It has been proposed that duplications of 8p23.1 are either euchromatic variants of the 8p23.1 defensin domain with no phenotypic consequences or true duplications associated with developmental delay and heart defects. Here, we provide evidence for both alternatives in two new families. A duplication of most of band 8p23.1 (circa 5 Mb) was found in a girl of 8 years with pulmonary stenosis and mild language delay. BAC fluorescence in situ hybridisation (FISH) and multiplex amplifiable probe hybridisation (MAPH) showed that the two copies of the duplicated segment were sited, in an alternating fashion, between three copies of a circa 300–450 kb segment from 8p23.1 distal to REPD. Copy number of the variable 8p23.1 defensin domain was consistent with duplication but within the normal range. Duplication of the GATA-binding protein 4 gene (GATA4) in this patient and others with and without heart defects, suggests it is a dosage-sensitive gene with variable penetrance. A cytogenetically similar duplication of 8p23.1 was found at prenatal diagnosis in a fetus, father and grandmother. There was no duplication using BAC FISH but MAPH showed 11 copies of the 360 kb variable defensin domain which is within the expanded range found in previous euchromatic variant carriers. Semiquantitative FISH (SQ-FISH) was consistent with a simultaneous expansion of the adjacent olfactory receptor repeats. These results distinguish duplications of 8p23.1 with clinically significant consequences from benign copy number variants, which have not yet been associated with qualitative or quantitative traits.
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We are indebted to the patients who contributed additional samples and photographs. We are grateful to the Sanger Centre for providing the Ensembl tiling path clones and to Dr Hiroaki Shizuya for kindly providing BAC 51D11. VM is supported as part of the National Genetics Reference Laboratory (Wessex) by the UK Department of Health Genetics, Embryology and Assisted Conception Unit and TL was supported in parts by the Dr Robert Pfleger-Stiftung fund. EJH is supported by a Welcome Trust Bioarchaeology Postdoctoral Fellowship (Grant no. 071024). The image enhancement equipment used for parts of this work was provided by the Wellcome Trust and Trust Funds of Salisbury NHS Health Care Trust. Finally, we thank Simon Thomas for his constructive reading of the manuscript.
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Barber, J., Maloney, V., Hollox, E. et al. Duplications and copy number variants of 8p23.1 are cytogenetically indistinguishable but distinct at the molecular level. Eur J Hum Genet 13, 1131–1136 (2005). https://doi.org/10.1038/sj.ejhg.5201475
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