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PubMed2024

Bioinformatics pipeline for the systematic mining genomic and proteomic variation linked to rare diseases: The example of monogenic diabetes.

Monogenic diabetes is characterized as a group of diseases caused by rare variants in single genes. Like for other rare diseases, multiple genes have been linked to monogenic diabetes with different measures of pathogenicity, but the information on the genes and variants is not unified among different resources, making it challenging to process them informatically. We have developed an automated pipeline for collecting and harmonizing data on genetic variants linked to monogenic diabetes. Furthermore, we have translated variant genetic sequences into protein sequences accounting for all protein isoforms and their variants. This allows researchers to consolidate information on variant genes and proteins linked to monogenic diabetes and facilitates their study using proteomics or structural biology. Our open and flexible implementation using Jupyter notebooks enables tailoring and modifying the pipeline and its application to other rare diseases.

Humans↗

PubMed2025

Discovery of a MET -driven monogenic cause of steatotic liver disease.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease affects about a third of adults worldwide and is projected soon to be the leading cause of liver cirrhosis. It occurs when fat accumulates in hepatocytes and can progress to metabolic dysfunction-associated steatohepatitis, liver cirrhosis, and HCC. Metabolic dysfunction-associated steatotic liver disease pathogenesis is believed to involve a combination of genetic and environmental risk factors. Single nucleotide polymorphisms have been implicated, but non-syndromic monogenic causes are lacking. APPROACH AND RESULTS: We identified a novel genetic variant in a familial case of metabolic dysfunction-associated steatohepatitis and performed deep variant functional analysis, including protein modeling, dynamics, and cell-based assays to assess molecular mechanisms of dysfunction and altered cellular signaling. We analyzed exome sequencing data of 3904 individuals with steatotic liver disease (SLD) to identify additional cases and establish the link between specific gene variants and SLD diagnosis. We discovered and functionally validated the NM_000245.4:c.3505A>T; p.(Ile1169Phe) variant in the MET (mesenchymal-epithelial transition) kinase domain as a monogenic cause of SLD. Subsequently, we detected additional ultra-rare, previously uninterpreted, and likely deleterious variants in MET from screening sequencing data. Among individuals with confirmed SLD based on electronic record review, 1.1% (45/3904) had rare predicted deleterious MET variants. Eight of 45 (17.7%) individuals had predicted deleterious variants in the MET kinase domain confirmed to be functionally like the familial case variant. CONCLUSIONS: We report the first germline nonmalignant rare MET -driven disease, a monogenic form of SLD.

Adult↗

PubMed2026

Swimming Upstream to Understand Congenital Anomalies of the Kidney and Urinary Tract: Zebrafish Models for Developmental Biology, Disease Mechanisms, and Functional Interpretation of Genetic Variation.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of pediatric chronic kidney disease (CKD) and comprise a heterogeneous group of developmental disorders with a substantial genetic contribution. Advances in next-generation sequencing have facilitated the identification of numerous candidate genes and rare variants associated with CAKUT. However, establishing causality and defining the biological functions of implicated genes remain major challenges. Functional validation is therefore essential to bridge the gap between gene discovery and mechanistic understanding, enabling the interpretation of genetic variation within the context of kidney development and disease. The zebrafish (Danio rerio) has emerged as a powerful in vivo model for studying renal development and interrogating the function of CAKUT-associated genes. Its utility stems from a high degree of genetic and developmental conservation with humans, conserved nephrogenic pathways, optical transparency during embryogenesis, and the relative ease of genetic manipulation. In this review, we provide an overview of zebrafish kidney development within the broader context of vertebrate nephrogenesis, highlighting the key genetic programs governing intermediate mesoderm specification, nephron segmentation, and pronephric morphogenesis. We then systematically examine CAKUT-associated genes that have been modeled in zebrafish, focusing on studies that have linked genetic perturbations to renal development and structural phenotypes. Finally, we discuss the strengths and limitations of zebrafish models for functional genomics and variant interpretation and consider their emerging role in bridging genetic discovery with mechanistic insights into CAKUT pathogenesis.

