Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis

Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.This study received funding from Novartis. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. This work was supported by grants from Foundation Fighting Blindness Career Development Award CDGE-0621-0809-RAD (SR), Foundation Fighting Blindness project program award PPA-0123-0841-UCL (SR and SdB), Retinitis Pigmentosa Fighting Blindness, Fight for Sight UK (RP Genome Project GR586), Ghent University Special Research Fund (BOF20/GOA/023) (EDB and BL); EJP RD Solve-RET EJPRD19-234 (EDB, BL, SB, CR, FC, and SR). EDB (1802220N) and BL (1803816N) are FWO Senior Clinical Investigators of the Research Foundation Flanders (FWO). EDB, BL, SB, FC, and SR are members of ERN-EYE (Framework Partnership Agreement No. 739534)

Oral therapy for riboflavin transporter deficiency - What is the regimen of choice?

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An Expanded Multi-Organ Disease Phenotype Associated with Mutations in YARS

Whole exome sequence analysis was performed in a Swedish mother-father-affected proband trio with a phenotype characterized by progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. A homozygous variant c.806T > C, p.(F269S) in the tyrosyl-tRNA synthetase gene (YARS) was the only identified candidate variant consistent with autosomal recessive inheritance. Mutations in YARS have previously been associated with both autosomal dominant Charcot-Marie-Tooth syndrome and a recently reported autosomal recessive multiorgan disease. Herein, we propose that mutations in YARS underlie another clinical phenotype adding a second variant of the disease, including retinitis pigmentosa and deafness, to the spectrum of YARS-associated disorders

An expanded multi-organ disease phenotype associated with mutations in YARS

Whole exome sequence analysis was performed in a Swedish mother–father-affected proband trio with a phenotype characterized by progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. A homozygous variant c.806T > C, p.(F269S) in the tyrosyl-tRNA synthetase gene (YARS) was the only identified candidate variant consistent with autosomal recessive inheritance. Mutations in YARS have previously been associated with both autosomal dominant Charcot-Marie-Tooth syndrome and a recently reported autosomal recessive multiorgan disease. Herein, we propose that mutations in YARS underlie another clinical phenotype adding a second variant of the disease, including retinitis pigmentosa and deafness, to the spectrum of YARS-associated disorders

Association of Sex With Frequent and Mild ABCA4 Alleles in Stargardt Disease

IMPORTANCE The mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management. OBJECTIVE To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1. DESIGN, SETTING, AND PARTICIPANTS Genetic data for this cross-sectional study were obtained from 2 multicenter genetic studies of 1162 patients with clinically suspected STGD1. Unrelated patients with genetically confirmed STGD1 were selected. The data were collected from June 2016 to June 2019, and post hoc analysis was performed between July 2019 and January 2020. MAIN OUTCOMES AND MEASURES Penetrance of reported mild ABCA4 variants was calculated by comparing the allele frequencies in the general population (obtained from the Genome Aggregation Database) with the genotyping data in the patient population (obtained from the ABCA4 Leiden Open Variation Database). The sex ratio among patients with and patients without an ABCA4 allele with incomplete penetrance was assessed. RESULTS A total of 550 patients were included in the study, among which the mean (SD) age was 45.7 (18.0) years and most patients were women (311 [57%]). Five of the 5 mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were calculated to have incomplete penetrance. The women to men ratio in the subgroup carrying c.5603A>T was 1.7 to 1; the proportion of women in this group was higher compared with the subgroup not carrying a mild allele (difference, 13%; 95% CI, 3%-23%; P=.02). The women to men ratio in the c.5882G>A subgroup was 2.1 to 1, and the women were overrepresented compared with the group carrying no mild allele (difference, 18%; 95% CI, 6%-30%; P=.005). CONCLUSIONS AND RELEVANCE This study found an imbalance in observed sex ratio among patients harboring a mild ABCA4 allele, which concerns approximately 25% of all patients with STGD1, suggesting that STGD1 should be considered a polygenic or multifactorial disease rather than a disease caused by ABCA4 gene mutations alone. The findings suggest that sex should be considered as a potential disease-modifying variable in both basic research and clinical trials on STGD1

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