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Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous PTHR1 variants resulting in constitutive activation of parathyroid hormone type 1 receptor. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing, and craniofacial CT scans. Five of 6 patients had good visual acuity. All patients had widely spaced eyes; 5/6 had downslanted palpebral fissures. One patient had proptosis, and another had bilateral ptosis. Two patients had incomplete closure of the eyelids (lagophthalmos), one had a history of progressive right facial nerve palsy with profuse epiphora, while the second had advanced optic nerve atrophy with corresponding retinal nerve fiber layer (RNFL) thinning on OCT and significant bilateral optic canal narrowing on CT scan. Additionally, this patient also had central visual field defects and abnormal color vision. A third patient had normal visual acuity, subtle temporal pallor of the optic nerve head, normal average RNFL, but decreased temporal RNFL and retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4/6 patients indicating a subclinical optic nerve atrophic process. None of the patients had glaucoma or high myopia. These data represent the first comprehensive report of ophthalmic findings in JMC. Patients with JMC have significant eye findings associated with optic canal narrowing due to extensive skull base dysplastic bone overgrowth that appear to be more prevalent and pronounced with age. Progressive optic neuropathy from optic canal narrowing may be a feature of JMC, and OCT GCA can serve as a useful biomarker for progression in the setting of optic canal narrowing. We suggest that patients with JMC should undergo regular ophthalmic examination including color vision, OCT, visual field testing, orbital, and craniofacial imaging. Lay Summary: Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by overactivity of the parathyroid hormone type 1 receptor, a receptor that is important for regulating bone development. Some patients report eye problems, but these have not been well-described. We therefore performed extensive eye examinations in 6 individuals with JMC. One had progressive right-sided facial paralysis associated with eye-tearing and dryness. A second individual had decreased central vision. Using optical coherence tomography (OCT), a method which takes detailed pictures of the retina, we found thinning of the retina's nerve layers (RNFL). Computed tomography (CT) of the skull showed narrowing of the bony canal through which the optic nerve passes. A third individual had normal vision but RNFL thinning just on the sides. Analysis of ganglion cells, the nerve cells carrying signals from the retina to the brain, showed localized deterioration of the optic nerve; skull CT also revealed optic canal narrowing. These findings suggest that JMC is associated with progressive damage to the optic nerve. Thus, patients with JMC would benefit from regular eye exams including OCT and visual field testing, in addition to routine imaging. Graphical Abstract [ABSTRACT FROM AUTHOR]

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker. [ABSTRACT FROM AUTHOR]

Background/Aims To characterise the ocular manifestations of Williams-Beuren syndrome (WBS) and compare these to patients with isolated elastin mediated supravalvular aortic stenosis (SVAS). Methods Fifty-seven patients with a diagnosis of WBS and five with SVAS underwent comprehensive ophthalmic evaluation at the National Institutes of Health from 2017 to 2020, including best-corrected visual acuity, slit-lamp biomicroscopy, optical biometry, dilated fundus examination, optical coherence tomography and colour fundus imaging. Results Mean age of the 57 WBS patients was 20.3 years (range 3–60 years). Best-corrected visual acuity ranged from 20/20 to 20/400 with mean spherical equivalent near plano OU. Twenty-four eyes (21.8%) had an axial length (AL) less than 20.5mm and 38 eyes (34.5%) had an AL measuring 20.5–22.0mm. Stellate iris and retinal arteriolar tortuosity were noted in 30 (52.6%) and 51 (89.5%) WBS patients, respectively. Novel retinal findings in WBS included small hypopigmented retinal deposits (OD 29/57, OS 27/57) and broad foveal pit contour (OD 44/55, OS 42/51). Of the five patients with SVAS, none had stellate iris or broad foveal pit contour while 2/5 had retinal arteriolar tortuosity. Conclusion WBS is a complex multisystem genetic disorder with diverse ophthalmic findings that differ from those seen in isolated elastin mediated SVAS. These results suggest other genes within the WBS critical region, aside from ELN, may be involved in observed ocular phenotypes and perhaps broader ocular development. Furthermore, retinal arteriolar tortuosity may provide future insight into systemic vascular findings in WBS. [ABSTRACT FROM AUTHOR]

Objectives: To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease.Methods: This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling.Results: The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow.Conclusion: ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy. [ABSTRACT FROM AUTHOR]