Animals↗

PubMed2025

Non-HLA Genetics and Application to Living Donor Candidates.

PURPOSE OF REVIEW: This review examines the expanding role of non-human leukocyte antigen (non-HLA) genetic factors in kidney transplantation, with a particular focus on their implications for living donor evaluation and outcomes. It emphasizes the potential of genetic testing to improve risk stratification beyond conventional HLA matching, especially for donor candidates with a family history of hereditary kidney disease. RECENT FINDINGS: Non-HLA genetic mismatches, including single nucleotide variants affecting minor histocompatibility antigens, can drive alloimmune responses, leading to graft rejection and failure even in HLA-matched transplants. The presence of non-HLA antibodies further contributes to adverse immunological outcomes. Genetic testing in related living donors can uncover monogenic kidney diseases, enabling early identification of at-risk individuals and enhancing donor safety. While polygenic risk scores and gene panels show promise in predicting complications and guiding post-transplant care, most genome-wide association studies have focused on recipients. There remains a significant gap in understanding how donor-specific genetic factors influence post-donation kidney function and long-term health outcomes. SUMMARY: The integration of non-HLA genetic testing into living donor evaluation supports a precision medicine approach to kidney transplantation, offering improved risk assessment and donor-recipient matching. As the field advances, longitudinal studies and robust data collection, particularly around donor genetics, are essential to optimize transplant outcomes, inform clinical decision-making, and uphold ethical standards in donor care.

genetics↗

PubMed2026

NCBoost v2: a classifier for non-coding single-nucleotide variants in Mendelian diseases.

MOTIVATION: The current diagnostic rate of rare diseases through whole-genome sequencing has stabilized at around 30% on average, highlighting the need for improved computational scores to identify pathogenic variants. In 2019, we developed NCBoost, a supervised-learning approach that mined a comprehensive set of sequence constraint features and proved particularly well suited to identifying high-effect pathogenic non-coding variants in genetic diseases. Since its first release, the substantial increase in the number of variants available for training, as well as the enhanced capacity to detect purifying selection signals from large-scale genome sequencing projects, motivated an update of NCBoost. RESULTS: We implemented NCBoost v2, a pathogenicity score for non-coding single-nucleotide variants, trained on the largest set of curated pathogenic variants in monogenic Mendelian diseases available to date. It leverages conservation features computed from recent large-scale genomic consortia such as Zoonomia and gnomAD, and incorporates recent splice-altering predictive scores. NCBoost v2 outperformed alternative state-of-the-art methods in a variety of scenarii, providing more consistent scores across non-coding genomic regions and fine-tuning the scoring of pathogenic splice-altering variants in Mendelian disease genes. AVAILABILITY AND IMPLEMENTATION: NCBoost v2 software is implemented in Python 3.10 and is freely available under the GNU General Public License Version 3 at https://doi.org/10.5281/zenodo.16029049 and https://github.com/RausellLab/NCBoost-2, together with precomputed scores for the human genome assembly GRCh38.

