%0 Journal Article %J Ophthalmic Genet %D 2015 %T Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull's Eye Maculopathy. %A Collison, Frederick T %A Xie, Yajing Angela %A Gambin, Tomasz %A Jhangiani, Shalini %A Muzny, Donna %A Gibbs, Richard %A Lupski, James R %A Fishman, Gerald A %A Allikmets, Rando %K Adult %K Carrier Proteins %K Electroretinography %K Exome %K Female %K Genetic Testing %K Heterozygote %K Homocystinuria %K Humans %K Macular Degeneration %K Mutation %K Oxidoreductases %K Pedigree %K Scotoma %K Sequence Analysis, DNA %K Tomography, Optical Coherence %K Visual Acuity %K Visual Fields %K Vitamin B 12 %K Vitamin B 12 Deficiency %K Vitamin B Complex %X

BACKGROUND: Methylmalonic aciduria and homocystinuria type C (cblC), a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene, presents with many systemic symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy are common in early onset form of the disease but are rare in adult onset forms.

MATERIALS AND METHODS: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull's eye-appearing macular lesions at 28 years of age. Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull's eye maculopathy, was negative. Subsequently, analysis with whole exome sequencing was performed.

RESULTS: Whole exome sequencing discovered compound heterozygous mutations in MMACHC, c.G482A:p.Arg161Gln and c.270_271insA:p.Arg91Lysfs*14, which segregated with the disease in the family. The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation.

CONCLUSIONS: In summary, a unique case of an adult patient with bull's eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.

%B Ophthalmic Genet %V 36 %P 270-5 %8 2015 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/25687216?dopt=Abstract %R 10.3109/13816810.2015.1010736 %0 Journal Article %J Hum Mol Genet %D 2014 %T Analysis of the ABCA4 genomic locus in Stargardt disease. %A Zernant, Jana %A Xie, Yajing Angela %A Ayuso, Carmen %A Riveiro-Álvarez, Rosa %A López-Martínez, Miguel-Ángel %A Simonelli, Francesca %A Testa, Francesco %A Gorin, Michael B %A Strom, Samuel P %A Bertelsen, Mette %A Rosenberg, Thomas %A Boone, Philip M %A Bo Yuan %A Ayyagari, Radha %A Nagy, Peter L %A Tsang, Stephen H %A Gouras, Peter %A Collison, Frederick T %A James R Lupski %A Fishman, Gerald A %A Allikmets, Rando %K Alleles %K ATP-Binding Cassette Transporters %K Blacks %K Case-Control Studies %K Comparative Genomic Hybridization %K Exons %K Female %K Gene Expression %K Genes, Recessive %K Genetic Loci %K Genetic Variation %K Heterozygote %K High-Throughput Nucleotide Sequencing %K Homozygote %K Humans %K Introns %K Macular Degeneration %K Male %K Mutation %K Pedigree %K Stargardt Disease %K Whites %X

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 which were specific to (isolated) ethnic groups. No copy number variation (large deletions and insertions) was detected in any patient suggesting that it is a very rare event in the ABCA4 locus. Many variants were excluded since they were not conserved in non-human primates, were frequent in African populations and, therefore, represented ancestral, and not disease-associated, variants. The sequence variability in the ABCA4 locus is extensive and the non-coding sequences do not harbor frequent mutations in STGD patients of European-American descent. Defining disease-associated alleles in the ABCA4 locus requires exceptionally well characterized large cohorts and extensive analyses by a combination of various approaches.

%B Hum Mol Genet %V 23 %P 6797-806 %8 2014 Dec 20 %G eng %N 25 %1 https://www.ncbi.nlm.nih.gov/pubmed/25082829?dopt=Abstract %R 10.1093/hmg/ddu396 %0 Journal Article %J Hum Mutat %D 2014 %T Genetic and clinical analysis of ABCA4-associated disease in African American patients. %A Zernant, Jana %A Collison, Frederick T %A Lee, Winston %A Fishman, Gerald A %A Nõupuu, Kalev %A Bo Yuan %A Cai, Carolyn %A James R Lupski %A Yannuzzi, Lawrence A %A Tsang, Stephen H %A Allikmets, Rando %K Adult %K African Americans %K ATP-Binding Cassette Transporters %K Comparative Genomic Hybridization %K DNA Mutational Analysis %K Electroretinography %K Female %K Genetic Predisposition to Disease %K Humans %K Macular Degeneration %K Male %K Middle Aged %K Mutation %K Stargardt Disease %K United States %K Whites %X

Autosomal recessive Stargardt disease (STGD1) is caused by hundreds of mutations in the ABCA4 gene, which are often specific to racial and ethnic groups. Here, we investigated the ABCA4 variation and their phenotypic expression in a cohort of 44 patients of African American descent, a previously under-characterized racial group. Patients were screened for mutations in ABCA4 by next-generation sequencing and array-comparative genomic hybridization (aCGH), followed by analyses for pathogenicity by in silico programs. Thorough ophthalmic examination was performed on all patients. At least two (expected) disease-causing alleles in the ABCA4 gene were identified in 27 (61.4%) patients, one allele in 11 (25%) patients, and no ABCA4 mutations were found in six (13.6%) patients. Altogether, 39 different disease-causing ABCA4 variants, including seven new, were identified on 65 (74%) chromosomes, most of which were unique for this racial group. The most frequent ABCA4 mutation in this cohort was c.6320G>A (p.(R2107H)), representing 19.3% of all disease-associated alleles. No large copy number variants were identified in any patient. Most patients reported later onset of symptoms. In summary, the ABCA4 mutation spectrum in patients of West African descent differs significantly from that in patients of European descent, resulting in a later onset and "milder" disease.

%B Hum Mutat %V 35 %P 1187-94 %8 2014 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/25066811?dopt=Abstract %R 10.1002/humu.22626