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Duplications and copy number variants of 8p23.1 are cytogenetically indistinguishable but distinct at the molecular level

Duplications and copy number variants of 8p23.1 are cytogenetically indistinguishable but distinct at the molecular level
Duplications and copy number variants of 8p23.1 are cytogenetically indistinguishable but distinct at the molecular level
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.
duplication, triplication, 8p23.1, copy number variation, GATA4
1018-4813
1131-1136
Barber, John C.K.
4785a6e4-bd63-4230-ab61-41a0ae12c761
Maloney, Viv
41016098-bf77-434e-b8ea-beec46340edb
Hollox, Edward J.
a07bae66-67dc-4c2c-a655-500ee79f081b
Stuke-Sontheimer, Annegret
91f149e9-3516-4736-b988-5e74ae4ab98e
du Bois, Gabi
576006a7-6024-4a1b-a19e-f0141c0e6b00
Daumiller, Eva
1added7c-755f-4d59-bedf-376b07d12128
Klein-Vogler, Ute
afbe4f0e-af40-407d-96e7-c3ed96bd3aa5
Dufke, Andreas
00af771e-f009-4f31-aa6c-5f178ba15802
Armour, John A.L.
ffd2ec97-97ac-43c8-8289-c55639351310
Liehr, Thomas
b99d17d3-69ab-4bac-8774-5d21177abcda
Barber, John C.K.
4785a6e4-bd63-4230-ab61-41a0ae12c761
Maloney, Viv
41016098-bf77-434e-b8ea-beec46340edb
Hollox, Edward J.
a07bae66-67dc-4c2c-a655-500ee79f081b
Stuke-Sontheimer, Annegret
91f149e9-3516-4736-b988-5e74ae4ab98e
du Bois, Gabi
576006a7-6024-4a1b-a19e-f0141c0e6b00
Daumiller, Eva
1added7c-755f-4d59-bedf-376b07d12128
Klein-Vogler, Ute
afbe4f0e-af40-407d-96e7-c3ed96bd3aa5
Dufke, Andreas
00af771e-f009-4f31-aa6c-5f178ba15802
Armour, John A.L.
ffd2ec97-97ac-43c8-8289-c55639351310
Liehr, Thomas
b99d17d3-69ab-4bac-8774-5d21177abcda

Barber, John C.K., Maloney, Viv, Hollox, Edward J., Stuke-Sontheimer, Annegret, du Bois, Gabi, Daumiller, Eva, Klein-Vogler, Ute, Dufke, Andreas, Armour, John A.L. and Liehr, Thomas (2005) Duplications and copy number variants of 8p23.1 are cytogenetically indistinguishable but distinct at the molecular level. European Journal of Human Genetics, 13 (10), 1131-1136. (doi:10.1038/sj.ejhg.5201475).

Record type: Article

Abstract

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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Published date: 2005
Keywords: duplication, triplication, 8p23.1, copy number variation, GATA4

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Local EPrints ID: 24618
URI: http://eprints.soton.ac.uk/id/eprint/24618
ISSN: 1018-4813
PURE UUID: 3183fdb1-7d6f-4697-9480-fef24ec41aab

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Date deposited: 03 Apr 2006
Last modified: 09 Dec 2019 19:10

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Contributors

Author: John C.K. Barber
Author: Viv Maloney
Author: Edward J. Hollox
Author: Annegret Stuke-Sontheimer
Author: Gabi du Bois
Author: Eva Daumiller
Author: Ute Klein-Vogler
Author: Andreas Dufke
Author: John A.L. Armour
Author: Thomas Liehr

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