A pathogenic haplotype, common in Europeans, causes autosomal recessive albinism and uncovers missing heritability in OCA1

• Published in: Scientific reports Vol. 9; no. 1; p. 645
• Main Authors: Grønskov, Karen, Jespersgaard, Cathrine, Bruun, Gitte Hoffmann, Harris, Pernille, Brøndum-Nielsen, Karen, Andresen, Brage S., Rosenberg, Thomas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.01.2019; Nature Publishing Group
• Subjects: 45/23; 45/44; 45/70; 45/77; 631/208/728; 692/699/3161/3165; Albinism; Autosomal recessive inheritance; Diagnosis; Genetic analysis; Genetic screening; Genotyping; Haplotypes; Heredity; Heritability; Humanities and Social Sciences; multidisciplinary; Nystagmus; Ocular albinism; Pathogenicity; Phenotypes; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-37272-5

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.