Regional phenotypic and functional differences in the retinal pigment epithelium (RPE) monolayer have been suggested to account for regional susceptibility in ocular diseases such as age-related macular degeneration (AMD), late-onset retinal degeneration (L-ORD), and choroideremia (CHM). However, a comprehensive description of human topographical RPE diversity is not yet available, thus limiting the understanding of regional RPE diversity and degenerative disease sensitivity in the eye. To develop a complete morphometric RPE map of the human eye, artificial intelligence–based software was trained to recognize, segment, and analyze RPE borders. Five statistically different, concentric RPE subpopulations (P1 to P5) were identified using cell area as a parameter, including a subpopulation (P4) with cell area comparable to that of macular cells in the far periphery of the eye. This work provides a complete reference map of human RPE subpopulations and their location in the eye. In addition, the analysis of cadaver non-AMD and AMD eyes and ultra-widefield fundus images of patients revealed differential vulnerability of the five RPE subpopulations to different retinal diseases. [ABSTRACT FROM AUTHOR]

The retinal dystrophy phenotype associated with CDHR1 retinopathy is clinically heterogenous. In this study, we describe the clinical and molecular findings of a retinal dystrophy cohort (10 patients) attributed to autosomal recessive CDHR1 and report novel variants in populations not previously identified with CDHR1-related retinopathy. Seven patients had evaluations covering at least a three-year period. The mean age of individuals at first symptoms was 36 ± 8.5 years (range 5–45 years). Visual acuity at the last visit ranged from 20/20 to 20/2000 (mean LogMAR 0.8 or 20/125). Three clinical subgroups were identified: rod–cone dystrophy (RCD), cone–rod dystrophy (CRD), and maculopathy. Extinguished scotopic electroretinography responses were noted in the RCD patients. Macular involvement was noted in all patients and documented on color fundus photography, fundus autofluorescence, and optical coherence tomography. Notable asymmetry of the degree of macular atrophy was present in two patients. The possible association between CDHR1 variants and clinical findings was predicted using molecular modeling. [ABSTRACT FROM AUTHOR]

Aim To describe the ophthalmologic findings on the largest cohort of patients with sialidosis type I due to deficiency of the lysosomal sialidase, neuraminidase 1 (NEU1) and to introduce a quantitative neuroretinal image analysis approach to the associated 'macular cherry-red spot'. Methods Seven patients with sialidosis type I (mutations in NEU1) and one with galactosialidosis (mutations in CTSA) were included. All patients underwent detailed ophthalmological examinations. The reflectivity of macular optical coherence tomography (OCT) was measured using greyscale analysis (Fiji) and compared with age-matched healthy volunteers. Four patients were evaluated over a time of 1.5+0.5 years. Results The mean age of the patients at their first visit was 27.5+9.8 years. All patients had a macular cherry-red spot, clear corneas and visually non-significant lenticular opacities. The mean visual acuity was LogMar 0.4 (20/50) +0.4 (20/20 to 20/125). Six patients had good visual function. Optic atrophy was present in two individuals with reduced acuity. A significant increase in macular reflectivity was present in all patients compared to agematched controls (p<0.0001). Conclusion Most of our patients (75%) have preserved visual acuity, even in adulthood. The presence of optic atrophy is associated with poor visual acuity. Increased macular reflectivity by OCT greyscale measurements is noted in all patients, although the underlying biological basis is unknown. These findings complement the current methods for examining and monitoring disease progression, especially in patients for whom visualisation of the cherry-red spot is not entirely clear. [ABSTRACT FROM AUTHOR]

Dark cone photoreceptors, defined as those with diminished or absent reflectivity when observed with adaptive optics (AO) ophthalmoscopy, are increasingly reported in retinal disorders. However, their structural and functional impact remain unclear. Here, we report a 3-year longitudinal study on a patient with oligocone trichromacy (OT) who presented with persistent, widespread dark cones within and near the macula. Diminished electroretinogram (ERG) cone but normal ERG rod responses together with normal color vision confirmed the OT diagnosis. In addition, the patient had normal to near normal visual acuity and retinal sensitivity. Occasional dark gaps in the photoreceptor layer were observed on optical coherence tomography, in agreement with reflectance AO scanning light ophthalmoscopy, which revealed that over 50% of the cones in the fovea were dark, increasing to 74% at 10° eccentricity. In addition, the cone density was 78% lower than normal histologic value at the fovea, and 20–40% lower at eccentricities of 5–15°. Interestingly, color vision testing was near normal at locations where cones were predominantly dark. These findings illustrate how a retina with predominant dark cones that persist over at least 3 years can support near normal central retinal function. Furthermore, this study adds to the growing evidence that cones can continue to survive under non-ideal conditions. [ABSTRACT FROM AUTHOR]

