title: Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family.
abstract: This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.
authors: Department of Medical Biosciences/Medical and Clinical Genetics, University of Umeå, Umeå, Sweden.
authors: Frida
authors: F
authors: Jonsson
authors: Marie S
authors: MS
authors: Burstedt
authors: Ola
authors: O
authors: Sandgren
authors: Anna
authors: A
authors: Norberg
authors: Irina
authors: I
authors: Golovleva
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D001483:Base Sequence; D020090:Chromosome Segregation / Q000235:genetics; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D005654:Fundus Oculi; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics*; D008268:Macular Degeneration / Q000151:congenital* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000080362:Stargardt Disease; D013548:Sweden
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; C448939:CRB1 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins