Hereditary optic atrophy is characterized by degeneration of retinal ganglion cells and may result from a wide range of genetic etiologies. While pathogenic variants in OPA1 and primary mitochondrial variants causing Leber hereditary optic neuropathy (LHON) account for a substantial proportion of cases, many patients remain genetically unsolved. We evaluated the diagnostic yield and clinical impact of comprehensive whole exome/genome sequencing (WES/WGS)-based virtual panel testing in 62 partially pre-screened individuals with suspected hereditary optic atrophy. A total of 51 genes associated with optic atrophy and mitochondrial DNA variants were analyzed. Clinical data were systematically retrieved from medical records, including information on extraocular manifestations. A genetic diagnosis was established in 21 patients (33.9%). Pathogenic or likely pathogenic variants in OPA1 accounted for 57.1% of solved cases, whereas 42.9% involved other genes, including WFS1, ACO2, NR2F1, UCHL1, CACNA1F, and COQ2. In the majority of patients with non-OPA1 findings, the genetic diagnosis prompted additional clinical evaluation, surveillance, or therapeutic intervention. Our findings demonstrate that broad WES/WGS-based testing increases diagnostic yield and expands the genetic spectrum beyond OPA1 and LHON, frequently revealing syndromic conditions with direct clinical implications. Comprehensive genomic testing with broader gene panels should therefore be considered part of the diagnostic workup when hereditary optic atrophy is suspected.

PURPOSE:To provide the first comprehensive, overview of the Danish Family Archive for Genetic Eye Diseases, a national umbrella registry on inherited eye disorders initiated in 1985. METHODS:A cross-sectional extraction of entries collected over 40 years was performed on 1 May 2025. Core variables included family identifier, clinical diagnosis, and genetic results. Descriptive statistics were generated within a secure registry environment. RESULTS:The registry contained 10,377 affected individuals from 3,412 unique families. Seventy-four distinct clinical diagnoses were documented; retinitis pigmentosa (1,709 cases) was the most frequent, followed by congenital cataract (1,220), autosomal dominant optic atrophy (1,077), congenital stationary night blindness (649) and Stargardt disease (555). Genetic data revealed 260 different disease-associated genes, the most prevalent being OPA1 (318 cases), ABCA4 (276), and USH2A (150). A confirmed genetic etiology was established for 2 972 individuals (28.6%) and in 2,052 families (60.9%). Syndromic involvement was recorded in 13%. CONCLUSIONS:The Danish Family Archive offers an unparalleled, nationwide overview of inherited eye disorders, confirming substantial diagnostic and genotypic heterogeneities. The registry data already accelerate clinical work-up and precision genetic counseling and enable rapid identification of well phenotyped and genotyped candidates for emerging therapies and clinical trials.

ATOH1 encodes a basic helix-loop-helix transcription factor critical for hindbrain development and mechanosensory system formation. While animal models have provided extensive functional insights, few human disease-causing variants in ATOH1 have been reported and with no clear functional validation. Here, we report three heterozygous frameshift variants identified in five unrelated families, leading to C-ter truncations of ATOH1 and consistently associated with hearing loss, subtle motor impairments, and a highly recognizable pattern of brainstem malformations. Diffusion tensor imaging in two individuals further revealed reproducible anomalies in specific fiber tracts, supporting a convergent neuroanatomical signature. We also report an early-truncating variant, which, in contrast, is recessive and causes a distinct neurodevelopmental syndrome with highly severe cerebellar and pontine hypoplasia. Functional assays demonstrate that, unlike recessive variants, C-terminal truncating variants retain transcriptional activity but display increased protein stability. In vivo modeling using zebrafish showed that C-terminal truncations of atoh1a are sufficient to disrupt hindbrain neurogenesis and lateral-line hair cell specification. Furthermore, comparisons with loss-of-function phenotypes support a gain-of-function mechanism. Altogether, our findings establish that dominant and recessive ATOH1 variants give rise to different neurodevelopmental syndromes through distinct pathological mechanisms. Our work also underscores the importance of tight temporal control of transcription factor activity during hindbrain development and demonstrates how even subtle neurological phenotypes can arise from early disruption of core developmental programs.

IntroductionOptic disc drusen (ODD) are believed to have a genetic predisposition, with autosomal dominant inheritance pattern with incomplete penetrance suggested through family pedigree analysis. ODD prevalence is higher in certain genetic disorders, such as pseudoxanthoma elasticum and retinitis pigmentosa. This study aimed to identify candidate genes potentially involved in the development of ODD.MethodsFamily members aged 18 years or older from families with ODD were included. Participants underwent optical coherence tomography of the optic nerve head, and blood samples were collected for whole-genome sequencing using the Illumina NovaSeq 6000 platform. Single nucleotide variants were identified with the Genome Analysis Toolkit (GATK) and filtered in VarSeq using a population frequency threshold of 1%. Selected genes were classified according to ACMG guidelines.ResultsA total of 10 families were included, three of which had more than two affected members. Thirty-three variants were identified, with the following genes selected for description: ABCC6, DDX50, TREX1, PLCB4, PTPRQ, LBR, RP1L1, and KRT3. The identified candidate genes showed a wide range of functions and are associated with different disorders. Of particular interest is ABCC6, which normally inhibits ectopic calcification.ConclusionWe identified a list of candidate genes. Studies including larger ODD families are necessary to identify robust candidate genes.

Purpose To describe the natural history of autosomal recessive IMPG2-associated retinal dystrophy. Design Multicenter international retrospective case series. Methods Review of clinical notes, retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), and molecular genetic testing, of sixty patients with molecularly confirmed IMPG2-associated retinal dystrophy from 14 tertiary eye centers. Qualitative OCT and FAF imaging analysis. Results In total, 60 patients from 52 pedigrees with likely disease-causing variants in IMPG2 from 14 tertiary referral centers in 11 countries were ascertained for phenotyping. Twenty-two patients were females (36.7%). Of those with documented age of disease onset, 23% had “late onset” (>18 years old [yo]) with a mean age of onset of 34.3 yo, and 77% had “early onset” disease (<18 yo) with a mean age of onset of 10.8 yo. Mean best-corrected visual acuity (BCVA) was 0.55 LogMAR at a mean age of 33 yo. Forty-eight percent of the patients presented with nyctalopia and 38% presented with decreased BCVA. Eighty-eight percent of the patients were myopic. Foveal involvement with atrophic changes was a common finding on OCT and FAF. Fifty-three variants were identified: 13 missense (25%), 12 nonsense (23%), 11 splicing variants (21%), 16 frameshifts (30%), and one large deletion (2%). Twenty-one (40%) of the variants were not previously clinically characterized. Conclusion Autosomal recessive IMPG2-retinal dystrophy is typically an early onset retinal dystrophy associated with poor visual acuity. Younger patients are more likely to benefit from intervention in future trials due to early macular involvement in most patients.

Objectives: To study the associations of central retinal vein occlusion (CRVO) with glaucoma and cataract before and after the onset of CRVO. Methods: This study included 439 fundus photographically verified CRVO cases and a 5:1 set of 2195 registry-based age- and sex-matched control subjects without a record of CRVO. The study assessed rates of cataract and glaucoma before and after CRVO based on diagnoses, procedures, and prescriptions and analyzed their association with CRVO. Odds ratio (OR) and incidence rate ratio (IRR) estimates for 10 years prior to a subject's first CRVO and incident comorbidity after CRVO were compared. Results: The median age at the time of presentation of 439 eligible patients with CRVO was 71 years (interquartile range 11 years). In the 10 years leading up to the incidence of CRVO, the ORs for glaucoma and cataract were 6.01 (95% confidence interval (CI95) 4.05 to 8.94) and 2.13 (CI95 1.45 to 3.12), respectively. During a mean follow-up of 5.7 years after CRVO, the incidence rate ratios for glaucoma and cataract were 16.7 (CI95 9.32-30.1) and 1.99 (CI95 1.39-2.84), respectively. Conclusions: Glaucoma and cataract occurred at elevated rates compared with the background population, both before and after the clinical presentation of CRVO. The results fit a disease model where retinal perfusion is compromised by chronic venous congestion, leading to glaucomatous retinal degeneration. Chronic venous congestion may subsequently convert to clinically manifest CRVO when retinal capillaries have been sufficiently weakened to produce hemorrhage, edema and vision loss.

PURPOSE:We lack knowledge on the potentially progressive nature of and the prevalence of complications to myopia as a characteristic trait of Stickler syndrome. METHODS:This cross-sectional study combines ophthalmic examination and medical record data on Danish patients with genetically confirmed Stickler syndrome type 1 (COL2A1) and type 2 (COL11A1). The main outcomes are axial length, spherical equivalent refraction (SER), SER over time, and myopic maculopathy category by fundus photography. RESULTS:The study includes 71 patients with type 1 (age: median = 29 years, IQR = 15-49 years; 44% male) and 13 with type 2 Stickler syndrome (age: median = 27 years, IQR = 9-33 years; 69% male). For type 1, the median SER was -6.00 dioptres (D) (IQR = -8.88 to -2.19 D) and -6.75. (IQR = -10.88 to -1.94) for type 2, (p = 0.52). Mean axial length was 25.99 ± 1.99 and 26.55 ± 3.45 mm, respectively (p = 0.57). SER was nonprogressive in childhood in both subtypes. Myopic maculopathy was present in 28 (43%) type 1 and five (42%) type 2 patients. The odds for higher category myopic maculopathy increased by a factor of 2.15 with each mm of axial elongation (95% CI = 1.14 to 4.04, p = 0.02) but not with age (odds ratio = 1.02 per year, 95% CI = 0.97 to 1.09, p = 0.39) in type 1. CONCLUSION:We find myopia in our cohort is nonprogressive. We find no difference in axial length or refractive error between subtypes. Myopic maculopathy is common, its severity depending on axial length, not age. These findings are relevant for risk stratification of vision-threatening myopia.

KITLG pathogenic variants have been associated to three distinct clinical presentations with different combinations of hearing loss and/or pigmentation abnormalities. However, its involvement in isolated hearing loss has not been confirmed since its initial description in two families. Besides, KITLG is so far the only gene prevailingly involved in unilateral isolated hearing loss. We therefore conducted a retrospective study of patients with KITLG alterations in the French national Reference Network for Genetic Hearing Loss and one case was added through the Genematcher exchange platform. We describe a series of monoallelic KITLG deletions and variations in a cohort of 14 symptomatic patients from eight unrelated families. All patients presented with unilateral, bilateral symmetric or asymmetric sensorineural hearing loss. When not profound, hearing loss was predominant on low frequencies. Most KITLG alterations are likely to result in loss-of-function and aggregate in the extracellular region, disrupting the KIT-binding domain or its structure. Penetrance is not complete, and unspecific pigmentation alterations were observed in only three patients. The present study confirms KITLG involvement in isolated unilateral, bilateral symmetric or asymmetric hearing loss. This confirmation indicates that genetic testing can be relevant in early-onset, non-sudden, isolated unilateral hearing loss.

IntroductionRetinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive photoreceptor degeneration. In a recent study, we reported co-existing optic disc drusen (ODD) at 30%, a prevalence 15 times higher than in the general population. The aims of this study were to a) assess if macular retinal nerve fiber layer thickness (RNFLt) was increased in our cohort of RP patients and b) compare RNFLt between RP patients with and without ODD.MethodsIn this post-hoc analysis, optical coherence tomography (OCT) scans of patients with RP and healthy controls were manually delineated, and macular RNFLt measurements were obtained. The analyses were conducted both a) for RP patients without ODD compared to controls and b) for RP patients with and without ODD.ResultsOCT scans of 32 patients with RP and 13 healthy controls were included. Macular RNFLt was significantly increased in RP patients compared to healthy controls and in RP patients with ODD compared to RP patients without ODD.DiscussionFurther studies will explore whether increased RNFLt leads to ODD development through dystrophic calcification or, conversely, if ODD in combination with RP-associated retinal ganglion cell damage causes the increased RNFLt through retrograde axoplasmic stasis.

We present an image that illustrates long-term visual field progression in patients with X-linked retinitis pigmentosa (XLRP) due to the retinitis pigmentosa GTPase regulator (RPGR) and retinitis pigmentosa 2 protein (RP2) gene variants. Longitudinal data from 84 genetically confirmed XLRP patients were collected from the Danish Retinitis Pigmentosa Registry, spanning the years 1948 to 2014. A visual field summation image revealed the characteristic pattern of retinal degeneration and visual field preservation in XLRP.

PURPOSE:To describe the phenotype of Danish patients with genetically verified achromatopsia (ACHM) with special focus on signs of progression on structural or functional parameters, and possible genotype-phenotype correlations. METHODS:Forty-eight patients were identified, with disease-causing variants in five different genes: CNGA3, CNGB3, GNAT2, PDE6C and PDE6H. Longitudinal evaluation was possible for 11 patients and 27 patients participated in a renewed in-depth phenotyping consisting of visual acuity assessment, optical coherence tomography (OCT), fundus autofluorescence, colour vision evaluation, contrast sensitivity, mesopic microperimetry and full-field electroretinography. Foveal morphology was evaluated based on OCT images for all 48 patients using a grading system based on the integrity of the hyperreflective photoreceptor band, the inner segment ellipsoid zone (ISe). Signs of progression were evaluated based on longitudinal data and correlation with age. RESULTS:We found a statistically significant positive correlation between OCT grade and age (Spearman ρ = 0.62, p < 0.0001) and we observed changes in the foveal morphology in 2 of 11 patients with ≥5 years of follow-up. We did not find any convincing correlation between age and functional parameters (visual acuity, retinal sensitivity and contrast sensitivity) nor did we find correlation between structural and functional parameters, or any clear genotype-phenotype correlation. CONCLUSIONS:Some patients with ACHM demonstrate signs of progressive foveal changes in OCT characteristics with increasing age. This is relevant in terms of possible new treatments. However, functional characteristics, such as visual acuity, remained stable despite changing foveal structure. Thus, seen from a patient perspective, ACHM can still be considered a non-progressive condition.

Optic disc drusen (ODD) may present in multiple individuals and generations within a family, indicating hereditary predisposition. Individuals are often unaware of their ODD, and consequently, the prevalence of ODD within families remains largely unknown. The aim of this study was to estimate the prevalence and consider the inheritance pattern of familial ODD and to investigate ODD-related symptoms and their association to ODD location and size. In this cross-sectional study, 22 ODD patients, aged 10 years or older, were included. Of these, 13 ODD probands had 24 family members participating. The presence, size, and anatomical location of ODDs and the presence of hyperreflective lines were ascertained using enhanced depth imaging optical coherence tomography (EDI-OCT) scan. Visual symptoms were ascertained, and these were correlated with ODD burden in terms of ODD location and size. Familial ODD was found in eight of the 13 screened families. Hyperreflective lines were present in all individuals with ODD, including both probands and their family members, and in seven out of the 14 family members without ODD. Visual symptoms were reported in 14-50% and associated significantly with superficial ODD location. We found familial ODD in eight of the 13 screened families. Our results aligned with the previously suggested autosomal dominant inheritance pattern with incomplete penetrance, assuming that hyperreflective lines represent a less expressed form of ODD. This emphasizes that ODD runs in families and supports the hypothesis that genetic factors may contribute to the etiology.

Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This natural history study aimed to further explore the course of disease and potential clinical differences between various genotypes. The retrospective design allowed for the study of a large cohort with a long follow-up. Patients were identified from the Danish national registries. If not already available, genetic analysis was offered to the patient. Clinical data from 1945-2022 were retrieved from medical records and included best-corrected visual acuity (BCVA), color vision, refractive error, nystagmus, visual fields and fundoscopic findings. We identified variants believed to be disease causing in five of the known achromatopsia genes: CNGA3; CNGB3; GNAT2; PDE6C and PDE6H; and novel variants were identified in CNGB3 and PDE6C. Progressive deterioration of BCVA only attributable to achromatopsia was found in three of 58 patients. Progressive phenotype was seen with variants in CNGB3 and PDE6C. The results indicate that myopia could be more frequently occurring with variants in GNAT2, PDE6C and PDE6H and support the evidence that achromatopsia is a predominantly stationary condition with respect to BCVA. Although a clear genotype-phenotype correlation can still not be concluded, there may be differences in phenotypical characteristics with variants in different genes.

Genetic conditions are often familial, but not all relatives receive counseling from the same institution. It is therefore necessary to ensure consistency in variant interpretation, counseling practices, and clinical follow up across health care providers. Furthermore, as new possibilities for gene-specific treatments emerge and whole genome sequencing becomes more widely available, efficient data handling and knowledge sharing between clinical laboratory geneticists and medical specialists in clinical genetics are increasingly important. In Denmark, these needs have been addressed through the establishment of collaborative national networks called Genetic Expert Networks or "GENets". These networks have enhanced patient and family care significantly by bringing together groups of experts in national collaborations. This promotes coordinated clinical care, the dissemination of best clinical practices, and facilitates the exchange of new knowledge.

