiers and provides long-term storage and controlled access services. MOLGENIS "RD3" and Café Variome "Discovery Nexus" connect data and metadata and offer discovery services, and secure cloud-based "Sandboxes" support multiparty data analysis. This successfully deployed and useful infrastructure design provides a blueprint for other projects that need to analyze large amounts of heterogeneous data.

PMID:39302238 | PMC:PMC11413801 | DOI:10.1093/gigascience/giae058

Ann Neurol. 2024 Sep 20. doi: 10.1002/ana.27077. Online ahead of print.

ABSTRACT

OBJECTIVE: De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.

METHODS: Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells.

RESULTS: We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells.

INTERPRETATION: Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024.

PMID:39301775 | DOI:10.1002/ana.27077

Front Immunol. 2024 Sep 5;15:1467807. doi: 10.3389/fimmu.2024.1467807. eCollection 2024.

ABSTRACT

[This corrects the article DOI: 10.3389/fimmu.2011.00015.].

PMID:39301018 | PMC:PMC11412001 | DOI:10.3389/fimmu.2024.1467807

Mol Genet Metab. 2024 Sep-Oct;143(1-2):108576. doi: 10.1016/j.ymgme.2024.108576. Epub 2024 Sep 10.

ABSTRACT

PURPOSE: This study investigated the relationship between mucopolysaccharidosis II (MPS II) iduronate-2-sulfatase gene (IDS) variants and phenotypic characteristics, particularly cognitive impairment, using data from the Hunter Outcome Survey (HOS) registry.

METHODS: HOS data for male patients (n = 650) aged ≥5 years at latest cognitive assessment with available genetic data were analyzed. Predefined genotype categories were used to classify IDS variants and report phenotypic characteristics by genotype.

RESULTS: At their latest cognitive assessment, 411 (63.2%) of 650 patients had cognitive impairment. Missense variants were the most common MPS II genotype, with about equal frequency for patients with and patients without cognitive impairment. Complete deletions/large rearrangements were associated with cognitive impairment. Cognitive impairment and behavioral issues were most common, and height and weight abnormalities most apparent, in patients with large IDS structural changes. Broadly, missense variants NM-000202.8:c.998C>T p.(Ser333Leu), NM-000202.8:c.1402C>T p.(Arg468Trp), NM-000202.8:c.1403G>A p.(Arg468Gln) and NM-000202.8:c.262C>T p.(Arg88Cys), and splice site variant NM-000202.8:c.257C>T p.(Pro86Leu), were associated with cognitive impairment, and variants NM-000202.8:c.253G>A p.(Ala85Thr), NM-000202.8:c.187 A>G p.(Asn63Asp), NM-000202.8:c.1037C>T p.(Ala346Val), NM-000202.8:c.182C>T p.(Ser61Phe) and NM-000202.8:c.1122C>T were not.

CONCLUSION: This analysis contributes toward the understanding of MPS II genotype-phenotype relationships, confirming and expanding on existing findings in a large, geographically diverse population.

PMID:39303318 | DOI:10.1016/j.ymgme.2024.108576

Med Sci (Paris). 2024 Aug-Sep;40(8-9):643-652. doi: 10.1051/medsci/2024100. Epub 2024 Sep 20.

ABSTRACT

Rare genetic diseases with neurodevelopmental disorders (NDDs) encompass several heterogeneous conditions (autism spectrum disorder (ASD), intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), specific learning disorder (SLD), among others). Currently, few treatments are available for these patients. The difficulty in accessing human brain samples and the discrepancies between human and animal models highlight the need for new research approaches. One promising approach is the use of the cerebral organoids. These 3D, self-organized structures, generated from induced pluripotent stem cells (iPSCs), enable the reproduction of the stages of human brain development, from the proliferation of neural stem cells to their differentiation into neurons, oligodentrocytes, and astrocytes. Cerebral organoids hold great promise in understanding brain development and in the search for treatments.

PMID:39303116 | DOI:10.1051/medsci/2024100

Expert Rev Med Devices. 2024 Oct;21(10):893-901. doi: 10.1080/17434440.2024.2404257. Epub 2024 Sep 20.

ABSTRACT

INTRODUCTION: The Medical Device Regulation (EU)745/2017, increased the regulatory requirements and thus the time and the cost associated with marketing medical devices. For a majority of medical device manufacturers, this has lead to reconsiderations of their product portfolio. The risk of important or essential devices being withdrawn is particularly relevant for pediatric patients and other rare disease patients where limited numbers of devices can be sold and hence the investment needed may not be recovered. This generates critical challenges and opportunities from a regulatory and public health perspective.

AREAS COVERED: This paper is based upon the experience of the authors who contributed to working groups, guidance development and research related to orphan and pediatric devices. We examine the use of medical devices in orphan and pediatric conditions, the relevant aspects of regulations and associated guidance, and we suggest possible policy and practice interventions to ensure the continued availability of essential devices for children and people with rare diseases.

EXPERT OPINION: We recommend a more proactive approach to identifying devices at risk and essential devices, increasing the use of exceptional market approvals, expanding the role of expert panels, engaging with the rare disease communities and supporting registries and standards.

PMID:39302881 | DOI:10.1080/17434440.2024.2404257

Chin Clin Oncol. 2024 Aug;13(Suppl 1):AB021. doi: 10.21037/cco-24-ab021.

ABSTRACT

BACKGROUND: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) constitutes approximately 1-3% of primary CNS tumors. This rare CNS tumor presents diverse clinical manifestations and variable imaging characteristics, making its diagnosis challenging using radiological modalities alone. Recognizing the role of imaging in different stages of treatment and understanding the various imaging patterns and radiological features is crucial for timely diagnosis and appropriate therapeutic decision-making.

CASE DESCRIPTION: A 62-year-old woman presented to our tertiary hospital with a 1-month history of left-sided headache and left hemiparesis. A computed tomography (CT) scan from a previous hospital revealed a space-occupying lesion in the right temporo-occipital region with signs of increased intracranial pressure but no evidence of hemorrhage or calcifications. Subsequent magnetic resonance imaging (MRI) demonstrated a solid intra-axial lesion in the right temporoparietooccipital region, which exhibited heterogeneous enhancement with diffusion restriction. The lesion appeared hypointense on T1-weighted and hyperintense on T2-fluid attenuated inversion recovery (T2-FLAIR) sequence, containing cystic components surrounded by edema and causing compression of the occipital horn of the right lateral ventricle without midline shift. Immunohistochemical analysis confirmed the diagnosis of high-grade DLCBL. The patient underwent surgical resection followed by chemotherapy. A follow-up MRI revealed a new lesion in the right temporoparietooccipital region, which had increased in size, suggestive of lymphoma recurrence. The variable radiological presentations of primary CNS lymphoma (PCNSL) can often mimic other pathologies, such as gliomas, infections, abscesses, and secondary lymphomas, making it a diagnostic challenge. The imaging findings in this case align with the typical features of PCNSL. Both initial and follow-up imaging played a crucial role in guiding therapeutic decisions and assessing treatment response.

CONCLUSIONS: This case report underscores the importance of recognizing the imaging characteristics of primary DLBCL of the CNS. Timely and accurate diagnosis based on imaging patterns is essential for expediting therapeutic decisions and evaluating the efficacy of treatment interventions, ultimately improving patient outcomes.

PMID:39295339 | DOI:10.21037/cco-24-ab021

Nat Commun. 2024 Sep 18;15(1):8196. doi: 10.1038/s41467-024-52407-1.

ABSTRACT

Emerging evidence implicates common genetic variation - aggregated into polygenic scores (PGS) - in the onset and phenotypic presentation of rare diseases. Here, we comprehensively map individual polygenic liability for 1102 open-source PGS in a cohort of 3059 probands enrolled in the Genomic Answers for Kids (GA4K) rare disease study, revealing widespread associations between rare disease phenotypes and PGSs for common complex diseases and traits, blood protein levels, and brain and other organ morphological measurements. Using this resource, we demonstrate increased polygenic liability in probands with an inherited candidate disease variant (VUS) compared to unaffected carrier parents. Further, we show an enrichment for large-effect rare variants in putative core PGS genes for associated complex traits. Overall, our study supports and expands on previous findings of complex trait associations in rare diseases, implicates polygenic liability as a potential mechanism underlying variable penetrance of candidate causal variants, and provides a framework for identifying novel candidate rare disease genes.

PMID:39294130 | PMC:PMC11411080 | DOI:10.1038/s41467-024-52407-1

Pediatrics. 2024 Oct 1;154(4):e2023065540. doi: 10.1542/peds.2023-065540.

ABSTRACT

Acute liver failure is rare in the neonatal and infant population; however, when encountered, it requires timely diagnosis, management, and identification of the underlying etiology to provide the best clinical outcomes. Here, we present a case of new-onset liver failure in a 4-month-old infant. She had previously been diagnosed with neonatal mucocutaneous herpes simplex virus disease, but had been healthy in the interval, and was referred to our hospital for evaluation of possible need for liver transplantation because of a rapidly progressing pace of disease. In this diagnostic dilemma article, we review the case history and presentation and consider the differential diagnosis from the points of view of the primary and consultative teams. We then follow the clinical evolution of disease, identify a final diagnosis, and explore the short- and long-term management and health implications of the diagnosis. This case should be of interest to primary care providers, intensivists who care for neonates or infants, and specialists who encounter liver failure in their clinical practice.

PMID:39290186 | DOI:10.1542/peds.2023-065540

Am J Hum Genet. 2024 Oct 3;111(10):2094-2106. doi: 10.1016/j.ajhg.2024.08.011. Epub 2024 Sep 16.

ABSTRACT

Efforts to implement and evaluate genome sequencing (GS) as a screening tool for newborns and infants are expanding worldwide. The first iteration of the BabySeq Project (2015-2019), a randomized controlled trial of newborn sequencing, produced novel evidence on medical, behavioral, and economic outcomes. The second iteration of BabySeq, which began participant recruitment in January 2023, examines GS outcomes in a larger, more diverse cohort of more than 500 infants up to one year of age recruited from pediatric clinics at several sites across the United States. The trial aims for families who self-identify as Black/African American or Hispanic/Latino to make up more than 50% of final enrollment, and key aspects of the trial design were co-developed with a community advisory board. All enrolled families receive genetic counseling and a family history report. Half of enrolled infants are randomized to receive GS with comprehensive interpretation of pathogenic and likely pathogenic variants in more than 4,300 genes associated with childhood-onset and actionable adult-onset conditions, as well as larger-scale chromosomal copy number variants classified as pathogenic or likely pathogenic. GS result reports include variants associated with disease (Mendelian disease risks) and carrier status of autosomal-recessive and X-linked disorders. Investigators evaluate the utility and impacts of implementing a GS screening program in a diverse cohort of infants using medical record review and longitudinal parent surveys. In this perspective, we describe the rationale for the second iteration of the BabySeq Project, the outcomes being assessed, and the key decisions collaboratively made by the study team and community advisory board.

PMID:39288765 | DOI:10.1016/j.ajhg.2024.08.011

OMICS. 2024 Oct;28(10):526-536. doi: 10.1089/omi.2024.0140. Epub 2024 Sep 17.

ABSTRACT

Rare diseases and conditions have thus far received relatively less attention in the field of precision/personalized medicine than common chronic diseases. There is a dire need for orphan drug discovery and therapeutics in ways that are informed by the precision/personalized medicine scholarship. Moreover, people with rare conditions, when considered collectively across diseases worldwide, impact many communities. In this overarching context, Activin A Receptor Type 1 (ACVR1) is a transmembrane kinase from the transforming growth factor-β superfamily and plays a critical role in modulating the bone morphogenetic protein signaling. Missense variants of the ACVR1 gene result in modifications in structure and function and, by extension, abnormalities and have been predominantly linked with two rare conditions: fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. We report here an extensive bioinformatic analyses assessing the pool of 50,951 variants and forecast seven highly destabilizing mutations (R206H, G356D, R258S, G328W, G328E, R375P, and R202I) that can significantly alter the structure and function of the native protein. Protein-protein interaction and ConSurf analyses revealed the crucial interactions and localization of highly deleterious mutations in highly conserved domains that may impact the binding and functioning of the protein. cBioPortal, CanSAR Black, and existing literature affirmed the association of these destabilizing mutations with posterior fossa ependymoma, uterine corpus carcinoma, and pediatric brain cancer. The current findings suggest these deleterious nonsynonymous single nucleotide polymorphisms as potential candidates for future functional annotations and validations associated with rare conditions, further aiding the development of precision medicine in rare diseases.

PMID:39288033 | DOI:10.1089/omi.2024.0140

J Allergy Clin Immunol Glob. 2024 Jul 23;3(4):100311. doi: 10.1016/j.jacig.2024.100311. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic syndrome among inborn errors of immunity. Although several aspects of CVID immunopathology have been elucidated, predictive factors for mortality are incompletely defined. A genetic cause can be identified only in approximately 30% of patients.

OBJECTIVE: We sought to develop a mortality predictive score on the basis of the immunophenotypes and genotypes of patients with CVID.

METHODS: Twenty-one patients diagnosed with CVID in Córdoba, Argentina, were analyzed for clinical and laboratory data. Immunophenotyping was done by flow cytometry. CVID-associated mutations were identified by whole-exome sequencing.

RESULTS: Alive (15) and deceased (6) patients were compared. Univariate analysis showed significant differences in CD4+ T cells (P = .002), natural killer (NK) cells (P = .001), and memory switched B cells (P = .001) between groups. Logistic regression analysis showed a negative correlation between CD4+, NK, and memory switched B-cell counts and probability of survival over a 10-year period (CD4+ T cells: odds ratio [OR], 1.01; 95% CI, 1.001-1.020; NK cells: OR, 1.07; 95% CI, 1.02-1.17; and memory switched B cells: OR, 26.23; 95% CI, 2.06-2651.96). Receiver-operating characteristic curve analysis identified a survival cutoff point for each parameter (CD4+ T cells: 546 cells/mL; AUC, 0.87; sensitivity, 60%; specificity, 100%; memory switched B cells: 0.84 cells/mL; AUC, 0.92; sensitivity, 100%; specificity, 85%; and NK cells: 45 cells/mL; AUC, 0.92; sensitivity, 83%; specificity, 100%). Genetic analysis on 14 (9 female and 5 male) patients from the cohort revealed mutations associated with inborn errors of immunity in 6 patients.

CONCLUSIONS: A score to predict mortality is proposed on the basis of CD4+ T, NK, and memory switched B-cell counts in patients with CVID.

PMID:39282620 | PMC:PMC11393598 | DOI:10.1016/j.jacig.2024.100311