Michael Gorin
University of California, Los Angeles, Ophthalmology, Faculty Member
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To identify the genetic basis of Schnyder crystalline corneal dystrophy (SCCD) through screening positional candidate genes and UBIAD1, in which mutations have been associated with SCCD, in affected families. The coding region of each of... more
To identify the genetic basis of Schnyder crystalline corneal dystrophy (SCCD) through screening positional candidate genes and UBIAD1, in which mutations have been associated with SCCD, in affected families. The coding region of each of the 16 positional candidate genes for which mutation screening has not been previously reported was screened with polymerase chain reaction (PCR) amplification and automated sequencing in four affected individuals from two families with SCCD. In addition, the coding region of UBIAD1, located just outside of the originally described SCCD candidate interval on chromosome 1p36, was directly sequenced in affected and unaffected individuals from three families with SCCD. Eighteen novel and 15 previously reported sequence variants were identified in 10 of the 16 positional candidate genes. Only two of the sequence variants segregated with the affected phenotype in either of the families screened. Both were novel single nucleotide polymorphisms (SNPs) pred...
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Research Interests: Aging, Biology, Gene expression, Extracellular Matrix, Biological Sciences, and 15 moreArticle, Gene, Age related macular degeneration, Aged, Exome Sequencing, Elastin, Adult, Controlled Study, Genetic Association, Amino Acid Sequence, Clinical Article, Chemical Structure, Exome, DNA mutational analysis, and Autosomal Dominant Inheritance
Research Interests: Genetics, Aging, Quality of life, Biology, Medicine, and 15 moreMultidisciplinary, Macular Degeneration, Complement System, Joint Action, Humans, Research article, Risk factors, Logistic Regression Analysis, Multifactor Dimensionality Reduction, PLoS one, Risk Factors, Complement Factor H, Complement Factor B, Case Control Studies, and Factor model
Research Interests: Ophthalmology, Photography, Optical coherence tomography, Medicine, Macular Degeneration, and 15 moreProspective studies, Humans, Female, Male, Follow-up studies, Age related macular degeneration, Clinical Sciences, Aged, Middle Aged, Optometry and Ophthalmology, Observer Variation, Public health systems and services research, Reproducibility, Reproducibility of Results, and Disease Progression
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Research Interests: Computer Science, Algorithms, Artificial Intelligence, Ophthalmology, Machine Learning, and 15 moreComputational Biology, Pattern Recognition, Vocabulary, Medicine, Macular Degeneration, Learning, Biological Sciences, Humans, System, Phenotype, Computer User Interface Design, Aged, Middle Aged, Automated, and Medical and Health Sciences
Research Interests: Genetics, Biology, Medicine, Macular Degeneration, Biological Sciences, and 14 moreHumans, Articles, Female, Calcium channels, Male, Risk factors, Genetic linkage analysis, Aged, Genotype, Single Nucleotide Polymorphism, Linkage Disequilibrium, Risk Factors, Gene Expression Regulation, and Medical and Health Sciences
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Research Interests: Genetics, Biology, Medicine, Sequence Analysis, Biological Sciences, and 15 moreDNA, Humans, Retinitis pigmentosa, Male, Human Molecular Genetics, Proteins, Introns, Ciliopathy, Amino Acid Sequence, Base Sequence, Chromosomes, Exon, Molecular Sequence Data, frameshift mutation, and Medical and Health Sciences
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We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P…
Research Interests: Genetics, Biology, Risk, Medicine, Multidisciplinary, and 11 moreMacular Degeneration, Humans, Regression Analysis, Age related macular degeneration, Genotype, Single Nucleotide Polymorphism, High Density Lipoprotein, Genetic variation, Case Control Studies, Academy of Sciences and Letters, and alleles
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Research Interests: Immunology, Risk, Medicine, Humans, Female, and 15 moreMale, Genetic Association Studies, Clinical Sciences, Newborn Infant, Republic of Korea, Genotype, Adult, Allele, Preterm Delivery, Premature Birth, Haplotype, DNA mutational analysis, Uterine contraction, Gene frequency, and Paediatrics and reproductive medicine
Research Interests: Genetics, Aging, Membrane Proteins, Medicine, Macular Degeneration, and 14 moreBiological Sciences, Humans, Female, Male, Human Molecular Genetics, Proteins, Clinical Sciences, Aged, Optometry and Ophthalmology, Public health systems and services research, Complement Factor H, Case Control Studies, Cohort Studies, and Medical and Health Sciences
Research Interests: Genetics, Biology, Membrane Proteins, Medicine, Macular Degeneration, and 15 moreHuman, Biological Sciences, Humans, Clinical research, Genetic linkage analysis, Human Genome, Odds ratio, Linkage Disequilibrium, European Continental Ancestry Group, Allele, Chromosomes, Case Control Studies, Cohort Studies, Gene frequency, and Medical and Health Sciences
Research Interests: Demography, Macular Degeneration, Longevity, Humans, Internal Medicine, and 15 moreMathematical Sciences, Female, Male, Cohort Study, American, Apolipoprotein E, Cohort, Age related macular degeneration, Aged, Genotype, DDC, Age Factors, European Continental Ancestry Group, Gene frequency, and Medical and Health Sciences
