Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8

• Published in: British journal of ophthalmology Vol. 103; no. 3; pp. 390 - 397
• Main Authors: Fujinami, Kaoru, Audo, Isabelle S, Birch, David G, Bomotti, Samantha M, Marino, Meghan J, Sahel, José-Alain, Sunness, Janet S, Wojciechowski, Robert, Zrenner, Eberhart, Michaelides, Michel, Scholl, Hendrik PN, Strauss, Rupert W, Wolfson, Yulia, Shah, Syed Mahmood, Ahmed, Mohamed, Traboulsi, Elias, Marino, Meghan, Crowe, Susan, Fecko, Tami, Applegate, Carol, Esposti, Simona Degli, Webster, Andrew, Connor, Sophie, Barnfield, Jade, Alfageme, Clara, Pefkianaki, Maria, Aboshiha, Jonathan, Liew, Gerald, Holder, Graham, Cajas Narvaez, Daniela Ivanova, Grigg, Catherine, Rughani, Avani, Amoah, Charles, Bibi, Kanom, Begum, Hamida, Carter, Andrew, Shinmar, Harpreet, Bernstein, Paul, Wegner, Kimberley, Carlstrom, Bonnie, Farnsworth, Kellian, Fry, Cyrie, Chandler, Melissa, Birch, David, Wang, Yi-Zhong, Rodriguez, Luis, Klein, Martin, Mejia, Paulina, Cideciyan, Artur V, Matsui, Rodrigo, Gruzensky, Michaela, Hahn, Gesa Astrid, Wilhelm, Barbara, Peters, Tobias, Koenig, Tilman, Kramer, Susanne, Mohand-Said, Saddek, Zeitz, Christina, Boyard, Fiona, Tran, Minh Ha, Chapon, Mathias, Emmert, David G, Herring, Mark, Bassinger, Jennifer, West, Sheila K, Ip, Michael S, Ho, Alex, Uji, Akihito, Hariri, Amirhossein, Elshafei, Anthony, Jenkins, Dennis, Baghdasaryan, Elmira, Samson, Feliz, Akil, Handan, Lei, Jianqin, Falavarjani, Khalil G, Espino, Kristina, Roded, Netali, Saleh, Nizar, Huang, Ping, Margaryan, Teresa, Murillo, Yamileth, Santos, Lisa, Perez, Silvia, Chao, Stephanie, Luna, Zoila, Menchaca, Anita, Robledo, Vicky, Baker, Kirstie, Bluemel, Daniel, Nava, Lorane, Oberoi, Michelle, Romero, Mark, Chiguil, Vivian, Bynum-Bain, Grantley, Mendiguren, Carolina, Huang, Xiwen, Eberhart, Zrenner, Hahn, Gesa
• Format: Journal Article
• Language: English
• Published: BMA House, Tavistock Square, London, WC1H 9JR BMJ Publishing Group Ltd 01.03.2019; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Adolescent; Adult; Age; Age of Onset; Aged; ATP-Binding Cassette Transporters - genetics; Atrophy; Child; Child, Preschool; Clinical Science; Cohort Studies; Databases, Factual; DNA Mutational Analysis; Female; Gene Frequency; genetics; Genotype & phenotype; Genotyping Techniques; Geography; Humans; Internationality; macula; Macular degeneration; Macular Degeneration - congenital; Macular Degeneration - diagnosis; Macular Degeneration - genetics; Male; Middle Aged; Mutation; Ophthalmology; Patients; Polymerase Chain Reaction; retina; Stargardt Disease; Visual acuity; Cleveland Ohio; United Kingdom > UK; France; Maryland; Baltimore Maryland; Germany; United States > US; retina; macula; genetics
• ISSN: 0007-1161; 1468-2079
• DOI: 10.1136/bjophthalmol-2018-312064

Background/aimsTo describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency.Methods345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.Results211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.ConclusionsThere is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.