title: Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions.
abstract: OBJECTIVE
  Stargardt macular dystrophy (STGD) results in early central vision loss. We sought to explain the genetic cause of STGD in a cohort of 88 patients from three different cultural backgrounds.
  
  
  METHODS
  Next-generation sequencing using a novel capture panel was used to search for disease-causing mutations. Patients with undetermined causes were clinically reexamined and tested for copy-number variations as well as intronic mutations.
  
  
  RESULTS
  We determined the cause of disease in 67% of our patients. Our analysis identified 35 novel ABCA4 alleles. Eleven patients had mutations in genes not previously reported to cause STGD. Finally, 45% of our patients with unsolved causes had single deleterious mutations in ABCA4, a recessive disease gene. No likely pathogenic copy-number variations were identified.
  
  
  CONCLUSIONS
  This study expands our knowledge of STGD by identifying dozens of novel alleles that cause the disease. The frequency of single mutations in ABCA4 among STGD patients is higher than that among controls, indicating that these mutations contribute to disease. Disease in 11 patients was explained by mutations outside ABCA4, underlining the need to genotype all retinal disease genes to maximize genetic diagnostic rates. Few ABCA4 mutations were observed in our French Canadian patients. This population may contain an unidentified founder mutation. Our results indicate that copy-number variations are unlikely to be a major cause of STGD.
authors.affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Zaneveld
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal Children's Hospital, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Sorath
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Huajin
authors.initials: H
authors.lastname: Li
authors.affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xia
authors.identifier: 0000000277501167
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal Children's Hospital, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Huanan
authors.initials: H
authors.lastname: Ren
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal Children's Hospital, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal Children's Hospital, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Allison
authors.initials: A
authors.lastname: Dorfman
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal Children's Hospital, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Khan
authors.affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA [2] Structural and Computational Biology and Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Salvo
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Violet
authors.identifier: 0000000332769554
authors.initials: V
authors.lastname: Gelowani
authors.affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Sui
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal Children's Hospital, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Robert
authors.identifier: 0000000166970411
authors.initials: R
authors.lastname: Koenekoop
authors.affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [3] Structural and Computational Biology and Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, USA [4] Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D056915:DNA Copy Number Variations / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008268:Macular Degeneration / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017384:Sequence Deletion / Q000235:genetics; D000080362:Stargardt Disease
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters