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

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

doi:10.1038/s41598-018-37272-5

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

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

Institut for Klinisk Medicin

12 Citationer (Scopus)

2 Downloads (Pure)

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.

Originalsprog	Engelsk
Artikelnummer	645
Tidsskrift	Scientific Reports
Vol/bind	9
Udgave nummer	1
Antal sider	7
ISSN	2045-2322
DOI	https://doi.org/10.1038/s41598-018-37272-5
Status	Udgivet - 1 dec. 2019

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10.1038/s41598-018-37272-5Licens: CC BY

A pathogenic haplotype, common in Europeans, causes autosomal recessive albinism and uncovers missing heritability in OCA1Forlagets udgivne version, 1,04 MBLicens: CC BY

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

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.",

author = "Karen Gr{\o}nskov and Cathrine Jespersgaard and Bruun, {Gitte Hoffmann} and Pernille Harris and Karen Br{\o}ndum-Nielsen and Andresen, {Brage S.} and Thomas Rosenberg",

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T1 - A pathogenic haplotype, common in Europeans, causes autosomal recessive albinism and uncovers missing heritability in OCA1

AU - Grønskov, Karen

AU - Jespersgaard, Cathrine

AU - Bruun, Gitte Hoffmann

AU - Harris, Pernille

AU - Brøndum-Nielsen, Karen

AU - Andresen, Brage S.

AU - Rosenberg, Thomas

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-018-37272-5

DO - 10.1038/s41598-018-37272-5

M3 - Journal article

C2 - 30679655

SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 645

ER -

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

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