title: Expansion of a 12-kb VNTR containing the REXO1L1 gene cluster underlies the microscopically visible euchromatic variant of 8q21.2.
abstract: Copy number variants visible with the light microscope have been described as euchromatic variants (EVs) and EVs with extra G-light material at 8q21.2 have been reported only once before. We report four further patients with EVs of 8q21.2 ascertained for clinical (3) or reproductive reasons (1). Enhanced signal strength from two overlapping bacterial artificial chromosomes (BACs) and microarray analysis mapped the EV to a 284-kb interval in the reference genome. This interval consists of a sequence gap flanked by segmental duplications that contain the 12-kb components of one of the largest Variable Number Tandem Repeat arrays in the human genome. Using digital NanoString technology with a custom probe for the RNA exonuclease 1 homologue (S. cerevisiae)-like 1 (REXO1L1) gene within each 12-kb repeat, significantly enhanced diploid copy numbers of 270 and 265 were found in an EV family and a median diploid copy number of 166 copies in 216 controls. These 8q21.2 EVs are not thought to have clinical consequences as the phenotypes of the probands were inconsistent, those referred for reproductive reasons were otherwise phenotypically normal and the REXO1L1 gene has no known disease association. This EV was found in 4/3078 (1 in 770) consecutive referrals for chromosome analysis and needs to be distinguished from pathogenic imbalances of medial 8q. The REXO1L1 gene product is a marker of hepatitis C virus (HCV) infection and a possible association between REXO1L1 copy number and susceptibility to HCV infection, progression or response to treatment has not yet been excluded.
authors.affiliation: Cytogenetics, Department of Pathology, Royal Columbian Hospital, New Westminster, British Columbia, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Tyson
authors.affiliation: The Mindich Child Health and Development Institute, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, NY, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sharp
authors.affiliation: Cytogenetics, Department of Pathology, Royal Columbian Hospital, New Westminster, British Columbia, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Hrynchak
authors.affiliation: Department of Medical Genetics, UBC, Vancouver, British Columbia, Canada.
authors.forename: Siu L
authors.initials: SL
authors.lastname: Yong
authors.affiliation: Department of Genetics, University of Leicester, Leicester, UK.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hollox
authors.affiliation: The Mindich Child Health and Development Institute, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, NY, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Warburton
authors.affiliation: Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: John Ck
authors.initials: JC
authors.lastname: Barber
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D015894:Genome, Human; D016174:Hepacivirus; D006526:Hepatitis C / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007231:Infant, Newborn; D007621:Karyotyping; D008297:Male; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D056916:Segmental Duplications, Genomic
chemical_list: D002352:Carrier Proteins; D005819:Genetic Markers; D009687:Nuclear Proteins; C477883:REXO1 protein, human
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