Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Judith Lechner, Louise F. Porter, Aine Rice, Veronique Vitart, David J. Armstrong, Daniel F. Schorderet, Francis L. Munier, Alan F. Wright, Chris F. Inglehearn, Graeme C. Black, David A. Simpson, Forbes Manson, Colin Willoughby

    Research output: Contribution to journalArticle

    29 Citations (Scopus)

    Abstract

    Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date.
    LanguageEnglish
    Pages5527-5535
    JournalHuman Molecular Genetics
    Volume23
    Issue number20
    DOIs
    Publication statusAccepted/In press - 19 May 2014

    Fingerprint

    Keratoconus
    Cornea
    Alleles
    Genes
    Mutation
    Sclera
    Corneal Transplantation
    Genome-Wide Association Study
    Connective Tissue
    Single Nucleotide Polymorphism
    Rupture
    Phenotype
    Protein Domains
    Proteins

    Keywords

    • keratoconus
    • genetics
    • brittle cornea syndrome
    • ZNF469

    Cite this

    Lechner, J., Porter, L. F., Rice, A., Vitart, V., Armstrong, D. J., Schorderet, D. F., ... Willoughby, C. (Accepted/In press). Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus. Human Molecular Genetics, 23(20), 5527-5535. https://doi.org/10.1093/hmg/ddu253
    Lechner, Judith ; Porter, Louise F. ; Rice, Aine ; Vitart, Veronique ; Armstrong, David J. ; Schorderet, Daniel F. ; Munier, Francis L. ; Wright, Alan F. ; Inglehearn, Chris F. ; Black, Graeme C. ; Simpson, David A. ; Manson, Forbes ; Willoughby, Colin. / Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 20. pp. 5527-5535.
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    title = "Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus",
    abstract = "Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5{\%} of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date.",
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    author = "Judith Lechner and Porter, {Louise F.} and Aine Rice and Veronique Vitart and Armstrong, {David J.} and Schorderet, {Daniel F.} and Munier, {Francis L.} and Wright, {Alan F.} and Inglehearn, {Chris F.} and Black, {Graeme C.} and Simpson, {David A.} and Forbes Manson and Colin Willoughby",
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    Lechner, J, Porter, LF, Rice, A, Vitart, V, Armstrong, DJ, Schorderet, DF, Munier, FL, Wright, AF, Inglehearn, CF, Black, GC, Simpson, DA, Manson, F & Willoughby, C 2014, 'Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus', Human Molecular Genetics, vol. 23, no. 20, pp. 5527-5535. https://doi.org/10.1093/hmg/ddu253

    Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus. / Lechner, Judith; Porter, Louise F.; Rice, Aine; Vitart, Veronique; Armstrong, David J.; Schorderet, Daniel F.; Munier, Francis L.; Wright, Alan F.; Inglehearn, Chris F.; Black, Graeme C.; Simpson, David A.; Manson, Forbes; Willoughby, Colin.

    In: Human Molecular Genetics, Vol. 23, No. 20, 19.05.2014, p. 5527-5535.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

    AU - Lechner, Judith

    AU - Porter, Louise F.

    AU - Rice, Aine

    AU - Vitart, Veronique

    AU - Armstrong, David J.

    AU - Schorderet, Daniel F.

    AU - Munier, Francis L.

    AU - Wright, Alan F.

    AU - Inglehearn, Chris F.

    AU - Black, Graeme C.

    AU - Simpson, David A.

    AU - Manson, Forbes

    AU - Willoughby, Colin

    PY - 2014/5/19

    Y1 - 2014/5/19

    N2 - Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date.

    AB - Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date.

    KW - keratoconus

    KW - genetics

    KW - brittle cornea syndrome

    KW - ZNF469

    U2 - 10.1093/hmg/ddu253

    DO - 10.1093/hmg/ddu253

    M3 - Article

    VL - 23

    SP - 5527

    EP - 5535

    JO - Human Molecular Genetics

    T2 - Human Molecular Genetics

    JF - Human Molecular Genetics

    SN - 0964-6906

    IS - 20

    ER -

    Lechner J, Porter LF, Rice A, Vitart V, Armstrong DJ, Schorderet DF et al. Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus. Human Molecular Genetics. 2014 May 19;23(20):5527-5535. https://doi.org/10.1093/hmg/ddu253