Individuals with monoallelic gain-of-function variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss of DOT1L remains unclear. Here, we sought to define the effects of partial DOT1L loss by applying bulk and single-nucleus RNA-sequencing, ChIP-sequencing, imaging, multielectrode array recordings and behavioural analysis of zebrafish and multiple mouse models. We present a cohort of 16 individuals (12 females, 4 males) with neurodevelopmental disorders and monoallelic DOT1L variants, including a frameshift deletion, an in-frame deletion, a nonsense, and missense variants clustered in the catalytic domain. We demonstrate that specific variants cause loss of methyltransferase activity. In primary cortical neurons, Dot1l knockdown disrupts transcription of synaptic genes, neuron branching, expression of a synaptic protein and neuronal activity. Further in the cortex of heterozygous Dot1l mice, Dot1l loss causes sex-specific transcriptional responses and H3K79me2 depletion, including within downregulated genes. Lastly, using both zebrafish and mouse models, we found behavioural disruptions that include developmental deficits and sex-specific social behavioural changes. Overall, we define how DOT1L loss leads to neurological dysfunction by demonstrating that partial Dot1l loss impacts neuronal transcription, neuron morphology and behaviour across multiple models and systems.

PURPOSE:To define the phenotypic spectrum and genotype-phenotype correlations associated with pathogenic RERE variants and inform clinical management and genetic counseling for neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). METHODS:We assembled a cohort of 54 individuals with heterozygous pathogenic, likely pathogenic, and variants of uncertain significance in RERE, including 30 previously unreported cases. Individuals were classified into 5 subcohorts based on variant type and location: loss-of-function, missense variants inside and outside a specific histidine-rich region (HRR), and HRR in-frame deletions and duplications. Phenotypic features were analyzed and compared across groups. Protein modeling was performed to assess potential structural effects. RESULTS:Developmental delay, intellectual disability, and/or autism spectrum disorder were prevalent across all groups. Loss-of-function variants are associated with fewer multisystem anomalies than missense variants and are more likely to be inherited from a mildly symptomatic or asymptomatic parent. In contrast, HRR-associated missense variants and in-frame HRR duplications were associated with more multisystem phenotypes and usually arise de novo. HRR missense variants were structurally stabilizing, suggesting a gain-of-function or dominant-negative mechanism. CONCLUSION:These findings expand the clinical spectrum of RERE-related disorders, refine genotype-phenotype correlations, and support variant-specific approaches to management and genetic counseling.

Background: Genetic studies have disproportionately focused on populations of European ancestry, limiting the generalizability of allele-frequency references and genetic associations to underrepresented groups, including South American populations. This gap is particularly relevant for rare diseases and cancer, where accurate variant interpretation depends in part on appropriate population context. In addition, population-specific haplotype structure influence genome-wide association analyses and the portability of polygenic scores across ancestries. By focusing on the Chilean population, our work aims to bridge these gaps, providing more accurate reference data for genetic research and enhancing diagnostic and therapeutic strategies for underrepresented communities. Methods: We aggregated exomes from seven Chilean cohorts and processed samples using a standardized best practices workflow, including population-scale quality control and relatedness filtering. Aggregated variants were annotated with VEP (including LOFTEE, REVEL, AlphaMissense, EVE, and CADD) and clinically classified using InterVar. Population structure was assessed with PCA/admixture. We compared overlap and allele frequencies against external references, performed gene-level variant burden analysis, and constructed phased haplotypes for ancestry association using linear regression with Bonferroni correction. Finally, we developed a dashboard with R shiny framework to enable gene-wise exploration of annotated variants. Results: We present CHANGER (Chilean Aggregated National Genomics Resource), a comprehensive aggregation of 902 unrelated Chilean exomes designed to create a detailed reference of genetic variation in Chile. By incorporating data from multiple cohorts, we identified 774,110 unique genetic variants, with an average of 42,601 aggregated variants per individual. We identified 132,363 novel variants, of which 31,470 were common within our cohort (frequency > 1 %). We provide variant annotation and direct comparisons with other publicly available general population references. Beyond variant discovery, CHANGER supports gene-level burden scans (61 Missense-Damaging depleted genes; 2 Loss-of-Function enriched genes) and a haplotype resource for ancestry association (51,171 haplotypes), enabling downstream interpretation, improved imputation, and more powerful genome-wide association analyses in Chileans. Conclusions: CHANGER provides a valuable resource for genetic research and a reference for local variant interpretation. Importantly, CHANGER follows a high-quality methodological baseline and an open, FAIR-aligned infrastructure designed to grow, increasing its value for discovery, imputation, and equitable clinical interpretation over time.

Background. Rare diseases (RD; enfermedades poco frecuentes, EPoF, in Chilean policy terminology) collectively affect 3.5-5.9% of the population and are associated with long diagnostic trajectories. Chile lacks a reproducible national operational definition for identifying RD in administrative hospital data. Methods. We conducted a retrospective observational analysis of Chilean GRD-IR events (IR-29301 version) for 2019-2024 released through FONASA Datos Abiertos, covering hospital discharges and major ambulatory surgery reported by 72 public establishments for FONASA-covered persons. The canonical analytical cohort contained 5,779,482 DRG events in 4,027,921 linked patients. We constructed a Chilean Orphanet-ICD-10 homologation and audited it through an agentic human-in-the-loop pipeline, yielding a conservative RD operational catalogue (434 final ICD-10 codes in the KEEP + MAP\_TO\_SPECIFIC_ORPHA scenario). RD-coded DRG events were labeled as observed inpatient odysseys when at least one prior DRG event existed for the same patient. We quantified prior events, DRG-observed inpatient trajectory time, nonspecific prior diagnoses, DRG weight, and bridge-code associations. Bridge-code enrichment was estimated using patient-level Fisher exact tests with Benjamini-Hochberg false-discovery correction; event-level estimates were retained as sensitivity analyses. Results. The audited conservative catalogue identified 55,284 primary-diagnosis RD-coded DRG events in 45,784 patients and 374,866 RD-coded events in any diagnostic field. We characterized 63,685 observed inpatient odyssey cases in 25,648 unique patients across 371 audited RD ICD-10 codes. Median DRG-observed inpatient trajectory time to RD-coded diagnosis was 241 days, and mean prior events per odyssey was 8.1. Bridge-code analysis identified 616 associations with support >= 10 patients and 390 with q < 0.05; 350 significant associations were no-same-code administrative trajectory signals. These signals varied in interpretation, including clinically plausible precursors, diagnostic refinement, and care-process bridges. The Odyssey Index reordered conditions relative to raw prior-event counts, separating high-volume entities from stronger trajectory signatures. Conclusions. To our knowledge, we provide the first nationwide audited and reproducible characterization of inpatient RD diagnostic odysseys in Latin America using administrative hospital data. The framework supports trajectory surveillance, registry design, quality-control analyses, and prioritization of candidate signals for prospective clinical validation under Chile's Law 21,743. Bridge-code associations should be interpreted as statistically enriched administrative signals, not as validated causal or clinical pathways. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was partially supported by the Chilean National Agency for Research and Development (ANID), Anillo Project ID ATE250004. The funder had no role in study design, data analysis, interpretation, manuscript preparation, or the decision to submit this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used anonymized, publicly available FONASA-DRG administrative data. The study protocol was reviewed by the Scientific Ethics Committee of ICIM, Faculty of Medicine, Universidad del Desarrollo - Clinica Alemana, which determined that the use of these de-identified public data did not require formal ethics approval and granted an exemption. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data analyzed in this study are publicly available through FONASA Datos Abiertos. The public repository for this paper contains the manuscript source, analysis scripts, audited catalogues, aggregate association tables, and figure assets: https://github.com/gear-go/epof-odiseas-diagnosticas-paper. Repository folder names retain the original Spanish EPoF acronym used during pipeline development.

Importance:22q11.2 deletion syndrome (22q11DS) is among the strongest genetic risk factors for neuropsychiatric disorders and has marked effects on brain structure. Yet, it remains unclear which neuroanatomical features reflect uniform effects of the deletion versus inter-individual biological processes relevant to psychiatric outcomes. Identifying these features is critical for developing targeted treatments and interventions. Objective:To identify brain regions where 22q11DS exerts its most consistent and most variable impacts, and to test whether these patterns align with normative neurotransmitter receptor distributions and cortical growth trajectories. Design:Multisite cross-sectional case-control study. Setting:T1-weighted brain MRI data were obtained across 15 scanners. MRI data underwent standardized processing, quality control procedures and statistical site-adjustment using ComBat. Participants:A total of N = 438 individuals with 22q11DS (5-54 years, 48% females) and 380 typically developing controls (6-58 years, 48% females). Main Outcomes and Measures:Primary outcomes were global and regional cortical thickness and surface area. Mean and dispersion estimates were calculated using double generalized linear models, correcting for age, age2, sex (and intracranial volume for surface area). Quantile shift functions characterized fine-scale distributional differences. Sensitivity analyses adjustedt for co-occurring neuropsychiatric disorders, antipsychotic use and deletion subtype. Secondary outcomes included spatial correspondence between regional structural alterations and normative maps of neurotransmitter receptor density and cortical expansion. Results:Compared with controls, individuals with 22q11DS showed widespread mean differences in cortical thickness and surface area. Notably, 22q11DS was associated with greater regional heterogeneity in both measures, except for reduced dispersion in the anterior cingulate. Effects were attenuated after covariate adjustment. Cortical thickness differences spatially overlapped with regions enriched for glutamatergic and GABAergic receptors. There was partial evidence linking surface area dispersion patterns to normative cortical growth trajectories. Conclusions and Relevance:22q11DS exerts broad effects on cortical structure consistent with a global developmental mechanism, reflected in widespread mean shifts. Beyond these, region-specific variability, particularly in cortical thickness, suggests individualized neurobiological processes. The anterior cingulate emerges as a region of consistent structural deviation. Overall, structural variability in 22q11DS aligns with normative patterns of excitatory-inhibitory signaling and cortical development, implicating these pathways as potential targets for intervention.

This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicentre survey exploring genotypes, phenotypes and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was 6 years (range 0-80 years, n = 622). We detected 331 different (118 unpublished) PDHA1 variants, of which 75% (305/405) had occurred de novo. Variants in this study were uploaded to ClinVar (SCV006297015-SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine per cent of the variants were private; missense (50%) and frameshift (20%) variants were most common. Frameshift/nonsense (FS/N) variants in males (44/401, 11%) were confined to regions escaping nonsense-mediated decay (NMD) and were significantly less frequent than in females (151/461, 33%). Neonatal or infantile (405/529, 77%) presentations were most frequent, with pre/perinatal abnormalities reported in 47% (159/342). FS/N variants in the NMD-predicted region 3.9 [95% confidence interval (CI) 1.54-11.04] times increased the odds of fetal findings. Females presented significantly earlier [2 months, interquartile range (IQR) 7.0, n = 224] than males (8 months, IQR 16.6, n = 233), with increased risk of neonatal presentation [odds ratio (OR) 3.01 (95% CI 1.279-7.616)] when harbouring FS/N variants in the NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9-11.9) years. On average, females survived 4.5 (95% CI 2.62-6.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex [hazard ratio (HR) 3.3 (95% CI 1.95-5.62)], neonatal presentation [HR 5.5 (95% CI 2.17-14.09)], FS/N variants in the NMD-predicted region [HR 4.0 (95% CI 1.78, 9.16)] and splice variants [HR 2.3 (95% CI 1.15, 4.59)]. More severe clinical phenotypes were predicted by neonatal or infantile presentations and by female sex. Developmental delay (DD), intellectual disability (ID), muscle hypotonia, abnormal movements, seizures, feeding difficulties and microcephaly were the most frequent phenotypes, all occurring in more than half. Corpus callosum or basal ganglia alterations and cerebral atrophy were common. Four per cent (36/891) were reported to have mild phenotypes with no DD nor ID (25/36 males). This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines the disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds substantial improvement to counselling.

Exome sequencing (ES) has become a key diagnostic tool for rare diseases (RDs). However, most evidence on ES performance comes from high-income countries and patients from European ancestry. In countries such as Chile, limited access to next generation sequencing amplifies health disparities and highlights the need to identify which patients are most likely to benefit from ES. This study presents the second phase of the Chilean DECIPHERD project, in which we performed ES in a new group of patients with RDs presenting with multiple congenital anomalies (MCA), neurodevelopmental disorders (NDD), and/or suspected inborn errors of immunity. To identify clinical and demographic factors associated with an increased probability of obtaining an informative ES result, we conducted a logistic regression analysis, combining the results of the first and second phases of the project. We also objectively evaluated global ancestry measured using ADMIXTURE, as a potential factor. Sixty-seven patients participated in this second phase of DECIPHERD with a median age of 6 years (range: 0–27); 55.2% were female, with an average (± s.d.) proportion of Native American ancestry of 0.615 ± 0.18. Clinically, 52.2% presented with both MCA and NDD, and the rest had other phenotype combinations. An informative result, including pathogenic or likely pathogenic variants in genes consistent with the patient’s phenotype, was identified in 34.3% of the cohort; 61% of these variants had not been previously reported in databases such as ClinVar. By combining the two phases of the study, we reached a total of 167 patients, in whom the presence of NDD and/or MCA significantly increased the probability of achieving an informative ES outcome. In contrast, previous use of gene panel testing was associated with a decreased likelihood of receiving an informative result. Ancestry was not associated with diagnostic yield. This study demonstrates the utility of ES in achieving a diagnosis in a clinically diverse cohort of Chilean patients with RDs, and characterized features associated with a higher diagnostic yield. These findings may contribute to evidence-based patient prioritization strategies in settings with limited access to NGS resources.

Congenital heart disease (CHD) occurs in over half of individuals with 22q11.2 deletion syndrome (22q11.2DS), but lesion type varies widely. We analyzed 3,016 unrelated postnatal individuals with 22q11.2DS from specialized centers in the United States, Canada, Europe, South America, Israel, and Australia, including 1,868 with whole-genome sequencing. The typical 3 Mb LCR22 A-D deletion was present in 2,788 individuals (92.4%), with smaller A-B (n=172, 5.7%) and A-C (n=56, 1.9%) deletions comprising the remaining cohort. In multivariable mixed-effects logistic regression adjusting for sex, deletion group, genome-wide principal components (PCs), and recruitment site, four non-intercept associations, to test relationships, met study-wide FDR statistical significance. Compared with the A-B deletion, the A-D deletion was associated with lower odds of persistent truncus arteriosus (OR=0.37, 95% CI 0.18-0.75) and higher odds of isolated septal defects (OR=4.68, 95% CI 1.71-12.83), although precision was limited by the smaller A-B group. PC2 was associated with lower odds of pulmonary stenosis/atresia with additional lesions (OR=0.73, 95% CI 0.61-0.87), and PC4 with higher odds of abnormal origin of the subclavian arteries (OR=2.59, 95% CI 1.37-4.89). ADMIXTURE-derived continental ancestry proportions did not show independent associations with these two PC-associated outcomes. These lesion-specific findings suggest the hypothesis that deletion interval and broader genetic background may contribute to CHD variability in 22q11.2DS, pending future replication. KEY MESSAGES:What is already known on this topic: Chromosome 22q11.2DS is a rare genetic disorder associated with serious medical challenges. Most affected individuals have congenital heart disease but with variable phenotypic expression. One of the main questions still an open topic in the field is why individuals with 22q11.2DS show extensive phenotypic heterogeneity.What this study adds: Analysis of retrospective data on 3,016 individuals with 22q11.2DS and 1,868 with sequence data suggest that deletion type and genetic variation influence phenotypic expression of congenital heart disease.How this study might affect research, practice or policy: This work informs the clinician as to the importance of testing for deletion type and obtaining accurate cardiac phenotypes to diagnose 22q11.2DS that will improve the prognosis and disease progression. It also implicates the complexity of sex and ancestry as confounding factors that will help guide future research studies to identify genetic modifiers of congenital heart disease.

Background:Heterozygous variants in CTNND2, encoding the brain-specific protein δ-catenin, are associated with a broad spectrum of neurodevelopmental disorders, including dyslexia, attention deficit hyperactivity disorder, intellectual disability, and autism. Despite its clinical significance, the full phenotypic spectrum of CTNND2-associated disorders and the neurodevelopmental role of δ-catenin, a key component of the cadherin-catenin cell adhesion complex, remain poorly defined. Methods:Through international collaboration, we assembled the phenotypic and molecular information for 57 individuals, 42 previously unpublished, carrying heterozygous CTNND2 variants. All individuals were evaluated by local clinicians, and the variants were identified through exome or genome sequencing, clinical microarray, or karyotyping. To investigate the effects of δ-catenin loss on early neurogenesis, we performed neural differentiation and transcriptomic profiling in three patient-derived neural stem cell lines and three CRISPR-Cas9-generated CTNND2 knockout lines. In one patient-derived line, we further analyzed cerebral organoid development and performed pathway modulation to assess phenotypic rescue. Results:The 41 CTNND2 variants included 12 previously reported loss-of-function- and one missense variant, and 28 novel variants comprising 10 missense and 18 predicted loss-of-function changes. Eight of the novel variants occurred de novo, and 12 were inherited from a parent with a neurodevelopmental phenotype. The most common clinical features were developmental delay (90%), intellectual disability (74%), and behavioral abnormalities (79%). Functional studies revealed impaired early neurogenesis in one patient-derived line, characterized by aberrant neural rosette formation. Transcriptome analysis showed dysregulated WNT signaling, and partial rescue of these defects was achieved by modulating the WNT pathway, highlighting δ-catenin's role in early neural development. Conclusions:This study defines the clinical symptoms of CTNND2-related neurodevelopmental disorders, outlining a recognizable yet variable phenotype that overlaps with other forms of intellectual disability and autism. Our findings provide preliminary evidence of genotype-phenotype correlations and highlight δ-catenin's critical role in modulating WNT signaling during early neural development. These insights advance our understanding of CTNND2-associated disorders and support the importance of mechanistic studies to inform personalized diagnostics and therapies.

Comorbidities are common in Parkinson's disease and significantly impact the disease progression and management. While polygenic scores have been widely used to assess genetic risk for complex diseases, their role in comorbidity presentation in Parkinson's disease remains unclear. This study investigates whether genetic predisposition to comorbidities, as measured by polygenic scores, differs between individuals with Parkinson's disease and the general population and explores how genetic risk influences disease onset and sex-related differences. We analysed data from 4144 individuals with Parkinson's disease and 370 480 individuals from the general population in the UK Biobank, focusing on four comorbidities with high-quality genome-wide association study data: Type 2 diabetes, major depressive disorder, migraine headaches and epilepsy. We first compared polygenic score distributions between individuals with Parkinson's disease and the general population. While our findings indicate that comorbidities and polygenic risk scores do not significantly differ between individuals with Parkinson's disease and the general population, we show an association with disease onset and sex-specific differences. Individuals with earlier disease onset (50-70 years old) had higher genetic risk for major depressive disorder (odds ratio: 2.19, P-value: 1.27 × 10⁻¹⁵) and epilepsy (odds ratio: 1.58, P-value: 0.00845). Additionally, a female participant with Parkinson's disease exhibited higher genetic risk scores for major depressive disorder (odds ratio: 1.5, P-value: 0.0119) and migraine headaches (odds ratio: 2.1, P-value: 0.0155), while a male participant displayed higher genetic risk scores for Type 2 diabetes (odds ratio: 2.7, P-value: 2.11 × 10⁻¹⁷). Comorbidity-polygenic score did not differ between people with versus without Parkinson's disease, yet within Parkinson's disease, a higher genetic burden for specific comorbidities was linked to earlier onset and sex-specific presentation, implicating common variants as modifiers of clinical heterogeneity rather than the primary disease risk. These results enhance our understanding of the genetic influences shaping the broader clinical presentation of Parkinson's disease and highlight the need for further research into the interplay between genetic risk factors, comorbidities and disease heterogeneity.