Polymorphism, Single Nucleotide↗

PubMed2025

Diagnostic Implications and Correlates of Plasma Adenosine Deaminase 2 Activity and ADA2 Variants.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease manifested as polyarteritis nodosa, stroke, and bone marrow failure. Leveraging an international cohort of 200 DADA2 cases, we aimed to characterize the diagnostic utility of a plasma ADA2 enzyme activity assay and understand the implications of residual ADA2 activity. METHODS: Data were collected from individuals who underwent ADA2 testing from 2018 to 2025. Plasma ADA2 activity was determined using an established spectrophotometric assay. ADA2 variants were analyzed in transfected cells by enzyme assay and western blotting. RESULTS: We determined that plasma ADA2 activity is 99.0% and 96.0% sensitive and 99.7% and 98.8% specific in distinguishing genetically confirmed DADA2 cases from controls and carriers, respectively. Eighteen individuals with DADA2 (9%) possessed detectable ADA2 activity, including several cases with levels seen in carriers. Residual ADA2 activity was associated with the vasculitis/inflammatory phenotype but not with disease severity. Genotype analysis revealed that 14 of 18 cases with residual plasma activity possessed at least one hypomorphic missense variant with greater than 20% residual ADA2 function when overexpressed in 293T cells, often occurring in trans with a more deleterious variant. In vitro analysis revealed that missense ADA2 variants exert variable dominant-negative effects by forming large intracellular protein aggregates via disulfide bond formation at a cysteine residue (Cys408). CONCLUSION: We confirmed the utility of plasma ADA2 activity as a diagnostic assay and showed that the inflammatory phenotype of DADA2 occurred in cases with residual activity. In vitro findings illustrate potential interactions of ADA2 variants to synergistically disrupt protein function.

Humans↗

PubMed2025

Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism.

NLRP3 mosaicism is a well-established mechanism causing the monogenic autoinflammatory disease named cryopyrin-associated periodic syndromes (CAPS). The number of reported patients with NLRP3 mosaicism is small, and the knowledge about the long-term disease behavior is limited. Herein we assembled the largest cohort of individuals with NLRP3 mosaicism reported to date to obtain additional evidence that strengthens the understanding of this disease. The novel genetic data were obtained by using Sanger and next-generation sequencing methods, whereas in vitro analyses determined the functional consequences of detected variants. A total of seventeen individuals with NLRP3 mosaicism were enrolled, with 16/17 experiencing different CAPS phenotypes. An overrepresentation of late-onset forms was detected (37.5%). Overall, clinical manifestations, analytical results, and outcomes of treatments were markedly similar to those detected in patients with germline variants. A large mutational diversity was identified, with 16 different variants among 17 individuals. Two main patterns of mosaicism (extended vs. myeloid-restricted) were detected, with the last one overrepresented in the late-onset group. The evaluation of mosaicism over time identified three different patterns, being the group with stable mosaicism the largest one. Collected evidence supports the marked similarities among patients carrying somatic or germline NLRP3 variants. The overrepresentation of NLRP3 mosaicism in late-onset forms should be considered in patients with inflammatory manifestations starting in adulthood. Analysis of mosaicism at the biological level confirms the two known patterns of corporal distribution and reveals that mosaicism remains stable over time in most patients, but it may also vary during the course of the disease.

Humans↗

PubMed2025

Identification of four novel ACADVL variants in eight Chinese unrelated patients with very long-chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a disorder of mitochondrial fatty acid oxidation with an autosomal recessive manner and is due to the VLCAD enzyme deficiency which is encoded by the ACADVL gene. The purpose of this study was to elucidate the clinical manifestations and analyze the molecular findings of eight Chinese patients with VLCADD. METHODS: We investigated eight Chinese VLCADD patients (three males, five females) from eight unrelated families. Molecular analysis was performed under the application of next-generation sequencing (NGS) in combination with Sanger sequencing validation to confirm the likely pathogenic variants in these patients. RESULTS: Patient 1 (P1) exhibited the most severe clinical features and passed away 3 h after admission on the second day of life. Unfortunately, P2 succumbed to hypoketotic hypoglycemia at 5 months of age. Except for asymptomatic P7, the remaining patients also developed clinical presentations of varying severity at different ages. Molecular data revealed that all affected individuals were compound heterozygotes for ACADVL variants. A total of 14 variants (4 novel and 10 known) were identified and the pathogenicity was evaluated based on the American College of Medical Genetics and Genomics (ACMG) criteria and different in silico prediction tools. CONCLUSIONS: The analysis of genotype-phenotype relationships preliminarily suggests that the compound heterozygous variants identified in these patients are likely the primary cause of VLCADD. Our study expands the mutation spectrum of ACADVL and highlights the significance of genetic analysis in early diagnosis and therapeutic intervention of monogenic hereditary diseases especially those with rapid disease progression.

Female↗

PubMed2024

Estimation of carrier frequencies of autosomal and X-linked recessive genetic conditions based on gnomAD v4.0 data in different ancestries.

PURPOSE: Monogenic rare diseases contribute significantly to infant deaths and pediatric hospitalizations and cause burden to the patients and their families. The American College of Medical Genetics and Genomics recommended in 2021 that carrier screening of autosomal recessive and X-linked conditions with a carrier frequency of ≥1/200 and a severe or moderate phenotype should be offered when planning or during pregnancy. In November 2023 gnomAD v4.0 was released. It contains in total 807,162 individuals, being nearly 5× larger than previous versions, which have been used to estimate gene carrier frequencies (GCF). METHODS: We utilized gnomAD v4.0 (GRCh38) to calculate the GCFs for available genetic ancestry groups for variants having pathogenic or likely pathogenic classification (>80% of submissions) in ClinVar. We calculated GCF separately for exomes and genomes, combined data, and at-risk couple frequencies (ACF) per genetic ancestry group. RESULTS: In total, 324 genes had a GCF ≥1/200 in at least 1 ancestry subgroup. The number of genes with GCF ≥1/200 varied greatly between subgroups. ACFs were more similar, Ashkenazi Jewish having the highest ACF of 6.11%. CONCLUSION: Improved understanding of carrier risks and updated carrier screening content would allow patients to make more informed reproductive decisions.

Humans↗

PubMed2026

Adeno-Associated Virus Gene Therapy Translation: Lessons from Early Regulatory Meetings.

The Platform Vector-Gene Therapy (PaVe-GT) program is a National Institutes of Health (NIH) initiative that aims to develop adeno-associated virus (AAV) gene therapies for four monogenic rare diseases, two organic acidemias and two congenital myasthenic syndromes. PaVe-GT's platform-based approach identifies and diminishes redundancies and applies efficiencies in preclinical, clinical, and regulatory activities. The program's hypothesis is that implementing these efficiencies can accelerate clinical trial initiation. Based on its platform-centric experience and public-serving mission, the PaVe-GT program actively shares its scientific and regulatory learnings with the public to benefit the development of similar gene therapy products for rare diseases. PaVe-GT's first investigational AAV gene therapy candidate is AAV serotype 9 human propionyl-CoA carboxylase alpha subunit (AAV9-hPCCA) for propionic acidemia caused by PCCA deficiency, which received initial feedback from the Food and Drug Administration (FDA) in an INitial Targeted Engagement for Regulatory Advice on CBER/Center for Drug Evaluation and Research (CDER) ProducTs (INTERACT) meeting. Upon further product development that took into consideration the FDA's initial advice, the program obtained the Agency's feedback in pre-investigational new drug (IND) (Type B) and Type C meetings. Here, we share our experience from these meetings, including strategy, preparation, pre- and post-meeting feedback from the FDA, and lessons learned during the AAV9-hPCCA regulatory process, which the program plans to apply across the PaVe-GT platform. Topics discussed in the regulatory meetings included animal model and efficacy studies, toxicology study plans, manufacturing of the investigational AAV product, and clinical trial design. The main lessons learned from the pre-IND and Type C meetings for AAV9-hPCCA are: (1) Pharmacology/Toxicology studies in a single rodent species are sufficient for filing an initial IND; (2) FDA feedback guides product quality improvements and early development of a quantitative potency assay; (3) use of biomarkers as potential surrogate endpoints in a future efficacy trial benefits from collection of data in the natural history study and the first-in-human Phase 1/2 study; and (4) evidence from the Phase 1/2 clinical trial could be leveraged to support a license application. Lightly redacted regulatory documents and comprehensive templates developed by the PaVe-GT team are available on the PaVe-GT website.

