Swept-source optical coherence tomography changes and visual acuity among Palestinian retinitis Pigmentosa patients: a cross-sectional study

Background: Retinitis pigmentosa (RP) is a heterogeneous group of inherited ocular diseases that result in progressive retinal degeneration. This study aims to describe different Swept-source Optical Coherence Tomographic (SS-OCT) changes in Palestinian RP patients and to explore possible correlations with Visual Acuity (VA). Methods: A cross-sectional observational study was conducted on Retinitis Pigmentosa patients diagnosed with RP in a tertiary eye hospital. Full history and ocular examination were made. SS-OCT imaging was done for all eyes assessing the presence of cystoid macular edema, epiretinal membrane, macular holes, and external limiting membrane, ellipsoid zone status. Also, central macular thickness and choroidal vascular thickness were measured. // Results: The study was run on 161 eyes of 81 patients; 53 males and 28 females. The average age at examination was 26.1 (6–78) years. Twenty-six eyes (16.1%) were of syndromic RP patients, mostly Usher syndrome; 20 eyes (12.4%). The mean Logaritmic minimal angle of resolution (LogMAR) of Best Corrected Visual Acuity (BCVA)of the study sample was 0.66 ± 0.7. The most prevalent change was cystoid macular edema [28 eyes, (17.4%)], followed by epiretinal membrane [17eye, (10.6%)]. A macular hole was noted only in one eye (0.6%). Ellipsoid zone and external limiting membrane were absent in 55 eyes (35.0%) and 60 eyes 37.5%. Vitreous hyperreflective foci were found in 35 eyes (43.8%). LogMAR of BCVA was associated significantly with cystoid macular edema (p = 0.001), ellipsoid zone(p = 0.001), and external limiting membrane (p = 0.001). // Conclusions: Detailed SS-OCT assessment in Palestinian patients diagnosed with RP identified different morphologies from other populations. Cystoid macular edema and vitreous hyperreflective foci may reflect signs of early or intermediate stages of the disease. Disease progression can be monitored by measuring the length/width (area) of ellipsoid zone +/− external limiting membrane and choroidal vascular thickness, which should be evaluated serially using high-resolution OCT

Detailed Clinical, Ophthalmic, and Genetic Characterization of ADGRV1-Associated Usher Syndrome

Purpose: To present the clinical characteristics, retinal features, natural history, and genetics of ADGRV1-Usher syndrome (USH). Design: Multicenter international retrospective cohort study. Methods: Clinical notes, hearing loss history, multimodal retinal imaging, and molecular diagnosis were reviewed. Thirty patients (28 families) with USH type 2 and disease-causing variants in ADGRV1 were identified. Visual function, retinal imaging, and genetics were evaluated and correlated, with retinal features also compared with those of the commonest cause of USH type 2, USH2A-USH. Results: The mean age at the first visit was 38.6 ± 12.0 years (range: 19-74 years), and the mean follow-up time was 9.0 ± 7.7 years. Hearing loss was reported in the first decade of life by all patients, 3 (10%) described progressive loss, and 93% had moderate-severe impairment. Visual symptom onset was at 17.0 ± 7.7 years of age (range: 6-32 years), with 13 patients noticing problems before the age of 16. At baseline, 90% of patients had no or mild visual impairment. The most frequent retinal features were a hyperautofluorescent ring at the posterior pole (70%), perimacular patches of decreased autofluorescence (59%), and mild-moderate peripheral bone-spicule–like deposits (63%). Twenty-six (53%) variants were previously unreported, 19 families (68%) had double-null genotypes, and 9 were not-double-null. Longitudinal analysis showed significant differences between baseline and follow-up central macular thickness (−1.25 µm/y), outer nuclear layer thickness (−1.19 µm/y), and ellipsoid zone width (−40.9 µm/y). The rate of visual acuity decline was 0.02 LogMAR (1 letter)/y, and the rate of constriction of the hyperautofluorescent ring was 0.23 mm2/y. Conclusions: ADGRV1-USH is characterized by early-onset, usually non-progressive, mild-to-severe hearing loss and generally good central vision until late adulthood. Perimacular atrophic patches and relatively retained ellipsoid zone and central macular thickness in later adulthood are more often seen in ADGRV1-USH than in USH2A-USH

CRB1-associated Retinal Dystrophies: Genetics, Clinical Characteristics and Natural History

PURPOSE: To analyse the clinical characteristics, natural history, and genetics of CRB1-associated retinal dystrophies. DESIGN: Multicenter international retrospective cohort study. METHODS: Review of clinical notes, ophthalmic images, and genetic testing results of 104 patients (91 probands) with disease-causing CRB1 variants. Macular optical coherence tomography (OCT) parameters, visual function, fundus characteristics, and associations between variables were our main outcome measures. RESULTS: The mean age of the cohort at the first visit was 19.8 ± 16.1 (median 15) years of age, with a mean follow-up of 9.6 ± 10 years. Based on history, imaging, and clinical examination, 26 individuals were diagnosed with retinitis pigmentosa (RP, 26%), 54 with early-onset severe retinal dystrophy/Leber Congenital Amaurosis (EOSRD/LCA, 51%), and 24 with macular dystrophy (MD, 23%). Severe visual impairment was most frequent after 40 years of age for patients with RP and after 20 years of age for EOSRD/LCA. Longitudinal analysis revealed a significant difference between baseline and follow up best corrected visual acuity in the three sub-cohorts. Macular thickness decreased in most patients with EOSRD/LCA and MD, whereas the majority of patients with RP had increased perifoveal thickness. CONCLUSIONS: A subset of individuals with CRB1 variants present with mild, adult-onset RP. EOSRD/LCA phenotype was significantly associated with null variants, and 167_169 deletion was exclusively present in the MD cohort. The poor OCT lamination may have a degenerative component, as well as being congenital. Disease symmetry and reasonable window for intervention highlight CRB1 retinal dystrophies as a promising target for trials of novel therapeutics

Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD

Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype–phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD

SENIOR-LØKEN SYNDROME: A Case Series and Review of the Renoretinal Phenotype and Advances of Molecular Diagnosis

PURPOSE: To report genetic and clinical findings in a case series of 10 patients from eight unrelated families diagnosed with Senior-Løken syndrome. METHODS: A retrospective study of patients with Senior-Løken syndrome. Data collected included clinical findings electroretinography and ocular imaging. Genetic analysis was based on molecular inversion probes, whole-exome sequencing (WES), and Sanger sequencing. RESULTS: All patients who underwent electrophysiology (8/10) had widespread photoreceptor degeneration. Genetic analysis revealed two mutations in NPHP1, two mutations in NPHP4, and two mutations in IQCB1 (NPHP5). Five of the six mutations identified in the current study were found in a single family each in our cohort. The IQCB1-p.R461* mutation has been identified in 3 families. Patients harboring mutations in IQCB1 were diagnosed with Leber congenital amaurosis, while patients with NPHP4 and NPHP1 mutations showed early and sector retinitis pigmentosa, respectively. Full-field electroretinography was extinct for 6 of 10 patients, moderately decreased for two, and unavailable for another 2 subjects. Renal involvement was evident in 7/10 patients at the time of diagnosis. Kidney function was normal (based on serum creatinine) in patients younger than 10 years. Mutations in IQCB1 were associated with high hypermetropia, whereas mutations in NPHP4 were associated with high myopia. CONCLUSION: Patients presenting with infantile inherited retinal degeneration are not universally screened for renal dysfunction. Modern genetic tests can provide molecular diagnosis at an early age and therefore facilitate early diagnosis of renal disease with recommended periodic screening beyond childhood and family planning

ABCA4 c.859-25A>G, a Frequent Palestinian Founder Mutation Affecting the Intron 7 Branchpoint, Is Associated With Early-Onset Stargardt Disease

