title: Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes.
abstract: Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants and copy number variants that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes.
authors.affiliation: Department of Ophthalmology, Columbia University, New York, NY, USA.
authors.forename: Winston
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, Columbia University, New York, NY, USA.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Ophthalmology, Columbia University, New York, NY, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Zernant
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Ophthalmology, Columbia University, New York, NY, USA.
authors.forename: Srilaxmi
authors.initials: S
authors.lastname: Bearelly
authors.affiliation: Department of Ophthalmology, Columbia University, New York, NY, USA.|Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Tsang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Ophthalmology, Columbia University, New York, NY, USA. rla22@cumc.columbia.edu.|Department of Pathology and Cell Biology, Columbia University, New York, NY, USA. rla22@cumc.columbia.edu.
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004596:Electroretinography; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008266:Macula Lutea / Q000473:pathology*; D008268:Macular Degeneration / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D000080362:Stargardt Disease
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters