Abstract
Background/aims: To 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. Methods: 345 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. Results: 211 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. Conclusions: There 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.
| Original language | English (US) |
|---|---|
| Journal | British Journal of Ophthalmology |
| DOIs | |
| State | Accepted/In press - Jun 19 2018 |
| Externally published | Yes |
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Keywords
- genetics
- macula
- retina
ASJC Scopus subject areas
- Ophthalmology
- Sensory Systems
- Cellular and Molecular Neuroscience
Cite this
Detailed genetic characteristics of an international large cohort of patients with Stargardt disease : ProgStar study report 8. / Fujinami, Kaoru; Strauss, Rupert W.; Chiang, Pei-Wen; Audo, Isabelle S.; Bernstein, Paul S.; Birch, David G.; Bomotti, Samantha M.; Cideciyan, Artur V.; Ervin, Ann Margret; Marino, Meghan J.; Sahel, José Alain; Mohand-Said, Saddek; Sunness, Janet S.; Traboulsi, Elias I.; West, Sheila; Wojciechowski, Robert; Zrenner, Eberhart; Michaelides, Michel; Scholl, Hendrik P.N.
In: British Journal of Ophthalmology, 19.06.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Detailed genetic characteristics of an international large cohort of patients with Stargardt disease
T2 - ProgStar study report 8
AU - Fujinami, Kaoru
AU - Strauss, Rupert W.
AU - Chiang, Pei-Wen
AU - Audo, Isabelle S.
AU - Bernstein, Paul S.
AU - Birch, David G.
AU - Bomotti, Samantha M.
AU - Cideciyan, Artur V.
AU - Ervin, Ann Margret
AU - Marino, Meghan J.
AU - Sahel, José Alain
AU - Mohand-Said, Saddek
AU - Sunness, Janet S.
AU - Traboulsi, Elias I.
AU - West, Sheila
AU - Wojciechowski, Robert
AU - Zrenner, Eberhart
AU - Michaelides, Michel
AU - Scholl, Hendrik P.N.
PY - 2018/6/19
Y1 - 2018/6/19
N2 - Background/aims: To 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. Methods: 345 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. Results: 211 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. Conclusions: There 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.
AB - Background/aims: To 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. Methods: 345 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. Results: 211 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. Conclusions: There 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.
KW - genetics
KW - macula
KW - retina
UR - http://www.scopus.com/inward/record.url?scp=85048874367&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048874367&partnerID=8YFLogxK
U2 - 10.1136/bjophthalmol-2018-312064
DO - 10.1136/bjophthalmol-2018-312064
M3 - Article
C2 - 29925512
AN - SCOPUS:85048874367
JO - British Journal of Ophthalmology
JF - British Journal of Ophthalmology
SN - 0007-1161
ER -