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Inside the 8p23.1 duplication syndrome; eight microduplications of likely or uncertain clinical significance

Inside the 8p23.1 duplication syndrome; eight microduplications of likely or uncertain clinical significance
Inside the 8p23.1 duplication syndrome; eight microduplications of likely or uncertain clinical significance
The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000. The core 3.68?Mb duplication contains 32 genes of which five are currently candidates for the phenotypic features. Here we describe four patients and five families with eight microduplications of 8p23.1 ranging from 187 to 1082?kb in size and one atypical duplication of 4?Mb. These indicate that a minimal region of overlap (MRO) in medial 8p23.1 can give rise to features of 8p23.1 DS including developmental delay, dysmorphism, macrocephaly and otitis media, but not congenital heart disease (CHD). This MRO spans 776?kb (chr8:10,167,881–10,943,836 hg19) and contains SOX7 and seven of the other 32 core 8p23.1 DS genes. In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS. The clinical significance of three further 8p23.1 microduplications was uncertain due to additional genetic factors without which the probands might not have come to medical attention. Variable expressivity was indicated by the almost entirely unaffected parents in all five families and the mildly affected sibling in one. Intronic interruptions of six genes by microduplication breakpoint intervals had no apparent additional clinical consequences. Our results suggest that 8p23.1 DS is an oligogenetic condition largely caused by the duplication and interactions of the SOX7 and GATA4 transcription factors
microduplication, 8p23.1, clinical significance, candidate genes, SOX7, GATA4, variable penetrance, DNA array
1552-4825
2052-2064
Barber, John C.K.
4785a6e4-bd63-4230-ab61-41a0ae12c761
Rosenfeld, Jill A.
718bacb4-744a-4023-bb03-a3a1f8ea8d71
Graham, John M.
6b7d9d9c-6f1b-423a-bc14-12895ea12094
Kramer, Nancy
a662bf9c-af26-48ad-ba8d-131006d1f291
Lachlan, Katherine L.
175ce889-ede8-477e-93eb-afefc1af5dda
Bateman, Mark S.
78a529cd-b8d1-4cf3-9f46-1da3cb19bfaa
Collinson, Morag N.
e1313be8-5065-4e8a-a4df-ccf5bf29d466
Stadheim, Barbro Fossøy
67c9df80-6b47-4809-88da-a073a618927e
Turner, Claire L.S.
ff0d9c38-aaeb-47cf-8339-4a2a5c62baaf
Gauthier, Jacqueline N.
3b303bbf-42de-4e42-84df-2a05c04ee559
Reimschisel, Tyler E.
4cced6ba-dd47-431a-882d-ee131c5684f9
Qureshi, Athar M.
3ec6758a-8eb9-4a36-93ab-bfded0496b3f
Dabir, Tabib A.
556fc755-d586-4238-89e5-38c6fd91457e
Humphreys, Mervyn W.
14c6c848-bfd0-4600-af64-3c135db05516
Marble, Michael
afacbf5c-1066-485c-9ac8-215adcac8d73
Huang, Taosheng
a734fc91-6c1e-4f21-8784-3f269d929866
Beal, Sarah J.
8b91d0cb-d94a-40a5-b15f-0ada984555b5
Massiah, Joanne
bc607b37-cce3-4b8e-86e2-414c10313a91
Taylor, Emma-Jane
15ca3766-cb76-4217-999e-ada378903d58
Wynn, Sarah L.
c652fb85-4468-41f5-b9b2-9b3de3017b46
Barber, John C.K.
4785a6e4-bd63-4230-ab61-41a0ae12c761
Rosenfeld, Jill A.
718bacb4-744a-4023-bb03-a3a1f8ea8d71
Graham, John M.
6b7d9d9c-6f1b-423a-bc14-12895ea12094
Kramer, Nancy
a662bf9c-af26-48ad-ba8d-131006d1f291
Lachlan, Katherine L.
175ce889-ede8-477e-93eb-afefc1af5dda
Bateman, Mark S.
78a529cd-b8d1-4cf3-9f46-1da3cb19bfaa
Collinson, Morag N.
e1313be8-5065-4e8a-a4df-ccf5bf29d466
Stadheim, Barbro Fossøy
67c9df80-6b47-4809-88da-a073a618927e
Turner, Claire L.S.
ff0d9c38-aaeb-47cf-8339-4a2a5c62baaf
Gauthier, Jacqueline N.
3b303bbf-42de-4e42-84df-2a05c04ee559
Reimschisel, Tyler E.
4cced6ba-dd47-431a-882d-ee131c5684f9
Qureshi, Athar M.
3ec6758a-8eb9-4a36-93ab-bfded0496b3f
Dabir, Tabib A.
556fc755-d586-4238-89e5-38c6fd91457e
Humphreys, Mervyn W.
14c6c848-bfd0-4600-af64-3c135db05516
Marble, Michael
afacbf5c-1066-485c-9ac8-215adcac8d73
Huang, Taosheng
a734fc91-6c1e-4f21-8784-3f269d929866
Beal, Sarah J.
8b91d0cb-d94a-40a5-b15f-0ada984555b5
Massiah, Joanne
bc607b37-cce3-4b8e-86e2-414c10313a91
Taylor, Emma-Jane
15ca3766-cb76-4217-999e-ada378903d58
Wynn, Sarah L.
c652fb85-4468-41f5-b9b2-9b3de3017b46

Barber, John C.K., Rosenfeld, Jill A., Graham, John M., Kramer, Nancy, Lachlan, Katherine L., Bateman, Mark S., Collinson, Morag N., Stadheim, Barbro Fossøy, Turner, Claire L.S., Gauthier, Jacqueline N., Reimschisel, Tyler E., Qureshi, Athar M., Dabir, Tabib A., Humphreys, Mervyn W., Marble, Michael, Huang, Taosheng, Beal, Sarah J., Massiah, Joanne, Taylor, Emma-Jane and Wynn, Sarah L. (2015) Inside the 8p23.1 duplication syndrome; eight microduplications of likely or uncertain clinical significance. American Journal of Medical Genetics Part A, 167 (9), 2052-2064. (doi:10.1002/ajmg.a.37120).

Record type: Article

Abstract

The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000. The core 3.68?Mb duplication contains 32 genes of which five are currently candidates for the phenotypic features. Here we describe four patients and five families with eight microduplications of 8p23.1 ranging from 187 to 1082?kb in size and one atypical duplication of 4?Mb. These indicate that a minimal region of overlap (MRO) in medial 8p23.1 can give rise to features of 8p23.1 DS including developmental delay, dysmorphism, macrocephaly and otitis media, but not congenital heart disease (CHD). This MRO spans 776?kb (chr8:10,167,881–10,943,836 hg19) and contains SOX7 and seven of the other 32 core 8p23.1 DS genes. In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS. The clinical significance of three further 8p23.1 microduplications was uncertain due to additional genetic factors without which the probands might not have come to medical attention. Variable expressivity was indicated by the almost entirely unaffected parents in all five families and the mildly affected sibling in one. Intronic interruptions of six genes by microduplication breakpoint intervals had no apparent additional clinical consequences. Our results suggest that 8p23.1 DS is an oligogenetic condition largely caused by the duplication and interactions of the SOX7 and GATA4 transcription factors

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More information

Accepted/In Press date: 3 April 2015
e-pub ahead of print date: 11 June 2015
Published date: September 2015
Keywords: microduplication, 8p23.1, clinical significance, candidate genes, SOX7, GATA4, variable penetrance, DNA array
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 378321
URI: https://eprints.soton.ac.uk/id/eprint/378321
ISSN: 1552-4825
PURE UUID: 618dad3b-ced9-49e3-8b49-82eb3230111a

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Date deposited: 29 Jun 2015 13:44
Last modified: 09 Feb 2018 17:31

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Contributors

Author: John C.K. Barber
Author: Jill A. Rosenfeld
Author: John M. Graham
Author: Nancy Kramer
Author: Katherine L. Lachlan
Author: Mark S. Bateman
Author: Morag N. Collinson
Author: Barbro Fossøy Stadheim
Author: Claire L.S. Turner
Author: Jacqueline N. Gauthier
Author: Tyler E. Reimschisel
Author: Athar M. Qureshi
Author: Tabib A. Dabir
Author: Mervyn W. Humphreys
Author: Michael Marble
Author: Taosheng Huang
Author: Sarah J. Beal
Author: Joanne Massiah
Author: Emma-Jane Taylor
Author: Sarah L. Wynn

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