PURPOSE: The effect of noncoding variants is often unknown in the absence of functional assays. Here, we characterized an ABCA4 intron 7 variant, c.859-25A>G, identified in Palestinian probands with Stargardt disease (STGD) or cone-rod dystrophy (CRD). We investigated the effect of this variant on the ABCA4 mRNA and retinal phenotype, and its prevalence in Palestine. METHODS: The ABCA4 gene was sequenced completely or partially in 1998 cases with STGD or CRD. The effect of c.859-25A>G on splicing was investigated in silico using SpliceAI and in vitro using splice assays. Homozygosity mapping was performed for 16 affected individuals homozygous for c.859-25A>G. The clinical phenotype was assessed using functional and structural analyses including visual acuity, full-field electroretinography, and multimodal imaging. RESULTS: The smMIPs-based ABCA4 sequencing revealed c.859-25A>G in 10 Palestinian probands from Hebron and Jerusalem. SpliceAI predicted a significant effect of this putative branchpoint-inactivating variant on the nearby intron 7 splice acceptor site. Splice assays revealed exon 8 skipping and two partial inclusions of intron 7, each having a deleterious effect. Additional genotyping revealed another 46 affected homozygous or compound heterozygous individuals carrying variant c.859-25A>G. Homozygotes shared a genomic segment of 59.6 to 87.9 kb and showed severe retinal defects on ophthalmoscopic evaluation. CONCLUSIONS: The ABCA4 variant c.859-25A>G disrupts a predicted branchpoint, resulting in protein truncation because of different splice defects, and is associated with early-onset STGD1 when present in homozygosity. This variant was found in 25/525 Palestinian inherited retinal dystrophy probands, representing one of the most frequent inherited retinal disease-causing variants in West-Bank Palestine

Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics

Contains fulltext : 225504.pdf (Publisher’s version ) (Closed access)PURPOSE: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. METHODS: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. RESULTS: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. CONCLUSION: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases

Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics

Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.Fil: Khan, Mubeen. Radboud University Nijmegen Medical Centre; Países BajosFil: Cornelis, Stéphanie S.. Radboud University Nijmegen Medical Centre; Países BajosFil: Del Pozo Valero, Marta. Hospital Universitario Fundación Jiménez Díaz; España. Radboud University Nijmegen Medical Centre; Países BajosFil: Whelan, Laura. Trinity College; Estados UnidosFil: Runhart, Esmee H.. Radboud University Nijmegen Medical Centre; Países BajosFil: Mishra, Ketan. Radboud University Nijmegen Medical Centre; Países BajosFil: Bults, Femke. Radboud University Nijmegen Medical Centre; Países BajosFil: AlSwaiti, Yahya. St John of Jerusalem Eye Hospital Group; Palestina (ANP)Fil: AlTalbishi, Alaa. St John of Jerusalem Eye Hospital Group; Palestina (ANP)Fil: De Baere, Elfride. University of Ghent; BélgicaFil: Banfi, Sandro. Seconda Universita Degli Studi Di Napoli; ItaliaFil: Banin, Eyal. The Hebrew University of Jerusalem; IsraelFil: Bauwens, Miriam. University of Ghent; BélgicaFil: Ben Yosef, Tamar. The Ruth And Bruce Rappaport Faculty Of Medicine; IsraelFil: Boon, Camiel J. F.. Leiden University. Leiden University Medical Center; Países BajosFil: van den Born, L. Ingeborgh. Rotterdam Ophthalmic Institute; Países BajosFil: Defoort, Sabine. Universite Lille; FranciaFil: Devos, Aurore. Universite Lille; FranciaFil: Dockery, Adrian. Trinity College; Estados UnidosFil: Dudakova, Lubica. Charles University and General University Hospital; República ChecaFil: Fakin, Ana. Charles University and General University Hospital; República ChecaFil: Farrar, G. Jane. Trinity College; Estados UnidosFil: Ferraz Sallum, Juliana Maria. Universidade Federal de Sao Paulo; BrasilFil: Fujinami, Kaoru. UCL Institute of Ophthalmology; Reino UnidoFil: Gilissen, Christian. Radboud University Nijmegen Medical Centre; Países BajosFil: Glavac, Damjan. University of Ljubljana; EsloveniaFil: Gorin, Michael B.. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Greenberg, Jacquie. University of Cape Town; SudáfricaFil: Hayashi, Takaaki. The Jikei University School of Medicine; JapónFil: Hettinga, Ymkje M.. Bartiméus Diagnostic Center for Complex Visual Disorders; Países BajosFil: Hoischen, Alexander. Radboud University Nijmegen Medical Centre; Países BajosFil: Hoyng, Carel B.. Radboud University Nijmegen Medical Centre; Países BajosFil: Hufendiek, Karsten. University Eye Hospital Hannover Medical School; AlemaniaFil: Jägle, Herbert. University Regensburg; AlemaniaFil: Kamakari, Smaragda. OMMA Ophthalmological Institute of Athens; GreciaFil: Karali, Marianthi. Seconda Universita Degli Studi Di Napoli; ItaliaFil: Kellner, Ulrich. No especifíca;Fil: Klaver, Caroline C. W.. Radboud University Nijmegen Medical Centre; Países BajosFil: Kousal, Bohdan. Charles University and General University Hospital; República ChecaFil: Lamey, Tina M.. University of Western Australia; AustraliaFil: MacDonald, Ian M.. University of Alberta; CanadáFil: Matynia, Anna. University of California at Los Angeles. School of Medicine; Estados UnidosFil: McLaren, Terri L.. University of Western Australia; AustraliaFil: Mena, Marcela D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Meunier, Isabelle. Université Montpellier II; FranciaFil: Miller, Rianne. Radboud University Nijmegen Medical Centre; Países BajosFil: Newman, Hadas. Universitat Tel Aviv; IsraelFil: Ntozini, Buhle. University of Cape Town; SudáfricaFil: Oldak, Monika. No especifíca;Fil: Pieterse, Marc. Radboud University Nijmegen Medical Centre; Países BajosFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Puech, Bernard. Universite Lille; FranciaFil: Ramesar, Raj. University of Cape Town; SudáfricaFil: Rüther, Klaus. No especifíca;Fil: Salameh, Manar. No especifíca;Fil: Salles, Mariana Vallim. Universidade de Sao Paulo; BrasilFil: Sharon, Dror. The Hebrew University of Jerusalem; IsraelFil: Simonelli, Francesca. Seconda Universita Degli Studi Di Napoli; ItaliaFil: Spital, Georg. No especifíca;Fil: Steehouwer, Marloes. Radboud University Nijmegen Medical Centre; Países BajosFil: Szaflik, Jacek P.. No especifíca;Fil: Thompson, Jennifer A.. No especifíca;Fil: Thuillier, Caroline. Universite Lille; FranciaFil: Tracewska, Anna M.. No especifíca;Fil: van Zweeden, Martine. Radboud University Nijmegen Medical Centre; Países BajosFil: Vincent, Andrea L.. University of Auckland; Nueva ZelandaFil: Zanlonghi, Xavier. No especifíca;Fil: Liskova, Petra. Charles University and General University Hospital; República ChecaFil: Stöhr, Heidi. Universitat Regensburg; AlemaniaFil: De Roach, John N.. University of Western Australia; AustraliaFil: Ayuso, Carmen. Hospital Universitario Fundación Jiménez Díaz; EspañaFil: Roberts, Lisa. University of Cape Town; SudáfricaFil: Weber, Bernhard H. F.. Universitat Regensburg; AlemaniaFil: Dhaenens, Claire Marie. Universite Lille; FranciaFil: Cremers, Frans P. M.. Radboud University Nijmegen Medical Centre; Países Bajo