Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes.

TitleComplex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes.
Publication TypeJournal Article
Year of Publication2016
AuthorsLee, W, Xie, Y, Zernant, J, Yuan, B, Bearelly, S, Tsang, SH, Lupski, JR, Allikmets, R
JournalHum Genet
Volume135
Issue1
Pagination9-19
Date Published2016 Jan
ISSN1432-1203
KeywordsAdult, Aged, ATP-Binding Cassette Transporters, Comparative Genomic Hybridization, DNA Copy Number Variations, Electroretinography, Female, High-Throughput Nucleotide Sequencing, Humans, Macula Lutea, Macular Degeneration, Male, Middle Aged, Mutation, Pedigree, Phenotype
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.

DOI10.1007/s00439-015-1605-y
Alternate JournalHum. Genet.
PubMed ID26527198
PubMed Central IDPMC4699863
Grant ListR01 EY021237 / EY / NEI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
R24 EY019861 / EY / NEI NIH HHS / United States
P30 EY019007 / EY / NEI NIH HHS / United States
EY019007 / EY / NEI NIH HHS / United States
EY021237 / EY / NEI NIH HHS / United States
EY021163 / EY / NEI NIH HHS / United States
R01 EY021163 / EY / NEI NIH HHS / United States
EY019861 / EY / NEI NIH HHS / United States
HG0065342 / HG / NHGRI NIH HHS / United States