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Eur J Hum Genet. 2016 Jan;25(1):73-78. doi: 10.1038/ejhg.2016.130. Epub 2016 Oct 5.

Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1-q35.3 susceptibility locus identified by whole-exome sequencing.

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Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland.
Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
Department of Ophthalmology, Hospital Metropolitano, Quito, Ecuador.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Texas Children's Hospital, Houston, TX, USA.


Keratoconus (KTCN) is a protrusion and thinning of the cornea, resulting in impairment of visual function. The extreme genetic heterogeneity makes it difficult to discover factors unambiguously influencing the KTCN phenotype. In this study, we used whole-exome sequencing (WES) and Sanger sequencing to reduce the number of candidate genes at the 5q31.1-q35.3 locus and to prioritize other potentially relevant variants in an Ecuadorian family with KTCN. We applied WES in two affected KTCN individuals from the Ecuadorian family that showed a suggestive linkage between the KTCN phenotype and the 5q31.1-q35.3 locus. Putative variants identified by WES were further evaluated in this family using Sanger sequencing. Exome capture discovered a total of 173 rare (minor allele frequency <0.001 in control population) nonsynonymous variants in both affected individuals. Among them, 16 SNVs were selected for further evaluation. Segregation analysis revealed that variants c.475T>G in SKP1, c.671G>A in PROB1, and c.527G>A in IL17B in the 5q31.1-q35.3 linkage region, and c.850G>A in HKDC1 in the 10q22 locus completely segregated with the phenotype in the studied KTCN family. We demonstrate that a combination of various techniques significantly narrowed the studied genomic region and reduced the list of the putative exonic variants. Moreover, since this locus overlapped two other chromosomal regions previously recognized in distinct KTCN studies, our findings suggest that this 5q31.1-q35.3 locus might be linked with KTCN.

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