Background/Aims. Optic disc drusen (ODD) are calcified deposits of proteinaceous material in the optic disc, and their burden in ocular conditions is unknown. As ODD can be associated with visual field defects further compromising already degenerating visual function in patients with retinal degenerations, it is important to further our knowledge of ODD in inherited eye disease. The present study aims to evaluate prevalence, demographic features, and optic disc parameters of eyes with superficial ODD in inherited eye conditions. Materials and Methods. Electronic medical records of patients evaluated in the Ophthalmic Genetics clinic at the National Eye Institute (NEI) between 2008 and 2018 were searched for a superficial ODD diagnosis. Color fundus and autofluorescence images were reviewed to confirm ODD, supplemented with optical coherence tomography (OCT) in uncertain cases when available. Demographic information, examination, and genetic testing were reviewed. Disc areas and disc-to-macula distance to disc diameter ratios (DM : DD) were calculated. Results. Fifty six of 6207 patients had photographically confirmed ODD (0.9%). Drusen were predominantly bilateral (66%), with a female (62%) and Caucasian (73%) predilection. ODD prevalence in our cohort of patients with inherited retinal degenerations was 2.5%, and ODD were more prevalent in the rod-cone dystrophy subgroup at 2.95% (OR = 3.3 [2.1–5.3], P < 0.001) compared to the ophthalmic genetics cohort. Usher patients were more likely to have ODD (10/132, 7.6%, OR = 9.0 [4.3–17.7], P < 0.001) and had significantly smaller discs compared to the rest of our ODD cohort (disc area: P = 0.001 , DM : DD: P = 0.03). Discussion. While an association between ODD and retinitis pigmentosa has been reported, this study surveys a large cohort of patients with inherited eye conditions and finds the prevalence of superficial ODD is lower than that in the literature. Some subpopulations, such as rod-cone dystrophy and Usher syndrome, had a higher prevalence than the cohort as a whole. [ABSTRACT FROM AUTHOR]

Jalili syndrome is a rare multisystem disorder with the most prominent features consisting of cone‐rod dystrophy and amelogenesis imperfecta. Few cases have been reported in the Americas. Here we describe a case series of patients with Jalili syndrome examined at the National Eye Institute's Ophthalmic Genetics clinic between 2016 and 2018. Three unrelated sporadic cases were systematically evaluated for ocular phenotype and determined to have cone‐rod dystrophy with bull's eye maculopathy, photophobia, and nystagmus. All patients had amelogenesis imperfecta. Two of these patients had Guatemalan ancestry and the same novel homozygous CNNM4 variant (p.Arg236Trp c.706C > T) without evidence of consanguinity. This variant met likely pathogenic criteria by the American College of Medical Genetics guidelines. An additional patient had a homozygous deleterious variant in CNNM4 (c.279delC p.Phe93Leufs*31), which resulted from paternal uniparental isodisomy for chromosome 2p22‐2q37. This individual had additional syndromic features including developmental delay and spastic diplegia, likely related to mutations at other loci. Our work highlights the genotypic variability of Jalili syndrome and expands the genotypic spectrum of this condition by describing the first series of patients seen in the United States. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma–related oncogene (SCCRO, also known as DCUN1D1) is a component of the E3 for neddylation. As such, DCUN1D1 regulates the neddylation of cullin family members. Targeted inactivation of DCUN1D1 in mice results in male-specific infertility. Infertility in DCUN1D1-/- mice is secondary to primary defects in spermatogenesis. Time-dam experiments mapped the onset of the defect in spermatogenesis to 5.5 to 6 weeks of age, which temporally corresponds to defects in spermiogenesis. Although the first round of spermatogenesis progressed normally, the number of spermatozoa released into the seminiferous lumen and epididymis of DCUN1D1-/- mice was significantly reduced. Spermatozoa in DCUN1D1-/- mice had multiple abnormalities, including globozoospermia, macrocephaly, and multiple flagella. Many of the malformed spermatozoa in DCUN1D1-/- mice were multinucleated, with supernumerary and malpositioned centrioles, suggesting a defect in the resolution of intercellular bridges. The onset of the defect in spermatogenesis in DCUN1D1-/- mice corresponds to an increase in DCUN1D1 expression observed during normal spermatogenesis. Moreover, consistent with its known function as a component of the E3 in neddylation, the pattern of DCUN1D1 expression temporally correlates with an increase in the neddylated cullin fraction and stage-specific increases in the total ubiquitinated protein pool in wild-type mice. Levels of neddylated Cul3 were decreased in DCUN1D1-/- mice, and ubiquitinated proteins did not accumulate during the stages in which DCUN1D1 expression peaks during spermatogenesis in wild-type mice. Combined, these findings suggest that DCUN1D1-/- mice fail to release mature spermatozoa into the seminiferous lumen, possibly due to unresolved intercellular bridges. Furthermore, the effects of DCUN1D1 on spermatogenesis likely involve its regulation of cullin-RING-ligase (CRL)–type ubiquitin E3 activity during spermiogenesis through its role in promoting Cul3 neddylation. The specific CRLs required for spermiogenesis and their protein targets require identification. [ABSTRACT FROM AUTHOR]

