title: Autosomal-dominant microtia linked to five tandem copies of a copy-number-variable region at chromosome 4p16.
abstract: Recently, large-scale benign copy-number variations (CNVs)--encompassing over 12% of the genome and containing genes considered to be dosage tolerant for human development--were uncovered in the human population. Here we present a family with a novel autosomal-dominantly inherited syndrome characterized by microtia, eye coloboma, and imperforation of the nasolacrimal duct. This phenotype is linked to a cytogenetically visible alteration at 4pter consisting of five copies of a copy-number-variable region, encompassing a low-copy repeat (LCR)-rich sequence. We demonstrate that the approximately 750 kb amplicon occurs in exact tandem copies. This is the first example of an amplified CNV associated with a Mendelian disorder, a discovery that implies that genome screens for genetic disorders should include the analysis of so-called benign CNVs and LCRs.
authors.affiliation: Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Irina
authors.initials: I
authors.lastname: Balikova
authors.forename: Kevin
authors.initials: K
authors.lastname: Martens
authors.forename: Cindy
authors.initials: C
authors.lastname: Melotte
authors.forename: Mustapha
authors.initials: M
authors.lastname: Amyere
authors.forename: Steven
authors.initials: S
authors.lastname: Van Vooren
authors.forename: Yves
authors.initials: Y
authors.lastname: Moreau
authors.forename: David
authors.initials: D
authors.lastname: Vetrie
authors.forename: Heike
authors.initials: H
authors.lastname: Fiegler
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Carter
authors.forename: Thomas
authors.initials: T
authors.lastname: Liehr
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Ingele
authors.initials: I
authors.lastname: Casteels
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.forename: Joris Robert
authors.initials: JR
authors.lastname: Vermeesch
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D002894:Chromosomes, Human, Pair 4; D003103:Coloboma / Q000235:genetics / Q000473:pathology; D004431:Ear, External / Q000002:abnormalities*; D005260:Female; D018628:Gene Dosage; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D009301:Nasolacrimal Duct / Q000002:abnormalities; D010375:Pedigree; D013577:Syndrome