title: Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1-q35.3 susceptibility locus identified by whole-exome sequencing.
abstract: 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.
authors.affiliation: Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland.|Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Justyna A
authors.initials: JA
authors.lastname: Karolak
authors.affiliation: 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.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Ophthalmology, Hospital Metropolitano, Quito, Ecuador.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Pitarque
authors.affiliation: Department of Ophthalmology, Hospital Metropolitano, Quito, Ecuador.
authors.forename: Andrea
authors.initials: A
authors.lastname: Molinari
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jhangiani
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.|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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland. gamar@man.poznan.pl.|Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland. gamar@man.poznan.pl.
authors.forename: Marzena
authors.initials: M
authors.lastname: Gajecka
mesh_terms: D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D059472:Exome; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006593:Hexokinase / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics*; D007640:Keratoconus / Q000235:genetics* / Q000473:pathology; D008297:Male; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics*
chemical_list: C515924:IL17B protein, human; D020381:Interleukin-17; C000621462:PROB1 protein, human; D011506:Proteins; D044786:S-Phase Kinase-Associated Proteins; C097351:SKP1 protein, human; C000619342:HKDC1 protein, human; D006593:Hexokinase