Dependovirus↗

PubMed2026

Role and relevance of genetic testing in patients with kidney stones: a review from EAU Section of Endourology.

PURPOSE OF REVIEW: Kidney stones have a high heritability. More than 40 genes have been identified causing monogenic forms of kidney stone disease (KSD). Kidney stone formers with genetic variants implicated in monogenic forms of KSD often suffer from early onset, high recurrence rates, and chronic kidney disease. Some patients may also exhibit extrarenal disease requiring attention. RECENT FINDINGS: Recent analysis of KSD patients identified a likely monogenic cause in pediatric populations in 17-30% of participants while in adult unselected populations 2.7-8% had a positive finding. More patients carry single genetic variants in monogenic forms that are classically considered as autosomal recessive but may cause an intermediate genetic risk for the development of KSD possibly in interaction with environmental or lifestyle factors. Genome-wide association studies have identified additional risk loci associating with KSD. Their clinical relevance are currently investigated. Patients with recurrent kidney stone episodes may be at elevated risk of progressive chronic kidney disease. SUMMARY: Monogenic causes of KSD are prevalent in patients less than 25 years of age and in some patients with high-risk metabolic profiles. These patients should undergo genetic testing to enable a precise molecular genetic diagnosis and personalized therapy as well as family counseling and screening.

Humans↗

PubMed2024

Shared etiology of Mendelian and complex disease supports drug discovery.

BACKGROUND: Drugs targeting disease causal genes are more likely to succeed for that disease. However, complex disease causal genes are not always clear. In contrast, Mendelian disease causal genes are well-known and druggable. Here, we seek an approach to exploit the well characterized biology of Mendelian diseases for complex disease drug discovery, by exploiting evidence of pathogenic processes shared between monogenic and complex disease. One way to find shared disease etiology is clinical association: some Mendelian diseases are known to predispose patients to specific complex diseases (comorbidity). Previous studies link this comorbidity to pleiotropic effects of the Mendelian disease causal genes on the complex disease. METHODS: In previous work studying incidence of 90 Mendelian and 65 complex diseases, we found 2,908 pairs of clinically associated (comorbid) diseases. Using this clinical signal, we can match each complex disease to a set of Mendelian disease causal genes. We hypothesize that the drugs targeting these genes are potential candidate drugs for the complex disease. We evaluate our candidate drugs using information of current drug indications or investigations. RESULTS: Our analysis shows that the candidate drugs are enriched among currently investigated or indicated drugs for the relevant complex diseases (odds ratio = 1.84, p = 5.98e-22). Additionally, the candidate drugs are more likely to be in advanced stages of the drug development pipeline. We also present an approach to prioritize Mendelian diseases with particular promise for drug repurposing. Finally, we find that the combination of comorbidity and genetic similarity for a Mendelian disease and cancer pair leads to recommendation of candidate drugs that are enriched for those investigated or indicated. CONCLUSIONS: Our findings suggest a novel way to take advantage of the rich knowledge about Mendelian disease biology to improve treatment of complex diseases.

Humans↗

PubMed1975

Broad-beta disease (type III hyperlipoproteinemia) in a large kindred. Evidence for a monogenic mechanism.

The inheritance of broad-beta disease (as specified by a type III lipoprotein pattern) has remained an enigma. Previous reports have variously implicated a single gene (autosomal dominant mode), a double dose of a single gene (autosomal recessive), two separate genes (mixed heterozygosity), or multiple genes (polygenic inheritance). The present study of a single, large kindred of 108 members spanning 4 generations provides evidence for an autosomal dominant mode, since at least 1 member of the first generation pair was normal, at least 5 of their 9 children had type III patterns, and at least 2 of these (whose spouses were normal) transmitted this pattern to their offspring. The findings also suggest that in this kindred the common occurrence of hypertriglyceridemia (in a type IV pattern) may represent either a variable phenotypic expression of the gene for broad-beta disease or the coexistence of a second, independent genetic lipid disorder.

