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

Justyna A. Karolak , Tomasz Gambin , Jose A. Pitarque , Andrea Molinari , Shalini N. Jhangiani , Pawel Stankiewicz , James R. Lupski , Marzena Gajecka


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 o0.001 in control population) nonsynonymous variants in both affected individuals. Among them, 16 SNVs were selected for further evaluation. Segregation analysis revealed that variants c.475T4G in SKP1, c.671G4A in PROB1, and c.527G4A in IL17B in the 5q31.1–q35.3 linkage region, and c.850G4A 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.
Author Justyna A. Karolak - [Poznan University of Medical Sciences]
Justyna A. Karolak,,
, Tomasz Gambin (FEIT / IN)
Tomasz Gambin,,
- The Institute of Computer Science
, Jose A. Pitarque - [Hospital Metropolitano]
Jose A. Pitarque,,
, Andrea Molinari - [Hospital Metropolitano]
Andrea Molinari,,
, Shalini N. Jhangiani - [Baylor College of Medicine]
Shalini N. Jhangiani,,
, Pawel Stankiewicz - [Baylor College of Medicine]
Pawel Stankiewicz,,
, James R. Lupski - [Baylor College of Medicine]
James R. Lupski,,
, Marzena Gajecka - [Poznan University of Medical Sciences]
Marzena Gajecka,,
Journal seriesEuropean Journal of Human Genetics, ISSN 1018-4813
Issue year2016
NoOnline 2016
Publication size in sheets0.5
ASJC Classification2716 Genetics(clinical); 1311 Genetics
ProjectDevelopment of new algorithms in the areas of software and computer architecture, artificial intelligence and information systems and computer graphics . Project leader: Rybiński Henryk, , Phone: +48 22 234 7731, start date 18-05-2015, end date 30-11-2016, II/2015/DS/1, Completed
WEiTI Działalność statutowa
Languageen angielski
VariantsInSKP1.pdf 383.87 KB
Score (nominal)35
Score sourcejournalList
ScoreMinisterial score = 35.0, 15-05-2020, ArticleFromJournal
Ministerial score (2013-2016) = 35.0, 15-05-2020, ArticleFromJournal
Publication indicators WoS Citations = 4; Scopus Citations = 3; GS Citations = 3.0; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.376; WoS Impact Factor: 2016 = 4.287 (2) - 2016=3.977 (5)
Citation count*3 (2018-01-18)
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