July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Genetic and molecular study of keratoconus in a Brazilian family
Author Affiliations & Notes
  • Rossen Mihaylov Hazarbassanov
    Department of Ophthalmology and Visual Sciences, Paulista School of Medicine, Federal University of São Paulo, São Paulo, Brazil
    Department of Genetics and Evolutionary Biology, Instituto de Biociências - Universidade de São Paulo, São Paulo, SP, Brazil
  • Alan Besborodco
    Department of Genetics and Evolutionary Biology, Instituto de Biociências - Universidade de São Paulo, São Paulo, SP, Brazil
  • Paulo A Otto
    Department of Genetics and Evolutionary Biology, Instituto de Biociências - Universidade de São Paulo, São Paulo, SP, Brazil
  • Regina Celia Mingroni Netto
    Department of Genetics and Evolutionary Biology, Instituto de Biociências - Universidade de São Paulo, São Paulo, SP, Brazil
  • Footnotes
    Commercial Relationships   Rossen Hazarbassanov, None; Alan Besborodco, None; Paulo Otto, None; Regina Netto, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5415. doi:
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      Rossen Mihaylov Hazarbassanov, Alan Besborodco, Paulo A Otto, Regina Celia Mingroni Netto; Genetic and molecular study of keratoconus in a Brazilian family. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5415.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To search for genetic factors that could increase susceptibility to keratoconus by genomic wide linkage scans (GWLS).

Methods : This study was approved by local IRB and followed the Declaration of Helsinki. A large 4-generation mixed background family composed of 19 individuals - 18 with previous diagnosis of keratoconus - was selected. The following examinations were performed: biometrics, topography, pachymetry, retinography, corneal tomography (Pentacam), autorefraction, best corrected visual acuity and biomicroscopy. Venous blood was collected from individuals after informed consent. Genotyping was performed with high-density array SNPsAxiom® Genome-Wide Human Origins 1. For estimation of keratoconus penetrance rate standardized methods were applied under the hypothesis of dominant autosomal transmission. The results of the genotyping were analyzed by Morgan software that performs the Logarithm of the Odds (LOD) Score calculations of multiple points. Concomitantly, a wide exome sequencing (WES) of an affected individual was performed to identify candidate pathogenic variants to further investigate their transmission to other family members. Sanger sequencing was used to search for variants in candidate genes or to confirm their presence after massive parallel sequencing. Potentially disease-related variants were also evaluated in the remaining members of the family by conventional Sanger sequencing. The purified sequencing products were sent to the Human Genome and Stem Cell Research Center (Sao Paulo, Brazil), where the final steps of the sequencing reaction and capillary electrophoresis were performed using the "ABI 3730xl DNA Analyzer" equipment (ThermoFisher®).

Results : From the analysis of 123 suspected variants 5 chromosomal regions were calculated with LOD Score greater than 1, as found individual NGS analysis. In addition, 3 regions with LOD Score> 1 (1p35.2-p34.3; 2q32.3-q33.2; 3q23; 5q11.2-q13.2) and one with LOD Score> 2 (LOD=2.99) (19p13.11 -q12) were found.

Conclusions : The LOD score obtained is not sufficient to confirm the binding region. However, the value of 2.99 is strongly suggestive that the responsible gene is located in the mapped region of chromosome 19. Therefore, new molecular investigations may be useful for the implication of a new gene in the pathogenesis of keratoconus or in the heritability of one of its predisposition cofactors, such as central corneal thickness or corneal curvature angle.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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