Introduction To report a Japanese family with inherited retinal dystrophy (IRD) in which CDHR1 variants were identified, and to characterize the marked intrafamilial phenotypic variability. Methods This retrospective case series included three brothers diagnosed with retinal dystrophy at Juntendo University Hospital. Comprehensive ophthalmic evaluations were performed, including best-corrected visual acuity (BCVA), Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinogram (ERG). Genetic testing was conducted using next-generation sequencing with an IRD gene panel. Results All three patients exhibited progressive visual decline with onset in their 40s–50s. Fundus examination revealed severe macular atrophy in two brothers (Cases 1 and 2), consistent with cone–rod dystrophy, whereas the youngest (Case 3) showed diffuse retinal degeneration with bone-spicule pigmentation resembling retinitis pigmentosa. FAF demonstrated hypoautofluorescence in the macula and hyperautofluorescence at the borders of atrophic areas in Cases 1 and 2, but widespread hypoautofluorescence in Case 3. ERG revealed rod–cone dysfunction in Cases 1 and 2 and non-recordable responses in Case 3. Genetic analysis identified a single heterozygous CDHR1 c.748C>A (p.Pro250Thr) variant in Case 1. In Cases 2 and 3, two heterozygous CDHR1 variants—c.748C>A (p.Pro250Thr) and c.2027T>A (p.Ile676Asn)—were detected. Case 1 as having a single heterozygous CDHR1 variant with a phenotype overlapping that of Cases 2 and 3, and explicitly note that the genetic diagnosis in Case 1 remains inconclusive. Conclusions This study describes a Japanese family with IRD showing substantial intrafamilial phenotypic heterogeneity, ranging from macular-predominant cone–rod dystrophy to generalized rod–cone dystrophy, in the context of identified CDHR1 variants. These findings highlight the complexity of genotype–phenotype correlations in CDHR1 -related retinal disease and underscore the importance of cautious interpretation of genetic results, particularly when variants of uncertain significance are identified.

Several vascular diseases including coronary artery disease, hypertension, stroke, and abdominal aortic aneurysm, have significant genetic underpinnings. Genome-wide association studies have unveiled many genetic loci associated with one or more of these diseases. However, the causative genes at most of these loci are yet to be determined, which hampers the translation of the genetic findings into a better understanding of the disease mechanisms and the identification of new therapeutic targets. Here, in an integrative functional genomics analysis of these loci, we identify a panel of likely causal genes, some of which are pleiotropic for more than one of these vascular diseases. Pooled CRISPR knockout screen analyses of these likely causal genes indicate that many of them influence vascular smooth muscle cell behaviour, and validation experiments of selected genes confirm that FES, BCAR1, CARF and SMARCA4 exert such effects. Further functional experiments focusing on FES, a pleiotropic gene for both coronary artery disease and hypertension, show that it modulates the expression of genes involved in vascular remodeling and that Fes knockout in mice promotes atherosclerosis as well as raises blood pressure. These findings provide an insight into the genetic basis of vascular diseases and inform targets for therapeutic development.

This study aimed to identify prognostic biomarkers for gastric cancer (GC) by analyzing the methylation status of multiple tumor suppressor genes. Using the Epi-TOP™ methylation detection system, we analyzed 51 genes in 169 matched tumor and adjacent normal tissue samples. Methylation levels were quantified as Percent Methylated Reference (PMR) in tumor (PMR-T) and normal (PMR-N) tissues; the differential methylation (PMR-D) was also calculated. Tumor tissues exhibited significantly higher DNA methylation levels than matched normal tissues across 51 tumor suppressor genes (all p < 0.001). Clustering analysis based on PMR-T identified four epigenetic subtypes associated with known molecular classifications (epithelial-mesenchymal transition (EMT) and microsatellite instability-high (MSI-H)) and overall survival (p = 0.030). In contrast, clustering based on PMR-N showed no significant association with molecular subtypes or survival outcomes, suggesting limited prognostic relevance. Two prognostic gene panels were constructed: one PMR-T-based panel (ALX, BMP3, CDKN2A, MINT25, PTGDR) and another PMR-D-based panel (ADCYAP1, SOCS1, SEPTIN9, CDKN2B). Both panels independently predicted overall survival in multivariate Cox regression. The PMR-D panel demonstrated stronger prognostic performance (hazard ratio (HR) = 0.329, p = 0.002), while the PMR-T panel also demonstrated significant prognostic value (HR = 0.512, p = 0.012), highlighting that tumor methylation profiles alone may provide meaningful survival predictions for patients with GC. This study demonstrates that tumor-specific DNA methylation changes, particularly when evaluated using multi-gene panels can enhance prognostic stratification in GC. These findings support the potential use of methylation-based biomarkers for personalized management of GC.

Introduction Inborn errors of immunity (IEI) are particularly prevalent in regions with high rates of consanguinity, yet the genetic profiles in these populations are underreported. This study aims to describe the clinical and molecular characteristics of IEI in a highly consanguineous population and investigate the impact of genetic diagnosis on patient management. Method This retrospective study included 52 patients with suspected IEI, as defined by the IUIS criteria. Clinical, immunological, and demographic data were recorded. Genetic analyses were performed primarily using next-generation sequencing (NGS) gene panels, and all pathogenic variants were confirmed by Sanger sequencing. Variants were interpreted in accordance with the ACMG guidelines. Results A total of 52 patients were included in the study, with 92% of the individuals born to consanguineous parents, comprising 28 females and 24 males. The mean age at diagnosis was 4.63 ± 2.5 years. The median duration of follow-up was three years. The overall incidence was 0.3% representing the proportion of patients diagnosed with IEI among those referred to our center during the study period. A high rate of consanguineous marriage was observed, reported in 92% of the cases. The most frequently represented category was Predominantly Antibody Deficiencies (PAD), accounting for 20 patients (38.5%), including 12 cases (23%) of transient hypogammaglobulinemia of infancy (THI) and 7 cases (13%) of selective IgA deficiency. Among the 52 patients, 3 (5.8%) were diagnosed with severe combined immunodeficiency (SCID): 1 patient had ADA deficiency, and two patients had DNA ligase IV deficiency (LIG4). Additionally, 14 patients (26%) were diagnosed with combined Immunodeficiencies (CID). Thirty patients were treated with IVIG, and 3 patients underwent HSCT. A molecular diagnosis was established in 33 patients (63%). Genetic findings influenced clinical management in 82% of variant-positive cases, including decisions regarding HSCT, targeted therapy, and genetic counseling. Conclusion This study highlights the distinctive genetic characteristics of IEI in a population with high consanguinity, emphasizing the need to incorporate molecular diagnostics into standard immunology practice, particularly in areas where recessive disorders are prevalent.

Research note: Temporal and tissue-specific immune responses to Campylobacter jejuni colonization in broiler chickens.

Leveraging tumor multigene panel testing to identify germline variants in gynecologic cancers: A retrospective evaluation of an algorithm-based approach.

Li Fraumeni syndrome (LFS) is a hereditary multi-cancer syndrome caused by alterations in TP53 (MIM# 151623). Next generation sequencing (NGS) allows for the detection of TP53 variants at lower variant allele frequencies (VAFs). A TP53 variant with a VAF < 50% may represent mosaic LFS, aberrant clonal expansion (ACE), or possible circulating tumor DNA. Differentiation among these conditions is important for optimal patient management. Genetic testing was performed using a custom gene panel, with an average read depth of 350× (range 166-553×). DNA extracted from four different tissues (blood, saliva, cultured skin fibroblasts, and colon) was sequenced. Here, we describe an adult female patient with a history of an adrenocortical neoplasm and osteosarcoma, diagnosed at 2 and 16 years of age, respectively. Testing of peripheral blood identified a pathogenic TP53 variant, c.733G>A, p.(Gly245Ser) (NM_000546.6); however, subsequent invitro fertilization with preimplantation genetic testing for monogenic disorders (PGT-M) did not identify this TP53 variant in any of nine embryos tested. Testing for possible mosaicism in the proband was performed on four different specimens, revealing variable VAFs of the TP53 variant (saliva: 44%; blood: 31%; cultured skin fibroblasts: 18%; and colon tissue: 9%). These results suggest a post-zygotic event, consistent with mosaic LFS rather than ACE. This case highlights the complexity of interpreting mosaic variants in the TP53 gene, and we propose a testing algorithm to aid in the delineation of this phenomenon when relaying cancer and reproductive risk information in the context of mosaicism.

Our goal was to identify new environmental or genetic causes in heritable pulmonary arterial hypertension (HPAH) families outside the 18 known diagnostics PAH genes. PAH gene panel sequencing was performed for 47 HPAH families which revealed pathogenic variants in 39 families. Five of the remaining families agreed to whole exome sequencing and to fill in a drug and toxin exposure questionnaire. In Family 1 and 2, mother and daughter with HPAH carried a likely pathogenic variant in the CYBA gene and a variant of uncertain significance in the FKBP1A gene, respectively, following ACMG guidelines. In Family 3, we detected a likely pathogenic variant in the PTGR2 gene. These genes could play part in PAH pathogenesis but further functional analyses are required to corroborate these findings. In the remaining two families, we could not identify any plausible genetic cause. However, a father and son with PAH reported exposure to trichloroethylene, asbestos and tramadol in Family 4. In Family 5, two brothers with pulmonary veno-occlusive disease showed occupational toxin exposure. Thus, our findings indicate that not only a genetic predisposition but also environmental triggers should be investigated for HPAH patients.

Inherited retinal diseases (IRDs) are aclinically and genetically heterogeneous group of usually progressive retinal disorders that frequently lead to severe vision loss. The treatment options for these mostly monogenetic diseases are currently limited. As various treatment innovations are in the phase of clinical development, comprehensive clinical and genetic diagnostics are crucial. This study aimed to characterize aGerman IRD cohort of 1000 patients, both phenotypically and genetically, to determine clinical characteristics including the genetic clarification rate. Indications for improving care and future treatment can be derived from these. The medical records of patients reviewed in the IRD clinic at the University Eye Hospital Bonn between 2019 and 2023 were retrospectively reviewed. Demographic data, symptoms, age at symptom onset and diagnosis and genetic findings were collected. Genetic testing included Sanger sequencing, gene panels and exome/genome sequencing. Out of 1000 IRD patients (mean age: 40years), 822 underwent genetic testing. Acausative genetic mutation was identified in 78% of tested individuals. The most frequent clinical diagnoses were retinitis pigmentosa, macular dystrophies (including Stargardt disease). Accordingly, mutations were most frequently detected in the ABCA4, RPGR, USH2A and PRPH2 genes. The diagnostic yield of 78% is at the upper end of international IRD studies, which reflects the use of comprehensive sequencing methods. The most frequent IRD genes were consistent with findings from international cohorts. Mutations were detected in over 90different genes, underlining the genetic heterogeneity of IRDs. Overall, this emphasizes the importance of broad genetic testing, to identify IRD patients for clinical studies and new forms of treatment.

Unexplained liver disease in infants and children remains a significant diagnostic challenge as the spectrum of noninfectious pediatric liver disease expands. Timely, accurate etiologic assignment remains central to optimal care and resource allocation. Advances in next-generation sequencing, particularly whole-exome sequencing (WES), have transformed evaluation by enabling rapid identification of monogenic disorders that previously eluded standard algorithms. In this editorial, we synthesize recent evidence showing that comprehensive genetic testing substantially improves etiologic diagnosis in pediatric hepatology. WES markedly increases diagnostic yield in infants with cholestasis and in children with cryptogenic aminotransferase elevations, directly influencing management and outcomes. We compare yields across international reports from Asia, North America, and Europe, illustrating how WES and broad gene panels uncover heterogeneous genetic contributors to pediatric liver disease. We also address practical issues, including decreasing costs, faster turnaround times, and the importance of integrating conventional investigations with modern genomics. Finally, we emphasize that while WES is a powerful tool to “decode” unexplained disease and guide precision therapies, it must complement, not replace, careful clinical assessment and, in selected cases, liver biopsy. An integrated approach is essential for navigating heterogeneity, avoiding unnecessary procedures, and advancing personalized medicine in pediatric hepatology worldwide to improve outcomes and equity.

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening disease characterized by uncontrolled complement activation and is associated with various genetic factors, including multiple variants at the gene locus encoding the complement component 3 (C3). However, only a few functional amino acid substitutions have been identified in C3. We report a pediatric case of aHUS presenting with refractory hypertension and massive gastrointestinal bleeding. Comprehensive histopathological, immunohistochemical, genetic, and molecular structural analyses were performed. Biopsy specimens were stained for renin and the membrane-attack complex of the complement system (C5b-9). Plasma levels of the Ba fragment of complement factor B were measured to evaluate the alternative pathway activation. Genomic DNA was obtained with consent and analyzed by targeted next-generation sequencing using a custom gene panel, followed by Sanger sequencing for variant confirmation. The possible effects of the identified amino acid substitution on the molecular structure of C3 were analyzed using computer-aided simulation with MODELLER and DoGSiteScorer. As a result, the juxtaglomerular apparatus was hyperplastic and intensely stained for renin. Endothelial cells of renal and intestinal blood vessels were positive for C5b-9. The plasma Ba level was elevated compared to the control level. The ileal and colonic mucosae were denuded and highly edematous, with epithelial cells undergoing regenerative and metaplastic changes in the active phase. Mucosal blood vessels contained intraluminal red cell fragments and neutrophils attached to swollen endothelial cells. However, the colonic mucosa showed near-normal histology after disease convalescence. Genetic analyses identified a single nucleotide C3 variant NM_000064.4(C3):c.4811T&amp;gt;C (p.Met1604Thr), resulting in an M 1604 T substitution in the functional C345C domain. Molecular structural analyses indicated that this amino acid substitution can cause the formation of a large cavity within the hydrophobic core of the C-terminal domain, possibly destabilizing the spherical structure of C3. Our study highlights that the M 1604 T substitution in the C3 C345C domain may drive the observed excessive complement activation, C5b-9 deposition on endothelial cells, and severe circulatory disturbances in the intestinal mucosa.

To evaluate the diagnostic yield of whole exome sequencing (WES) vs targeted gene panel (TGP) testing in patients evaluated for autoinflammation at Great Ormond Street Hospital Autoinflammation Centre of Excellence. We retrospectively analysed 476 patients who underwent TGP testing between 2015-2022; and 210 patients who underwent WES between 2022-2025. Analysis of WES data combined: 1. a virtual gene panel of genes (germline and somatic) associated with inflammation; 2. agnostic filtering according to ClinVar classification of pathogenicity; 3. copy number variant analysis using ExomeDepth; and 4. phenotype-driven prioritisation using Exomiser. TGP testing identified molecular diagnoses in 71/476 patients (14.9%). WES increased the molecular diagnostic yield to 41/210 patients (19.5%). WES also enabled the discovery of novel genotype-phenotype associations. Significant incidental findings were identified in 29/210 (13.8%) of cases, including variants predisposing to cancer or cardiomyopathy. In patients with suspected autoinflammation, WES increased diagnostic yield compared with TGP testing while providing additional clinical value through novel gene discovery and capacity for future systematic reanalysis of unsolved cases. Incidental findings required careful and explicit a priori patient counselling and informed consent before offering WES. While there is an inevitable shift to whole genome sequencing, significant challenges remain, including costly large-data handling and storage, and uncertainty about the interpretation of variants in non-exonic regions. Our findings, therefore, demonstrate significant clinical impact of WES for the workup of autoinflammation, with pragmatic utility for timely return of results.

Systemic lupus erythematosus (SLE) and type 2 diabetes mellitus (T2DM) share inflammatory and metabolic disturbances, yet the molecular mechanism of their overlap remains unclear. This study used integrated bioinformatics to identify transcriptomic signatures and potential biomarkers common to both conditions. Gene expression profiles from publicly available datasets (SLE: 38 patients/32 controls; T2DM: 6 patients/6 controls; validation cohorts: 79/30 and 41/15, respectively) were analyzed to detect shared differentially expressed genes and co-expression modules. Functional enrichment, protein-protein interaction networks, and immune-cell composition analyses were performed. Diagnostic gene panels were constructed using random forest feature selection and logistic regression and evaluated through receiver operating characteristic analysis with external validation. A total of 551 shared differentially expressed genes were identified, enriched predominantly in type I interferon signaling, Toll-like/NOD receptor pathways, TNF signaling, necroptosis, and neutrophil extracellular trap formation. Across analytical methods, a 10-gene interferon-related hub (STAT1, IRF7, OAS1, OAS2, ISG15, MX2, IFI35, RSAD2, SAMD9, SAMD9L) genes demonstrated strong discriminative performance in both SLE and T2DM. A three-gene model further showed potential clinical utility (AUC 0.872–1.00 in discovery; 0.665–0.928 in validation).These signatures align with therapeutic axes in SLE (IFN/JAK-STAT) and intersect inflammatory-metabolic pathways in T2DM, supporting assayable biomarkers and compact diagnostic models that warrant validation in larger, medication-annotated cohorts.

Background. DNA methylation regulates numerous biological processes, mediating normal development. Alterations in methylation patterns are associated with multiple pathological conditions like hereditary diseases and cancer, making them valuable clinical biomarkers for patient stratification, disease monitoring, early diagnosis, and prediction of response to therapy. Highly targeted, high-throughput methodologies focusing on critical genomic loci enable precise identification of distinct methylation signatures. the aim of the study was to analyze and summarize literature data describing the use of high-throughput DNA methylation analysis technologies, including those based on targeted approaches. Material and Methods . A systematic analysis of literature data was conducted using the PubMed, Web of Science, and Scopus databases, focusing on the characteristics of high-throughput DNA methylation analysis used in cancer and some genetic diseases. A total of 113 sources were analyzed, chronologically covering the period from 2000 to June 2025, 32 of which were used to write the review. Results. The existing technologies for high-throughput methylome analysis, DNA conversion methods, and their advantages and limitations were summarized. In addition, the current targeted enrichment methods, their strengths and weaknesses, and potential applications in scientific and diagnostic practice were discussed. Conclusion. DNA methylation analysis has evolved from a basic research tool into a cornerstone of translational medicine, particularly in oncology. Modern methylome analysis techniques facilitate the discovery of epigenetic markers critical for diagnosing diseases, assessing prognosis, guiding therapy selection, and identifying molecular targets for targeted drugs. Targeted DNA enrichment increases analytical precision and sensitivity while reducing costs. Furthermore, specialized strategies permit targeted analysis even with challenging samples. Combined with the flexibility to focus on specific genomic regions, these advantages make targeted approaches viable not only in academic research but also in routine clinical diagnostics.

Background and study aimsPancreatic ductal adenocarcinoma (PDAC) is a poor prognostic malignancy. Comprehensive genomic profiling (CGP) has improved outcomes in many cancers, but widespread uptake in PDAC remains elusive. This study investigated the feasibility of using endoscopic ultrasound with fine-needle biopsy (EUS-FNB) for CGP in advanced PDAC.Patients and methods (experimental design)A multicenter prospective cohort study was conducted to assess the feasibility of using DNA and RNA extracted from fresh frozen or archival formalin-fixed paraffin-embedded (FFPE) EUS-FNB for CGP on advanced PDAC using the TSO-500 gene panel testing. Results of the CGP were reviewed at a molecular tumor board (MTB) and subsequent treatment recommendations were forwarded to the referring clinicians.ResultsCGP was successful in 129 of 143 patients (90%) enrolled between May 2020 to September 2023. Fresh frozen EUS-FNB provided suitable genetic material for CGP in 123 of 133 patients (92%). Conversely, CGP was successful on FFPE biopsy blocks from only six of 16 patients (38%). Fifty-two of 143 patients (36%) had a potentially targetable mutation detected, and eight of these patients (6%) were treated with targeted therapy based on their EUS-FNB-derived molecular profile. Patients who received personalized therapy had a significant (P< 0.0001) increase in survival versus standard or no therapy at 12 and 36 months. Median patient survival on standard therapy was 9.47 months versus > 18 months for personalized therapy.ConclusionsThis real-world study confirms the feasibility and utility of CGP using EUS-FNB in advanced PDAC. It illustrates the importance of timely access to personalized therapy informed by CGP, which can impact the treatment pathway and improve survival outcomes.

Single-cell RNA Sequencing-Based analysis of diverse ion-channel transcripts across human CD4+ T-cell subsets.

This study aimed to characterize the spectrum of germline pathogenic and likely pathogenic variants in cancer susceptibility genes among Uruguayan patients with breast, ovarian, or prostate cancer (BC, OvC, PCa) who self-funded multigene panel testing. We analyzed 119 unrelated adults (93 bc, 12 OvC, 14 PCa) who underwent clinical germline testing using commercially available next-generation sequencing panels (comprising both a 26 gene hereditary breast/ovarian subset and a comprehensive 85/90 gene panel). Variant classification followed international guidelines. Detection rates were calculated with 95% exact binomial confidence intervals. OvC and PCa cases were analyzed separately due to small sample sizes (n < 15). PGVs were found in 16/119 patients (13.4%): 10.8% in BC (10/93), 25% in OvC (3/12), and 21.4% in PCa (3/14). BRCA1/2 variants accounted for 25% of positive cases, while 61.5% involved non-BRCA genes (ATM, RAD51C, MUTYH). No recurrent founder mutations were detected, although MUTYH c.452A>G was observed in multiple unrelated individuals. Variants of uncertain significance were identified in 57% of BC patients (53/93), mostly missense variants in DNA repair genes. The mean age at diagnosis among PGV carriers was 50 years (range 32-66). The germline mutational spectrum in Uruguayan cancer patients is diverse. Most PGVs were found in genes other than BRCA1/2, supporting the use of MGPT for cancer risk assessment. Genetic testing should be considered for all cancer patients in Uruguay, regardless of ancestry or tumor type. Further research is needed to better understand the role of less-characterized genes in BC, OvC, and PCa predisposition.

Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease where current clinical practice guidelines remain focused on traditional cytogenetic markers. Despite recent advances demonstrating excellent diagnostic accuracy for gene expression signatures, a discontinuity exists between biomarker validation and clinical implementation. This study aimed to develop and validate a multiparametric gene expression signature using digital PCR (dPCR) to accurately diagnose pediatric ALL, with potential utility for monitoring measurable residual disease (MRD). We analyzed 130 bone marrow aspirates from pediatric patients from four clinical groups: non-leukemia, MRD-negative, MRD-positive and leukemia characterized by immunophenotype. Gene expression of an 8-gene panel (JUP, MYC, NT5C3B, GATA3, PTK7, CNP, ICOSLG, and SNAI1) was quantified by dPCR. The diagnostic performance of individual markers was assessed, and a Random Forest machine learning model was trained to classify active disease. The model was validated using a 5-fold stratified cross-validation approach. Individual markers, particularly JUP, MYC, and NT5C3B, showed good diagnostic accuracy for distinguishing leukemia from non-leukemia. However, integrating all eight markers into a multivariate Random Forest model significantly enhanced performance. The model achieved a mean cross-validated area under the curve (AUC) of 0.908 (±0.041) on receiver operator characteristic (ROC) analysis and 0.961 (±0.019) on Precision–Recall (PR) analysis, demonstrating high reliability and a favorable balance between sensitivity and precision. The integrated model achieved high sensitivity (88.9%) for detecting active disease, particularly at initial diagnosis. Although specificity was moderate (65.0%), the high positive predictive value (PPV 85.1%) and accuracy (81.5%) confirm the clinical utility of a positive result. While the panel showed promising performance for distinguishing MRD-positive from MRD-negative samples, the limited MRD-positive cohort size (n = 11) indicates that validation in larger MRD-focused studies is required before clinical implementation for treatment monitoring. This dPCR-based platform provides accessible, quantitative detection without requiring knowledge of clonal shifts or specific genomic landscape, offering potential advantages for resource-limited settings such as those represented in our Mexican pediatric cohort.

Targeted gene panel testing in pediatric epilepsy: Diagnostic outcomes and expanding genetic insights.

Inherited Retinal Disorders (IRDs) are a leading cause of blindness in working age adults. With the emergence of therapeutic approaches and pre-implantation genetic testing, obtaining a molecular diagnosis is increasingly important. As such we aimed to determine the caseload of IRD patients presenting to Scottish ophthalmology services over a 5-year period, and evaluated the diagnostic approaches used and results of genetic testing in order to determine any established inherited cause. Data from all patients presenting to ophthalmology services across Scotland from January 2018 to January 2023 diagnosed with an IRD were collected. History and examination findings were recorded, as were the methods of genetic testing used, the identified genetic variants and the time taken for molecular reporting. 532 patients were included in the analysis. The most common clinical diagnosis was retinitis pigmentosa (RP) (42.4%), followed by Stargardt Disease (9.0%), with Usher syndrome the most common syndromic RP. The most common initial test was a 176 gene panel, followed by direct testing for ABCA4, with different regions pursuing different testing strategies. 67.4% of patients received a molecular diagnosis. The most common causal gene was ABCA4, followed by USH2A and RDS/PRPH2. This study provides the first assessment of IRDs in Scotland over a 5 year period. We demonstrate that the most common clinical diagnoses are RP and Stargardt disease, and that the majority received a molecular diagnosis. This work provides a unique insight into the Scottish ophthalmic genetics service and serves as a benchmark for iterative improvement.