Abstract Background Rare diseases are conditions that have a low prevalence in the population and a high disease burden and are often chronic and progressive. International evidence concerning the experience of people and families living with rare diseases is scarce, leading to late and erroneous diagnoses, as well as non-specific treatments. This study explored the therapeutic trajectories of people and families living with rare diseases within Chile’s public and private healthcare systems from the perspective of patients, caregivers, and medical teams, including the initial symptoms, first consultation, testing, diagnosis, treatment, and follow-up. Methods A qualitative exploratory study was conducted through multiple case studies. Sixty participants were interviewed in person and/or virtually: patients (n = 16), caregivers (n = 22), healthcare workers (n = 20), and two patient organisation leaders. The material was analysed using thematic analysis. The project was approved by the Scientific Ethics Committee of Facultad de Medicina Clínica Alemana, Universidad del Desarrollo. Results After similar initial symptoms and first consultation, three main types of trajectories were identified: (i) the path taken by those who reach a diagnosis for a disease that has specific treatment available; (ii) the journey of those who reach a diagnosis for their health condition, but their disease does not have a specific treatment available; and (iii) the trajectory of those who have not reached a diagnosis and receive symptomatic treatments for symptoms. Conclusions The therapeutic trajectories of patients with rare symptoms are similar in terms of initial symptoms and first consultation. However, their paths diverge at the diagnostic stage, with diverse experiences related to these journeys, largely based on having a diagnosis and whether there is a specific treatment. Rare conditions in Chile requires further attention and urgent action that considers those who live with them and their families.

BACKGROUND:22q11.2 deletion syndrome (22q11.2DS) has been associated with increased risk of early-onset Parkinson's disease (PD). OBJECTIVE:To determine the prevalence and predictors of PD in a large international 22q11.2DS sample. METHODS:The sample comprised 856 adults (median age 28 (range 16-76) years; 53.0% female). PD was defined as clinical diagnosis by a neurologist (including bradykinesia, rest tremor and/or rigidity). Age-specific risk and predictors of PD were analyzed using Kaplan-Meier curve and Cox regression. RESULTS:PD was present in 1.8% (95% CI: 0.9-2.6%) of the sample, 3.4% (95% CI: 2.2-4.6%) when including uncertain PD (clinical diagnosis or suspicion, but not meeting all criteria), and 14.0% (95% CI: 6.9-21.0%) of those aged ≥50 years. Median age at motor onset was 45 (range 20-66) years. None of the factors considered were associated with PD. CONCLUSIONS:Given high PD prevalence and young onset, we propose periodic motor evaluations from age 40 years in 22q11.2DS.

Background. The coevolution of nuclear and mitochondrial genomes has guaranteed mitochondrial function for millions of years. The introduction of European (EUR) and African (AFR) genomes into the Ameridian continent during the Columbus exchange in Latin America created an opportunity to naturally test different combinations of nuclear and mitochondrial genomes. However, the impact of potential “mitonuclear discordance” (MND, differences in ancestries) has not been evaluated in Latin American admixed individuals (AMR) affected with developmental disorders, even though MND alters mitochondrial function and reduces viability in other organisms. Methods. To characterize MND in healthy and affected AMR individuals, we used AMR genotype data from the 1000 Genomes Project (n = 385), two cohorts of 22q.11 deletion syndrome patients 22qDS-ARG (n = 26) and 22qDS-CHL (n = 58), and a cohort of patients with multiple congenital anomalies and/or neurodevelopmental disorders (DECIPHERD, n = 170). Based on their importance to mitochondrial function, genes were divided into all mitonuclear genes (n = 1035), high-mt (n = 167), low-mt (n = 793), or OXPHOS (n = 169). We calculated local ancestry using FLARE and estimated MND as the fraction of nuclear mitochondrial genes ancestry not matching the mtDNA ancestry and ∆MND as (MNDoffspring—MNDmother)/MNDmother. Results. Generally, MND showed distinctive population and haplogroup distributions (ANOVA p < 0.05), with haplogroup D showing the lowest MND of 0.49 ± 0.17 (mean ± s.d.). MND was significantly lower in 22qDS-ARG patients at 0.43 ± 0.24 and DECIPHERD patients at 0.56 ± 0.12 compared to healthy individuals at 0.60 ± 0.09 (ANOVA p < 0.05). OXPHOS and high-mt showed the same trend, but with greater differences between healthy and affected individuals. Conclusions. MND seems to inform population history and constraint among affected individuals, especially for OXPHOS and high-mt genes.

