@article {344, title = {Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 Jan}, pages = {9-19}, 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.

}, keywords = {Adult, 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}, issn = {1432-1203}, doi = {10.1007/s00439-015-1605-y}, author = {Lee, Winston and Xie, Yajing and Zernant, Jana and Yuan, Bo and Bearelly, Srilaxmi and Tsang, Stephen H and Lupski, James R and Allikmets, Rando} } @article {216, title = {New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy.}, journal = {JAMA Ophthalmol}, volume = {133}, year = {2015}, month = {2015 Feb}, pages = {133-9}, abstract = {

IMPORTANCE: The families evaluated in this study represent the second report of cone-rod dystrophy (CRD) cases caused by mutations in RAB28, a recently discovered gene associated with CRD.

OBJECTIVE: To determine the disease-causing gene in 2 families of Spanish descent presenting with CRD who do not have ABCA4 mutations.

DESIGN, SETTING, AND PARTICIPANTS: Molecular genetics and observational case studies of 2 families, each with 1 affected proband with CRD and 3 or 5 unaffected family members. The affected individual from each family received a complete ophthalmic examination including assessment of refractive errors and best-corrected visual acuity, biomicroscopy, color fundus photography, electroretinography analysis, and visual-evoked potential analysis. After complete sequencing of the ABCA4 gene with negative results, the screening for disease-causing mutations was performed by whole-exome sequencing. Possible disease-associated variants were determined by filtering based on minor allele frequency, predicted pathogenicity, and segregation analysis in all family members.

MAIN OUTCOMES AND MEASURES: The appearance of the macula was evaluated by clinical examination, fundus photography, and fundus autofluorescence imaging, and visual function was assessed by electroretinography. Disease-causing mutations were assessed by sequence analyses.

RESULTS: Ophthalmologic findings included markedly reduced visual acuity, bull{\textquoteright}s eye maculopathy, foveal hyperpigmentation, peripapillary atrophy, dyschromatopsia, extinguished photopic responses, and reduced scotopic responses observed on electroretinography consistent with the CRD phenotype often associated with ABCA4 mutations. Although no ABCA4 mutations were detected in either patient, whole-exome sequencing analysis identified 2 new homozygous mutations in the recently described RAB28 gene, the c.172 + 1G>C splice site variant in IVS2 and the missense c.T651G:p.C217W substitution. Both variants were determined as deleterious by predictive programs and were segregated with the disease in both families. Sequencing of 107 additional patients of Spanish descent with CRD did not reveal other cases with RAB28 mutations.

CONCLUSIONS AND RELEVANCE: Deleterious mutations in RAB28 result in a classic CRD phenotype and are an infrequent cause of CRD in the Spanish population.

}, keywords = {Adolescent, Adult, Child, Diagnosis, Differential, DNA Mutational Analysis, Female, Follow-Up Studies, Genetic Predisposition to Disease, Hispanic Americans, Humans, Male, Microscopy, Acoustic, Mutation, Pedigree, Phenotype, rab GTP-Binding Proteins, Retinitis Pigmentosa, Retrospective Studies, Young Adult}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2014.4266}, author = {Riveiro-{\'A}lvarez, Rosa and Xie, Yajing Angela and L{\'o}pez-Mart{\'\i}nez, Miguel-{\'A}ngel and Gambin, Tomasz and P{\'e}rez-Carro, Raquel and {\'A}vila-Fern{\'a}ndez, Almudena and L{\'o}pez-Molina, Mar{\'\i}a-Isabel and Zernant, Jana and Jhangiani, Shalini and Muzny, Donna and Yuan, Bo and Boerwinkle, Eric and Gibbs, Richard and Lupski, James R and Ayuso, Carmen and Allikmets, Rando} }