Autosomal-Dominant Microtia Linked to Five Tandem Copies of a Copy-Number-Variable Region at Chromosome 4p16

• Published in: American journal of human genetics Vol. 82; no. 1; pp. 181 - 187
• Main Authors: Balikova, Irina, Martens, Kevin, Melotte, Cindy, Amyere, Mustapha, Van Vooren, Steven, Moreau, Yves, Vetrie, David, Fiegler, Heike, Carter, Nigel P., Liehr, Thomas, Vikkula, Miikka, Matthijs, Gert, Fryns, Jean-Pierre, Casteels, Ingele, Devriendt, Koen, Vermeesch, Joris Robert
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-01-2008; University of Chicago Press; Cell Press; Elsevier
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Biological and medical sciences; Biological variation; Chromosomes, Human, Pair 4; Classical genetics, quantitative genetics, hybrids; Coloboma - genetics; Coloboma - pathology; Ear, External - abnormalities; Female; Fundamental and applied biological sciences. Psychology; Gene Dosage; General aspects. Genetic counseling; Genes, Dominant; Genetic disorders; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Human; Humans; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Nasolacrimal Duct - abnormalities; Pedigree; Syndrome; Genetic mapping; Human; Copy number; Variable region; Chromosome; Genetic disease; Pinna; Aplasia; Malformation; Autosomal character; Genetics; Dominant character; Microtia
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2007.08.001

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 ∼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.