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

Karen Grønskov,Cathrine Jespersgaard,Pernille Harris,Thomas Rosenberg,Gitte Hoffmann Bruun,Karen Brøndum-Nielsen,Brage S Andresen

doi:10.1038/s41598-018-37272-5

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.

Highlights

Oculocutaneous albinism (OCA) is a genetically heterogeneous disorder which affects eyes, skin and hair
To search for the missing mutations, the genomic region of TYR was sequenced in 15 individuals with albinism of whom 12 were heterozygous for a mutation in TYR and three were heterozygous for a mutation in both TYR and OCA2 (Fig. S1 box 2; Table S1)
Rs147546939G is exclusively present in individuals with albinism who are either heterozygous for a TYR variant (21/58 alleles, MAF = 0.362) or mutation negative (17/94 alleles, MAF = 0.1809) (Fig. S1 box 3 and 5)

Summary

Introduction

Oculocutaneous albinism (OCA) is a genetically heterogeneous disorder which affects eyes, skin and hair. For all types of albinism, the ocular signs are nystagmus, refractive errors, reduced visual acuity, iris hypoplasia, peripheral retinal pallor, foveal hypoplasia, and misrouting of the optic pathways. None of these signs, are either obligate or diagnostic[2]. Molecular genetic analysis of the seven genes listed above, provides a genetic diagnosis in approximately half of the cases. This leaves relatively many affected individuals without a genetic diagnosis and an unexpectedly large proportion of these are heterozygous for mutations in TYR. With the implementation of Generation Sequencing (NGS), it has become possible to investigate non-coding regions of the genes and perform copy number variation (CNV) analysis

Methods

Results

Conclusion