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of…
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Research Interests: Genetics, Nursing, Genetic Epidemiology, Molecular Biology, Blindness, and 15 moreAging, Medicine, Macular Degeneration, Humans, Haplotypes, Disease, Physical sciences, Age related macular degeneration, Optometry and Ophthalmology, Linkage Disequilibrium, Genetic Recombination, Risk Assessment, Genetic Association, Amino Acid Substitution Rates, and Medical and Health Sciences
ABSTRACTMissing heritability in human diseases represents a major challenge. Although whole-genome sequencing enables the analysis of coding and non-coding sequences, substantial costs and data storage requirements hamper its large-scale... more
ABSTRACTMissing heritability in human diseases represents a major challenge. Although whole-genome sequencing enables the analysis of coding and non-coding sequences, substantial costs and data storage requirements hamper its large-scale use to (re)sequence genes in genetically unsolved cases. The ABCA4 gene implicated in Stargardt disease (STGD1) has been studied extensively for 22 years, but thousands of cases remained unsolved. Therefore, single molecule molecular inversion probes were designed that enabled an automated and cost-effective sequence analysis of the complete 128-kb ABCA4 gene. Analysis of 1,054 unsolved STGD and STGD-like probands resulted in bi-allelic variations in 448 probands. Twenty-seven different causal deep-intronic variants were identified in 117 alleles. Based on in vitro splice assays, the 13 novel causal deep-intronic variants were found to result in pseudo-exon (PE) insertions (n=10) or exon elongations (n=3). Intriguingly, intron 13 variants c.1938-621...
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Disease risk estimation plays an important role in disease prevention. Many studies have found that the ability to predict risk improves as the number of risk single-nucleotide polymorphisms (SNPs) in the risk model increases. However,... more
Disease risk estimation plays an important role in disease prevention. Many studies have found that the ability to predict risk improves as the number of risk single-nucleotide polymorphisms (SNPs) in the risk model increases. However, the width of the confidence interval of the risk estimate is often not considered in the evaluation of the risk model. Here, we explore how the risk and the confidence interval width change as more SNPs are added to the model in the order of decreasing effect size, using both simulated data and real data from studies of abdominal aortic aneurysms and age-related macular degeneration. Our results show that confidence interval width is positively correlated with model size and the majority of the bigger models have wider confidence interval widths than smaller models. Once the model size is bigger than a certain level, the risk does not shift markedly, as 100% of the risk estimates of the one-SNP-bigger models lie inside the confidence interval of the o...
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X-linked retinitis pigmentosa (XLRP) is a degenerative disease of the retina characterized in the early stages of disease by night blindness as a result of rod photoreceptor loss, progressing to severe disease with loss of central vision... more
X-linked retinitis pigmentosa (XLRP) is a degenerative disease of the retina characterized in the early stages of disease by night blindness as a result of rod photoreceptor loss, progressing to severe disease with loss of central vision by the third decade in affected males. XLRP displays exceptional genetic heterogeneity, with five reported loci on the human X-chromosome. To investigate the level of heterogeneity for XLRP in the patient pool in the current study, extensive haplotype analysis, linkage analysis, and mutation screening were performed. Haplotype analysis of a family with diagnosed XLRP was scored with more than 34 polymorphic markers spanning the entire X-chromosome, including regions already identified as harboring XLRP genes and retina-specific genes. Two-point and multipoint lod scores were calculated. Affected male DNA was amplified with primers specific for the retinoschisis gene (XLRS1), and the products were screened for nucleic acid alterations by direct autom...
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X-linked progressive cone dystrophy (COD1) causes progressive deterioration of visual acuity, deepening of central scotomas, macular changes, and bull's-eye lesions. The cone electroretinography (ERG) is variably abnormal in affected... more
X-linked progressive cone dystrophy (COD1) causes progressive deterioration of visual acuity, deepening of central scotomas, macular changes, and bull's-eye lesions. The cone electroretinography (ERG) is variably abnormal in affected males, and the rod ERG may also be abnormal. The clinical picture of heterozygous females ranges from asymptomatic to a widespread spectrum of cone-mediated dysfunction. A prior linkage study demonstrated linkage between the COD1 locus and the marker locus DXS84, assigned to Xp21.1, with no recombination. In the present study, we have clinically characterized a large four-generation family with COD1 and have performed a linkage analysis using seven polymorphic markers on the short arm of the X chromosome. No recombination was observed between the disease and the marker loci DXS7 and MAOA, suggesting that the location of COD1 is in the region Xp11.3, distal to DXS84 and proximal to ARAF1.