Aim To review the available evidence about the strategies implemented or proposed for coverage or reimbursement for currently approved gene therapies.Methods A scoping review was conducted to analyze the evidence published during the years 2016 to 2023. The main search criteria were coverage or reimbursement of gene therapy by healthcare systems. The eligible articles were those that described or proposed a financing model used to provide coverage in the various systems around the world.Results The study identified 279 publications, and after removing duplicates and screening for eligibility, 10 were included in the study. The results show that various financing models have been proposed, including subscription-based payment models, outcome-based payment models, and amortization strategies. However, several barriers to implementing these models were identified, such as deficiencies in informatics systems for data collection, changes in laws or regulations, the lack of accessible clinical endpoints and administrative costs.Conclusion This scoping review provides an overview of financing strategies for gene therapies. Gene therapies can cure rare or previously intractable diseases, but their high cost can make access difficult. Publishing experiences with these models can help evaluate their use and gather more evidence for their effectiveness.

Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the “diagnostic odyssey” for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.

Latin America (LatAm) has a rich and historically significant role in delineating both novel and well-documented genetic disorders. However, the ongoing advancements in the field of human genetics pose challenges to the relatively slow adaption of LatAm in the field. Here, we describe past and present contributions of LatAm to the discovery of novel genetic disorders, often referred as novel gene-disease associations (NGDA). We also describe the current methodologies for discovery of NGDA, taking into account the latest developments in genomics. We provide an overview of opportunities and challenges for NGDA research in LatAm considering the steps currently performed to identify and validate such associations. Given the multiple and diverse needs of populations and countries in LatAm, it is imperative to foster collaborations amongst patients, indigenous people, clinicians and scientists. Such collaborative effort is essential for sustaining and enhancing the LatAm´s contributions to the field of NGDA.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism. Using a novel source-based morphometry method called SS-Detect, we identified 12 structural brain patterns (SBPs) that discriminated individuals with 22q11.2 deletion syndrome from healthy controls. We further demonstrated that deletion size was related to structural covariance patterns; however, history of psychosis did not show a strong relationship with these covariance patterns.image

Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort. We identified ten variants predicted to cause HGF loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of our cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). We studied co-segregation within families, mRNA stability for non-sense variants, and in vitro functional effects of the missense variants. Analyses of the mRNA of patient cells revealed degradation of the nonsense mutant allele. Reduced protein secretion was detected for nine of the 14 missense variants expressed in COS-7 cells. Stimulation of lymphatic endothelial cells with these 14 HGF variant proteins resulted in decreased activation of the downstream targets AKT and ERK1/2 for three of them. Clinically, HGF-associated PL was diverse, but predominantly bilateral in the lower limbs with onset varying from early childhood to adulthood. Finally, aggregation study in a second independent cohort underscored that rare likely pathogenic variants in HGF explain about 2% of PL. Therefore, HGF signalling seems crucial for lymphatic development and/or maintenance in human beings and HGF should be included in diagnostic genetic screens for PL.

Achieving a diagnosis for Indigenous people living with a rare, often genetic, disease is crucial for equitable healthcare. The International Rare Disease Research Consortium convened a global Task Force to bridge the gap in diagnosing Indigenous rare diseases, and identify solutions to tackle the health inequity faced by Indigenous people.