Heřmanský–Pudlák syndrome (HPS), a rare autosomal recessive disorder, manifests with oculocutaneous albinism and a bleeding diathesis. However, severity of disease can be variable and is typically related to the genetic subtype of HPS; HPS type 6 (HPS‐6) is an uncommon subtype generally associated with mild disease. A Caucasian adult female presented with a history of severe bleeding; ophthalmologic examination indicated occult oculocutaneous albinism. The patient was diagnosed with a platelet storage pool disorder, and platelet whole mount electron microscopy demonstrated absent delta granules. Genome‐wide SNP analysis showed regions of homozygosity that included the HPS1 and HPS6 genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next‐generation sequencing identified a novel homozygous missense variant in HPS6 (c.383 T > C; p.V128A); this was associated with significantly reduced HPS6 mRNA and protein expression in the patient's fibroblasts compared to control cells. These findings highlight the variable severity of disease manifestations in patients with HPS, and illustrate that HPS can be diagnosed in patients with excessive bleeding and occult oculocutaneous albinism. Genetic analysis and platelet electron microscopy are useful diagnostic tests in evaluating patients with suspected HPS. Clinical Trial registration: Registrar: ClinicalTrials.gov Website: www.clinicaltrials.gov Registration Numbers: NCT00001456 and NCT00084305. [ABSTRACT FROM AUTHOR]

Introduction: It is important to understand albinism, since it is a disorder associated with visual impairment, predisposition to malignant melanomas, and social stigma. The main objective of this article is to review the genetics and biologic mechanisms of the non-syndromic albinism subtypes and to describe associated clinical manifestations. We also discuss research on its treatments. Methods: A review of the published literature on albinism subtypes was performed, spanning basic laboratory research, published case reports, and experiences of people with albinism. Results: Clear progress has been made in comprehending the causes of albinism; research has shed light on the complexity of the disorder and has led to the molecular classification of subtypes. Discussion: Despite the increase in knowledge with regards to albinism, gaps still exist. It is important to continue the pursuit of unraveling the mechanism of the disorder and to monitor the frequency of the subtypes worldwide in order to aid in the development of treatments. Furthermore, disseminating knowledge of albinism is crucial for future progress. Implications for practitioners: Albinism is a disorder characterized by hypopigmentation of the hair, skin, and eyes, with accompanying ocular abnormalities that remain relatively stable throughout life. The disorder is defined by a spectrum of pigmentation where albinism is more evident among individuals of dark complexion than their lighter-pigmented peers. Patients with albinism require protection against sun exposure and special resources to address visual impairments. When albinism patients are diagnosed and properly accommodated, they generally report a positive quality of life. [ABSTRACT FROM AUTHOR]