Research Interests: Genetics, Polymorphism, Biology, Medicine, Visual acuity, and 15 moreBiological Sciences, Humans, Child, Retinitis pigmentosa, Female, Male, Polymerase Chain Reaction, Genetic Map, Pedigree, Spectrum, Statistical Model, Genetic Markers, Linkage Analysis, Sex Characteristics, and Medical and Health Sciences
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Research Interests: Ophthalmology, Aging, Medicine, Family history, Neurodegenerative Diseases, and 15 moreMacular Degeneration, Population, Humans, Clinical research, Data Collection, Cohort, Aged, Prevalence, Middle Aged, Professional Practice, Questionnaires, Optometry and Ophthalmology, OPHTHALMIC GENETICS, Cohort Studies, and Surveys and Questionnaires
Research Interests: Statistics, Epidemiology, Medicine, Macular Degeneration, Prospective studies, and 12 moreHumans, Smoking, Female, Male, Aged, Genotype, Single Nucleotide Polymorphism, Public health systems and services research, Odds ratio, European Continental Ancestry Group, Complement Factor H, and Case Control Studies
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Research Interests: Genetics, Aging, Adolescent, Human, DNA, and 15 moreHumans, Child, Clinical research, Female, DNA analysis, American, Clinical Sciences, Eye, Aged, Atrophy, Adult, First Year, Chromosomes, Child preschool, and Autosomal Dominant
Research Interests: Aging, Biology, Adolescent, DNA, Child, and 15 moreClinical research, Female, American, Gene, Clinical Sciences, Eye, Aged, Gen, Atrophy, Chromosome, Adult, Chromosomes, Child preschool, Elderly patient, and Autosomal Dominant
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Research Interests: Genetics, Biology, Medicine, Heterogeneity, Biological Sciences, and 15 moreHumans, Mutation, Genetic determinism, Gene, Phenotype, Genetic linkage analysis, Gen, Amino Acid Sequence, Base Sequence, Neurosciences, Exon, Molecular Sequence Data, genetic heterogeneity, frameshift mutation, and Medical and Health Sciences
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Retinitis pigmentosa is a phenotype with diverse genetic causes. Due to this genetic heterogeneity, genome-wide identification and analysis of protein-altering DNA variants by exome sequencing is a powerful tool for novel variant and... more
Retinitis pigmentosa is a phenotype with diverse genetic causes. Due to this genetic heterogeneity, genome-wide identification and analysis of protein-altering DNA variants by exome sequencing is a powerful tool for novel variant and disease gene discovery. In this study, exome sequencing analysis was used to search for potentially causal DNA variants in a two-generation pedigree with apparent dominant retinitis pigmentosa. Variant identification and analysis of three affected members (mother and two affected offspring) was performed via exome sequencing. Parental samples of the index case were used to establish inheritance. Follow-up testing of 94 additional retinitis pigmentosa pedigrees was performed via retrospective analysis or Sanger sequencing. A total of 136 high quality coding variants in 123 genes were identified which are consistent with autosomal dominant disease. Of these, one of the strongest genetic and functional candidates is a c.269A>G (p.Tyr90Cys) variant in AR...
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Peptide mass-signature genotyping (PMSG) is a scanning genotyping method that identifies mutations and polymorphisms by translating the sequence of interest in more than one reading frame and measuring the masses of the resulting peptides... more
Peptide mass-signature genotyping (PMSG) is a scanning genotyping method that identifies mutations and polymorphisms by translating the sequence of interest in more than one reading frame and measuring the masses of the resulting peptides by mass spectrometry. PMSG was applied to the RDS/peripherin gene of 16 individuals from a family exhibiting autosomal dominant macular degeneration. The method revealed an A-->T transversion in the 5' splice site of intron 2 that is the likely cause of the disease. It also revealed four different minihaplotypes in exon 3 that represent particular combinations of SNPs at four different locations. This study demonstrates the utility of PMSG for identifying and characterizing point mutations and local minihaplotypes that are not readily analyzed by other approaches.
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Many genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of... more
Many genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of rare coding variation in these genes among unaffected individuals to provide context for variants that will be discovered when clinical subjects are sequenced. Publicly available data from the Exome Variant Project were analyzed, focusing on 36 genes known to harbor mutations causing autosomal dominant macular dystrophy. Rates of rare (minor allele frequency ≤0.1%) and private missense variants within autosomal dominant retinal dystrophy genes were found to occur at a high frequency in unaffected individuals, while nonsense variants were not. We conclude that rare missense variations in most of these genes identified in individuals with retinal dystrophy cannot be confidently classified as disease-causing in the absence of additional information such a...
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Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of ABCA4 in STGD patients identifies compound heterozygous or homozygous disease-associated alleles in 65-70% of... more
Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of ABCA4 in STGD patients identifies compound heterozygous or homozygous disease-associated alleles in 65-70% of patients and only one mutation in 15-20% of patients. This study was designed to find the missing disease-causing ABCA4 variation by a combination of next-generation sequencing (NGS), array-Comparative Genome Hybridization (aCGH) screening, familial segregation and in silico analyses. The entire 140 kb ABCA4 genomic locus was sequenced in 114 STGD patients with one known ABCA4 exonic mutation revealing, on average, 200 intronic variants per sample. Filtering of these data resulted in 141 candidates for new mutations. Two variants were detected in four samples, two in three samples, and 20 variants in two samples, the remaining 117 new variants were detected only once. Multimodal analysis suggested 12 new likely pathogenic intronic ABCA4 variants, some of...