Adult↗

PubMed2026

Whole exome sequencing of paediatric patients with Cogan's syndrome to identify monogenic mimics.

OBJECTIVES: Cogan's syndrome (CS) is a rare variable vessel vasculitis, describing sensorineural hearing loss (SNHL), inflammatory ocular disease and vestibular dysfunction. We hypothesized that within paediatric-onset (p)CS, a proportion would have monogenic disease, either autoinflammatory and/or associated with SNHL. METHODS: Whole exome sequencing (WES) was performed and analysed using an in-house pipeline incorporating virtual gene panels for inflammation and SNHL; copy number variant analysis (ExomeDepth); and phenotype-driven variant prioritization (Exomiser). Genetic variants were interpreted by a multi-disciplinary team according to American College of Medical Genetics and Genomics guidelines. RESULTS: Ten patients with a clinical diagnosis of pCS were enrolled. Three/10 (30%) had a monogenic contribution to the phenotype based on Class 4/5 variants: de novo NLRP3 p.T915R (n = 1) associated with Cryopyrin-associated periodic syndrome; MYO7A p.K542Qfs*5 (n = 1) causing SNHL; and HBB homozygous p.E7V causing sickle cell disease (associated with hearing loss and uveitis). A further two cases had possible monogenic contribution with the following rare variants of uncertain significance (class 3): ADGRV1 compound heterozygous variants (n = 1) associated with Usher syndrome; and a novel ALPK1 p.H735P (n = 1), associated with Retinal dystrophy Optic nerve oedema Splenomegaly Anhidrosis Headache (ROSAH) syndrome. CONCLUSIONS: In children presenting with features suggesting CS, genetic screening should be considered before conferring this rare diagnostic label since at least 30% had an alternative monogenic contribution to the phenotype rather than true pCS, with implications for treatment and prognosis. We thus advocate for genetic testing using next-generation sequencing for patients presenting with pCS.

Humans↗

PubMed2025

Genetic background of neurological disorders with basal ganglia calcification.

BACKGROUND: Bilateral basal ganglia calcifications (BGCs), if severe, are known hallmarks for idiopathic BGC disease (IBGC), but if milder, are often considered radiological findings of unknown significance. In previous studies, only a minority of patients with BGC had monogenic forms of IBGC. METHODS: We studied consecutive patients from a tertiary neurology clinic with bilateral BGCs of variable severity, and their families. We analyzed known IBGC genes, and an extended panel of genes linked to monogenic stroke and metabolic conditions. Clinical, radiological, and genetic data were collected, including vascular risk factors, cerebrovascular events, imaging findings (total calcification score, white matter hyperintensities, ischemic/hemorrhagic lesions), and relevant family history. RESULTS: Twenty-four families with BGCs and neurological symptoms were analyzed. Disease-causing variants were identified in 14 families (58.3%). Eight patients had IBGC (variants in SLC20A2, PDGFB, MYORG), 4 had mitochondrial disease (MT-TL1), and 2 had monogenic vascular conditions (GAL, MAP3K6). Three variants were novel. BGC severity was highest in IBGC cases, while vascular and mitochondrial cases had milder calcifications. White matter hyperintensities were seen in 94.7% of cases and correlated highly with the total calcification score. Clinical vascular events had occurred in 41.7% cases. No monogenic cause was found in 10 patients, although many of these showed clinical or radiological features suggestive of monogenic disease. CONCLUSIONS: Bilateral BGCs can occur in many neurogenetic disorders apart from IBGCs, and a broader genetic search increases the diagnostic yield. Patients with BGCs frequently had clinical cerebrovascular events, which emphasizes the role of cerebrovascular pathology in BGCs.

Humans↗

PubMed1976

Comparison of mouse liver sections and cultured mouse fibroblasts as substrates for the detection of antinuclear antibodies.

Immunofluorescent antinuclear antibody tests were performed on selected sera representing various connective-tissue diseases using mouse liver sections and mouse connective-tissue fibroblasts cultivated in vitro. Substrate sensitivities and patterns of staining were compared by indirect immunofluorescent method employing sera from 92 patients. Sensitivity (geometric mean serum endpoint titer) was significantly greater with the cultured cell substrate. This greater sensitivity was also detected with sera from 46 patients with systemic lupus erythematosus (SLE). No significant difference was observed in other clinical groups tested (rheumatoid arthritis, polyarthritis, drug-induced SLE, degenerative joint diseases, and progressive systemic sclerosis). Sera from 107 to 109 normal controls were negative on the mouse fibroblast substrate. The two substrates were equally sensitive in detecting homogenous, peripheral, or speckled patterns of fluorescence in patients' sera having antinuclear activity. Nucleolar staining was observed in only one serum specimen as a minor pattern. Neither substrate demonstrated a predominant immunofluorescent pattern with sera from SLE, polyarthritis, and progressive systemic sclerosis. Sera of patients with clinically diagnosed rheumatoid arthritis, drug-induced SLE, and degenerative joint diseases usually manifested monogeneous staning patterns. However, these differences in staining pattern among the various clinical groups were not statistically significant. The mouse tissue sections of equal specificity and significantly increased sensitivity for the detection of antinuclear antibody.

Animals↗

PubMed2025

Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations.

Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform in-depth analyses on individual patients with ultra-rare diseases. The increasing sizes of ultra-rare disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development. The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale case-based diagnostic analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical review, recapitulated known diagnoses and revealed new disease associations. We further release a software package, RaMeDiES, enabling automated cross-analysis of deidentified sequenced cohorts for new diagnostic and research discoveries. Gene-level findings and variant-level information across the cohort are available in a public-facing browser ( https://dbmi-bgm.github.io/udn-browser/ ). These results show that case-level diagnostic efforts should be supplemented by a joint genomic analysis across cohorts.

Humans↗

PubMed2026

Rare variant analysis of whole genome sequenced juvenile idiopathic arthritis multiplex pedigrees identifies rare variants in NOD2 and ACVR1.

Juvenile idiopathic arthritis is a complex rheumatic disease that is influenced by environmental and genetic factors. Linkage and genome-wide association studies have identified genes that contribute to the risk of developing juvenile idiopathic arthritis but are limited in their ability to identify disease-risk variants of large effect. Penetrant, heritable risk variants can be detected in high-risk families, but such cases are uncommon due to the low prevalence of juvenile idiopathic arthritis. This study utilizes whole-genome sequencing of 23 multiplex families, the largest such cohort to date, to discover variants and genes relevant to JIA pathogenesis. Pathogenic variants in NOD2 associated with Blau syndrome, an ultra-rare Mendelian inflammatory disorder, are the most recurrent variants in the cohort, consistent with previous reports that milder presentations of Blau syndrome are oftentimes misdiagnosed as juvenile idiopathic arthritis. For the first time, however, rare variants in ACVR1 and SMAD6, integral components of the Bone Morphogenic Protein pathway, are found to be associated with juvenile idiopathic arthritis. Identified ACVR1 variants map to critical protein domains. AlphaFold modeling predicts that the ACVR1 interaction with its inhibitor OGT is disrupted by these variants, indicating that the patient-mutated protein has a gain-of-function phenotype. Drosophila melanogaster expressing either a wild-type or patient-mutated version of ACVR1 exhibit embryonic lethality, with the mutant exhibiting 1.4-fold greater lethality than wild-type. The combination of family-based cohorts for gene discovery, AI-based computational tools, and animal model studies for tests of variant function underscores shared disease pathogenesis between JIA and monogenic disorders of immunity and connective tissue.

Arthritis, Juvenile↗