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- Title
A pathogenic haplotype, common in Europeans, causes autosomal recessive albinism and uncovers missing heritability in OCA1.
- Authors
Grønskov, Karen; Jespersgaard, Cathrine; Bruun, Gitte Hoffmann; Harris, Pernille; Brøndum-Nielsen, Karen; Andresen, Brage S.; Rosenberg, Thomas
- Abstract
Oculocutaneous albinism (OCA) is a genetically heterogeneous disorder. Six genes are associated with autosomal recessive OCA (TYR, OCA2, TYRP1, SLC45A2, SLC24A5 and LRMDA), and one gene, GPR143, is associated with X-linked ocular albinism (OA). Molecular genetic analysis provides a genetic diagnosis in approximately 60% of individuals with clinical OA/OCA. A considerably number of the remaining 40% are heterozygous for a causative sequence variation in TYR. To identify missing causative sequence variants in these, we used a NGS based approach, genotyping and segregation analysis. We report two putative pathogenic haplotypes which only differ by two extremely rare SNVs, indicating that the haplotypes have a common derivation. Both haplotypes segregate consistent with an autosomal recessive inheritance pattern and include the allele p.S192Y-p.R402Q. An explanation for the pathogenicity of the haplotypes could be the combination of p.S192Y and p.R402Q. Homozygosity for the pathogenic haplotypes causes a partial albinism phenotype. In our cohort, 15% of affected individuals had a molecular genetic diagnosis involving the pathogenic haplotype. Consequently, the prevalence of albinism seems to be substantially underestimated, and children with unexplained bilateral subnormal vision and/or nystagmus should be analysed clinically and molecularly for albinism.
- Publication
Scientific Reports, 2019, Vol 9, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-018-37272-5