Background/aim: To describe the clinical phenotype of retinitis pigmentosa (RP) caused by PRPF31-variants and clinical characterization of asymptomatic PRPF31 carriers. Materials and methods: We conducted a descriptive cross-sectional deep phenotyping study. We included subjects with PRPF31 variants predicted to be disease-causing, both individuals with RP and asymptomatic carriers. Participants underwent a comprehensive clinical examination of standard visual function parameters (visual acuity, contrast sensitivity, Goldmann visual field), full-field stimulus threshold (FST), full-field electroretinogram (ff-ERG), and a structural investigation with slit lamp and multimodal imaging. We used Spearman correlation analyses to evaluate associations between quantitative outcomes. Results: We included 21 individuals with disease-causing PRPF31-variants: 16 symptomatic and 5 asymptomatic subjects. The symptomatic subjects demonstrated a typical RP phenotype with constricted visual fields, extinguished ff-ERG, and disrupted outer retinal anatomy. FST was impaired and correlated significantly with other outcome measures in RP subjects. Structure-function correlations with Spearman correlation analysis showed moderate correlation coefficients due to a few outliers in each analysis. The asymptomatic individuals had normal best-corrected visual acuity and visual fields, but showed reduced ff-ERG amplitudes, borderline FST sensitivity, and structural abnormalities on OCT and fundoscopy. Conclusions: RP11 has a typical RP phenotype but varies in terms of severity. FST measurements correlated well with other functional and structural metrics and may be a reliable outcome measure in future trials as it is sensitive to a broad range of disease severities. Asymptomatic carriers showed subclinical disease manifestations, and our findings underline that reported non-penetrance in PRPF31-related RP is not an all-or-none phenomenon.

Background: Studies of patients with retinitis pigmentosa (RP) have reported an increased prevalence of optic disc drusen (ODD) compared with the ODD prevalence in the general population. The diagnostic gold standard method for identifying ODD is enhanced depth imaging optical coherence tomography (EDI-OCT), but this modality has not previously been used systematically for identifying ODD in patients with RP. This study aimed to estimate the prevalence of ODD in patients with RP using EDI-OCT. Methods: In this cross-sectional study, 40 patients with clinically diagnosed RP aged 18 years or older were included. All patients underwent an ophthalmic examination, including kinetic perimetry, EDI-OCT of the optic nerve head, and fundus photography. Genetic testing with a next-generation sequencing panel of retinal dystrophy genes was performed on the RP patients without a prior genetic diagnosis. Results: Twelve patients (30.0%) had at least one ODD. Six patients had bilateral ODD. No significant differences between patients with and without ODD were found according to age, refraction, best-corrected visual acuity, Bruch membrane opening, or visual field. The genetic variation causing RP was found in 11 of 12 cases in the ODD group and in 17 of 28 cases in the group without ODD. Conclusions: We found the prevalence of ODD in patients with RP to be 30.0%. This is 15 times higher than in the general population and much higher than previously estimated in most studies, potentially indicating that the 2 conditions might be pathogenically related.

(1) Background/aims: To examine potential genetic modifiers of disease penetrance in PRPF31-associated retinitis pigmentosa 11 (RP11). (2) Methods: Blood samples from individuals (n = 37) with PRPF31 variants believed to be disease-causing were used for molecular genetic testing and, in some cases (n = 23), also for mRNA expression analyses. Medical charts were used to establish if individuals were symptomatic (RP) or asymptomatic non-penetrant carriers (NPC). RNA expression levels of PRPF31 and CNOT3 were measured on peripheral whole blood using quantitative real-time PCR normalized to GAPDH. Copy number variation of minisatellite repeat element 1 (MSR1) was performed with DNA fragment analysis. (3) Results: mRNA expression analyses on 22 individuals (17 with RP and 5 non-penetrant carriers) revealed no statistically significant differences in PRPF31 or CNOT3 mRNA expression levels between individuals with RP and non-penetrant carriers. Among 37 individuals, we found that all three carriers of a 4-copy MSR1 sequence on their wild-type (WT) allele were non-penetrant carriers. However, copy number variation of MSR1 is not the sole determinant factor of non-penetrance, as not all non-penetrant carriers carried a 4-copy WT allele. A 4-copy MSR1 mutant allele was not associated with non-penetrance. (4) Conclusions: In this Danish cohort, a 4-copy MSR1 WT allele was associated with non-penetrance of retinitis pigmentosa caused by PRPF31 variants. The level of PRPF31 mRNA expression in peripheral whole blood was not a useful indicator of disease status.