Intravitreal injection of antisense oligonucleotides targeting mutated Ataxin-7 improves visual function in a mouse model of spinocerebellar ataxia type 7. Improving vision in spinocerebellar ataxia: Spinocerebellar ataxia type 7 (SCA7) is a genetic disorder caused by mutations in the ATAXIN-7 gene. SCA7 is characterized by impairments in coordination, balance, and speech and by retinal degeneration that results in complete blindness. Here, Niu et al. developed a strategy for treating visual impairments in SCA7 by inhibiting the mutated Ataxin-7 in the retina using antisense oligonucleotides (ASOs). Intravitreal injection of ASOs specifically targeting the mutated Ataxin-7 reduced protein expression in the retina and ameliorated pathology and vision loss in a SCA7 mouse model. The results suggest that ASOs targeting ATAXIN-7 might be effective in treating retinal degeneration in patients with SCA7. Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by cerebellar and retinal degeneration, and is caused by a CAG-polyglutamine repeat expansion in the ATAXIN-7 gene. Patients with SCA7 develop progressive cone-rod dystrophy, typically resulting in blindness. Antisense oligonucleotides (ASOs) are single-stranded chemically modified nucleic acids designed to mediate the destruction, prevent the translation, or modify the processing of targeted RNAs. Here, we evaluated ASOs as treatments for SCA7 retinal degeneration in representative mouse models of the disease after injection into the vitreous humor of the eye. Using Ataxin-7 aggregation, visual function, retinal histopathology, gene expression, and epigenetic dysregulation as outcome measures, we found that ASO-mediated Ataxin-7 knockdown yielded improvements in treated SCA7 mice. In SCA7 mice with retinal disease, intravitreal injection of Ataxin-7 ASOs also improved visual function despite initiating treatment after symptom onset. Using color fundus photography and autofluorescence imaging, we also determined the nature of retinal degeneration in human SCA7 patients. We observed variable disease severity and cataloged rapidly progressive retinal degeneration. Given the accessibility of neural retina, availability of objective, quantitative readouts for monitoring therapeutic response, and the rapid disease progression in SCA7, ASOs targeting ATAXIN-7 might represent a viable treatment for SCA7 retinal degeneration. [ABSTRACT FROM AUTHOR]

Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of genetic disorders typically manifesting with tyrosinase-positive oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis, in some subtypes. Most HPS subtypes are associated with defects in Biogenesis of Lysosome-related Organelle Complexes (BLOCs), which are groups of proteins that function together in the formation and/or trafficking of lysosomal-related endosomal compartments. BLOC-2, for example, consists of the proteins HPS3, HPS5, and HPS6. Here we present an HPS patient with defective BLOC-2 due to a novel intronic mutation in HPS5 that activates a cryptic acceptor splice site. This mutation leads to the insertion of nine nucleotides in-frame and results in a reduced amount of HPS5 at the transcript and protein level. In studies using skin fibroblasts derived from the proband and two other individuals with HPS-5, we found a perinuclear distribution of acidified organelles in patient cells compared to controls. Our results suggest the role of HPS5 in the endo-lysosomal dynamics of skin fibroblasts. [ABSTRACT FROM AUTHOR]

Fanconi anemia is an autosomal recessive disorder characterized by congenital malformations, bone marrow failure, and the development of squamous cell carcinomas (SCCs) and other cancers. Recent clinicopathologic evidence has raised the possibility that an environmental factor such as human papillomavirus (HPV) may be involved in the pathogenesis of SCCs in Fanconi anemia patients. Given the high prevalence of p53 mutations in SCCs among the general population and the lack of p53 mutations in HPV-related carcinogenesis, we evaluated the role of HPV and p53 mutations and polymorphisms in SCC from Fanconi anemia patients. We used polymerase chain reaction (PCR) screening and real-time PCR to detect and quantify HPV DNA in DNA extracted from microdissected SCCs obtained from 24 Fanconi anemia patients (n = 25 SCCs; case subjects) and 50 age-, sex-, and tumor site-matched SCC patients without Fanconi anemia (n = 50 SCCs; control subjects). We PCR-amplified and sequenced exons 4-9 of the p53 gene from SCC DNA. We detected HPV DNA in 84% of the SCC specimens from the case subjects and in 36% of the SCC specimens from the control subjects (P<.001). The prevalence of p53 mutations in SCCs from the case subjects (0%, 0/25) was statistically significantly lower than that of SCCs from the control subjects (36%, 12/33; P<.001). A greater proportion of patients with Fanconi anemia and SCC were homozygous for Arg72, a p53 polymorphism that may be associated with increased risk for HPV-associated human malignancies, than an ethnically-matched cohort of Fanconi anemia patients without SCC (75% versus 51%; P =.05). These data suggest that Fanconi anemia is associated with increased susceptibility to HPV-induced carcinogenesis. [ABSTRACT FROM AUTHOR]

Nanophthalmos is a rare condition defined by a small, structurally normal eye with resultant high hyperopia. While six genes have been implicated in this hereditary condition (MFRP, PRSS56, MYRF, TMEM98, CRB1,VMD2/BEST1), the relative contribution of these to nanophthalmos or to less severe high hyperopia (≥ + 5.50 spherical equivalent) has not been fully elucidated. We collected probands and families (n = 56) with high hyperopia or nanophthalmos (≤ 21.0 mm axial length). Of 53 families that passed quality control, plausible genetic diagnoses were identified in 10/53 (18.8%) by high-throughput panel or pooled exome sequencing. These include 1 TMEM98 family (1.9%), 5 MFRP families (9.4%), and 4 PRSS56 families (7.5%), with 4 additional families having single allelic hits in MFRP or PRSS56 (7.5%). A novel deleterious TMEM98 variant (NM_015544.3, c.602G>C, p.(Arg201Pro)) segregated with disease in 4 affected members of a family. Multiple novel missense and frameshift variants in MFRP and PRSS56 were identified. PRSS56 families were more likely to have choroidal folds than other solved families, while MFRP families were more likely to have retinal degeneration. Together, this study defines the prevalence of nanophthalmos gene variants in high hyperopia and nanophthalmos and indicates that a large fraction of cases remain outside of single gene coding sequences. [ABSTRACT FROM AUTHOR]

Purpose: In 2006 Warburg et al. described a patient with blepharophimosis, corneal vascularization, retinal degeneration, deafness, loss of subcutanous tissue, flexion contractures of the fingers and acro‐osteolysis. Some years later Cinotti et al. reported a similar patient. In addition, we identified tree individuals from two different families with a similar clinical picture. In total, all six individuals from four different families were examined to identify the gene mutation associated with this disease Methods: Exome sequencing was performed on affected individuals. Patient skin fibroblasts was obtained and examined using Elisa and Western blot analysis to determine levels of phosphorylated DDR2 and downstream effector proteins. Patient fibroblasts were also treated with Dasatabib, a protein kinase inhibitor affecting DDR2. Results: We found two recurrent de novo mutations in DDR2, p.Leu610Pro or p.Tyr740Cys, to be associated with the condition. Increased phosphorylation of DDR2 was found suggesting reduced receptor autoinhibition and ligand‐independent activation of the kinase. Dasatinib prevented DDR2 autophosphorylation. No effect of the mutations were found on the examined downstream effector proteins of DRR2. Conclusion: We found two recurrent, activating mutations in DDR2, p.Leu610Pro and p.Tyr740Cys, to be associated with this progressive fibrotic condition that we suggest to be called Warburgh‐Cinotti syndrome. In vitro dasatinib prevented autophosphorylation of DDR2 suggesting an approach to patient treatment. Reference: Xu et al. (2018): Recurrent, activating variants in the recetor tyrosine kinase DDR2 cause Warburg‐Cinotti syndrome. The American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2018.20.013. [ABSTRACT FROM AUTHOR]

Visualizing the cellular manifestation of disease has recently been aided by an increasing number of adaptive optics (AO)-based imaging modalities developed for the living human eye. However, simultaneous visualization of multiple, interacting cell types within a complete neural–epithelial–vascular complex has proven challenging. By incorporating AO with indocyanine green angiography, we demonstrate the possibility of imaging photoreceptors, retinal pigment epithelial cells, and choriocapillaris in the living human eye. Unexpectedly, we found that there was uptake of indocyanine green dye into the retinal pigment epithelial cells in the earliest phases of imaging, which formed the basis for devising a strategy to visualize the choriocapillaris. Our results expand the range of applications for an existing, FDA-approved, systemically injected fluorescent dye. The combined multimodal approach can be used to evaluate the complete outer retinal complex at the cellular level, a transformative step toward revealing the in vivo cellular status of neurodegenerative conditions and blinding diseases. HaeWon Jung, Tao Liu et al. combine multimodal adaptive optics with indocyanine green angiography to improve imaging of the human eye. This combination allowed visualization of photoreceptors, retinal pigment epithelial cells, and choriocapillaris of the living eye with remarkable resolution. [ABSTRACT FROM AUTHOR]