Autosomal-dominant microtia linked to five tandem copies of a copy-number-variable region at chromosome 4p16.
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.
Balikova
Irina
I
Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
Martens
Kevin
K
Melotte
Cindy
C
Amyere
Mustapha
M
Van Vooren
Steven
S
Moreau
Yves
Y
Vetrie
David
D
Fiegler
Heike
H
Carter
Nigel P
NP
Liehr
Thomas
T
Vikkula
Miikka
M
Matthijs
Gert
G
Fryns
Jean-Pierre
JP
Casteels
Ingele
I
Devriendt
Koen
K
Vermeesch
Joris Robert
JR
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