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 ∼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.