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Incomplete penetrance, variable expressivity or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities

Incomplete penetrance, variable expressivity or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities
Incomplete penetrance, variable expressivity or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities
The direct transmission of microscopically visible unbalanced chromosome abnormalities (UBCAs) is rare and usually has phenotypic consequences. Here we report four families in which a normal phenotype was initially found in one or more family members. Each UBCA was interpreted with regard to overlapping examples and factors previously associated with transmitted imbalances including incidental ascertainment, low gene density, benign copy number variation (CNV) content and gene relatedness. A 4.56 Mb deletion of 8p23.1-p23.2 was thought to be causal in the affected proband but showed incomplete penetrance in her mother and sibling (Family 1). Incomplete penetrance was also associated with a 10.88 Mb duplication of 13q21.31-q22.1 (Family 3) and dosage insensitivity with a 17.6 Mb deletion of 22pter-q11.21 (Family 4) that were both ascertained at prenatal diagnosis and each found in 4 unaffected family members. The 22pter-q11.21 deletion is part of a region with high benign CNV content and supports the mapping of cat eye syndrome to a 600 kb interval of 22q11.1-q11.21. Low gene densities of less than 2.0 genes/Mb were found in each of these three families but only after segmentally duplicated genes were excluded from the deletions of 8p and 22q. In contrast, gene density was average and variable expressivity associated with a 3.59 Mb duplication of 8p23.1 incidentally ascertained for paternal infertility (Family 2). Our results indicate that a greater degree of direct parental transmission, incomplete penetrance and variable expression are features of both sub-microscopic CNVs and UBCAs with relatively low gene and high benign CNV content.
1552-4825
319–329
Bateman, Mark
1fdbeb26-4d05-4ba7-80ce-f16680ddcad9
Collinson, Morag
e1313be8-5065-4e8a-a4df-ccf5bf29d466
Bunyan, David
d57bd2a7-d531-4892-bcce-e096dc95eee7
Collins, Amanda
c314bd0c-2043-471a-8db2-7b7a1a008ce0
Duncan, Philippa
bce63346-7272-4986-b2b7-04916d220e95
Firth, Rachel
bd1644e0-3b88-48b5-9827-edcd191d8e6d
Harrison, Victoria
39844b8f-ebf6-40f9-a2b5-5fd8d588c672
Homfrey, Tessa
72a7f675-6eb2-42f2-86f5-bf38b71447da
Huang, Shuwen
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Kirk, Beth
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Lachlan, Katherine
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Maloney, Viv
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Barber, John
4785a6e4-bd63-4230-ab61-41a0ae12c761
Bateman, Mark
1fdbeb26-4d05-4ba7-80ce-f16680ddcad9
Collinson, Morag
e1313be8-5065-4e8a-a4df-ccf5bf29d466
Bunyan, David
d57bd2a7-d531-4892-bcce-e096dc95eee7
Collins, Amanda
c314bd0c-2043-471a-8db2-7b7a1a008ce0
Duncan, Philippa
bce63346-7272-4986-b2b7-04916d220e95
Firth, Rachel
bd1644e0-3b88-48b5-9827-edcd191d8e6d
Harrison, Victoria
39844b8f-ebf6-40f9-a2b5-5fd8d588c672
Homfrey, Tessa
72a7f675-6eb2-42f2-86f5-bf38b71447da
Huang, Shuwen
50d7f3f2-2767-462c-a3f9-bf4711657e1f
Kirk, Beth
6c2eb6bb-304f-441d-8f99-f907c48af0b5
Lachlan, Katherine
175ce889-ede8-477e-93eb-afefc1af5dda
Maloney, Viv
41016098-bf77-434e-b8ea-beec46340edb
Barber, John
4785a6e4-bd63-4230-ab61-41a0ae12c761

Bateman, Mark, Collinson, Morag, Bunyan, David, Collins, Amanda, Duncan, Philippa, Firth, Rachel, Harrison, Victoria, Homfrey, Tessa, Huang, Shuwen, Kirk, Beth, Lachlan, Katherine, Maloney, Viv and Barber, John (2018) Incomplete penetrance, variable expressivity or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities American Journal of Medical Genetics Part A, 176, (2), 319–329. (doi:10.1002/ajmg.a.38564).

Record type: Article

Abstract

The direct transmission of microscopically visible unbalanced chromosome abnormalities (UBCAs) is rare and usually has phenotypic consequences. Here we report four families in which a normal phenotype was initially found in one or more family members. Each UBCA was interpreted with regard to overlapping examples and factors previously associated with transmitted imbalances including incidental ascertainment, low gene density, benign copy number variation (CNV) content and gene relatedness. A 4.56 Mb deletion of 8p23.1-p23.2 was thought to be causal in the affected proband but showed incomplete penetrance in her mother and sibling (Family 1). Incomplete penetrance was also associated with a 10.88 Mb duplication of 13q21.31-q22.1 (Family 3) and dosage insensitivity with a 17.6 Mb deletion of 22pter-q11.21 (Family 4) that were both ascertained at prenatal diagnosis and each found in 4 unaffected family members. The 22pter-q11.21 deletion is part of a region with high benign CNV content and supports the mapping of cat eye syndrome to a 600 kb interval of 22q11.1-q11.21. Low gene densities of less than 2.0 genes/Mb were found in each of these three families but only after segmentally duplicated genes were excluded from the deletions of 8p and 22q. In contrast, gene density was average and variable expressivity associated with a 3.59 Mb duplication of 8p23.1 incidentally ascertained for paternal infertility (Family 2). Our results indicate that a greater degree of direct parental transmission, incomplete penetrance and variable expression are features of both sub-microscopic CNVs and UBCAs with relatively low gene and high benign CNV content.

Text Bateman et al Transmitted imbalance paper 16-0986.R2 as re-submitted - Accepted Manuscript
Restricted to Repository staff only until 13 February 2019.
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Accepted/In Press date: 14 November 2017
e-pub ahead of print date: 1 December 2017
Published date: February 2018

Identifiers

Local EPrints ID: 415713
URI: https://eprints.soton.ac.uk/id/eprint/415713
ISSN: 1552-4825
PURE UUID: 2dcf1966-f4e8-4a6a-9301-5eb9db781eba

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Date deposited: 21 Nov 2017 17:30
Last modified: 21 Feb 2018 17:31

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Contributors

Author: Mark Bateman
Author: Morag Collinson
Author: David Bunyan
Author: Amanda Collins
Author: Philippa Duncan
Author: Rachel Firth
Author: Victoria Harrison
Author: Tessa Homfrey
Author: Shuwen Huang
Author: Beth Kirk
Author: Katherine Lachlan
Author: Viv Maloney
Author: John Barber

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