title: The clinical effect of homozygous ABCA4 alleles in 18 patients.
abstract: OBJECTIVE
  To describe the phenotypic presentation of a cohort of individuals with homozygous disease-associated ABCA4 variants.
  
  
  METHODS
  Retrospective case series.
  
  
  METHODS
  Eighteen affected individuals from 13 families ascertained from a total cohort of 214 families with ABCA4-related retinal disease presenting to a single center.
  
  
  METHODS
  A detailed history was obtained, and color fundus photography, autofluorescence (AF) imaging, optical coherence tomography (OCT), and electrophysiologic assessment were performed. Phenotypes based on ophthalmoscopy, AF, and electrophysiology were assigned using previously reported characteristics. ABCA4 mutation detection was performed using the ABCR400 microarray (Asper Biotech, Tartu, Estonia) and high-throughput DNA sequencing, with direct sequencing used to assess segregation.
  
  
  METHODS
  Detailed clinical, electrophysiologic, and molecular genetic findings.
  
  
  RESULTS
  Eleven disease-associated homozygous ABCA4 alleles were identified, including 1 frame shift, 2 stops, 1 intronic variant causing splice-site alteration, 2 complex missense variants, and 5 missense variants: p.Glu905fsX916, p.Arg1300X, p.Gln2220X, c.4253+4 C>T, p.Leu541Pro and p.Ala1038Val (homozygosity for complex allele), p.Val931Met and p.Arg1705Gln (complex allele), p.Arg212Cys, p.Cys1488Arg, p.Arg1640Trp, p.Gly1961Glu, and p.Leu2027Phe. Eight of these 11 homozygous alleles have not been reported previously. Six of 7 patients with homozygous null alleles had early-onset (<10 years) disease, with all 7 having a severe phenotype. Two patients with homozygous missense variants (p.Leu541Pro and p.Ala1038Val [complex], and p.Arg1640Trp) presented with a severe phenotype. Three patients with homozygous p.Gly1961Glu had adult-onset disease and a mild phenotype. One patient with homozygous p.Leu2027Phe showed a spared fovea and preserved visual acuity.
  
  
  CONCLUSIONS
  The phenotypes represented in patients identified as homozygous for presumed disease-associated ABCA4 variants gives insight into the effect of individual alleles. Null alleles have severe functional effects, and certain missense variants are similar to nulls, suggesting complete abrogation of protein function. The common alleles identified, p.Gly1961Glu and p. Leu2027Phe, both have a mild structural and functional effect on the adult retina; the latter is associated with relatively retained photoreceptor architecture and function at the fovea.
authors.affiliation: UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom; National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Fujinami
authors.forename: Panagiotis I
authors.initials: PI
authors.lastname: Sergouniotis
authors.forename: Alice E
authors.initials: AE
authors.lastname: Davidson
authors.forename: Donna S
authors.initials: DS
authors.lastname: Mackay
authors.forename: Kazushige
authors.initials: K
authors.lastname: Tsunoda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008268:Macular Degeneration / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D000080362:Stargardt Disease; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters