A germline chromothripsis event stably segregating in 11 individuals through three generations

Birgitte Bertelsen; Lusine Nazaryan-Petersen; Wei Sun; Mana M Mehrjouy; Gangcai Xie; Wei Chen; Lena E Hjermind; Peter E M Taschner; Zeynep Tümer

doi:10.1038/gim.2015.112

A germline chromothripsis event stably segregating in 11 individuals through three generations

Birgitte Bertelsen, Lusine Nazaryan-Petersen, Wei Sun, Mana M Mehrjouy, Gangcai Xie, Wei Chen, Lena E Hjermind, Peter E M Taschner, Zeynep Tümer

35 Citations (Scopus)

Abstract

Purpose:Parentally transmitted germ-line chromothripsis (G-CTH) has been identified in only a few cases. Most of these rearrangements were stably transmitted, in an unbalanced form, from a healthy mother to her child with congenital abnormalities probably caused by de novo copy-number changes of dosage sensitive genes. We describe a G-CTH transmitted through three generations in 11 healthy carriers.Methods:Conventional cytogenetic analysis, mate-pair sequencing, and polymerase chain reaction (PCR) were used to identify the chromosome rearrangement and characterize the breakpoints in all three generations.Results:We identified an apparently balanced translocation t(3;5), later shown to be a G-CTH, in all individuals of a three-generation family. The G-CTH stably segregated without occurrence of additional rearrangements; however, several spontaneous abortions were reported, possibly due to unbalanced transmission. Although seven protein-coding genes are interrupted, no clinical features can be definitively attributed to the affected genes. However, it can be speculated that truncation of one of these genes, encoding ataxia-telangiectasia and Rad3-related protein kinase (ATR), a key component of the DNA damage response, may be related to G-CTH formation.Conclusion:G-CTH rearrangements are not always associated with abnormal phenotypes and may be misinterpreted as balanced two-way translocations, suggesting that G-CTH is an underdiagnosed phenomenon.

Original language	English
Journal	Genetics In Medicine
Volume	18
Issue number	5
Pages (from-to)	494-500
Number of pages	7
ISSN	1098-3600
DOIs	https://doi.org/10.1038/gim.2015.112
Publication status	Published - 1 May 2016

Access to Document

10.1038/gim.2015.112

gim2015112.pdfFinal published version, 342 KB

Cite this

@article{42893fc367a74b949bcefb033f916984,

title = "A germline chromothripsis event stably segregating in 11 individuals through three generations",

abstract = "Purpose:Parentally transmitted germ-line chromothripsis (G-CTH) has been identified in only a few cases. Most of these rearrangements were stably transmitted, in an unbalanced form, from a healthy mother to her child with congenital abnormalities probably caused by de novo copy-number changes of dosage sensitive genes. We describe a G-CTH transmitted through three generations in 11 healthy carriers.Methods:Conventional cytogenetic analysis, mate-pair sequencing, and polymerase chain reaction (PCR) were used to identify the chromosome rearrangement and characterize the breakpoints in all three generations.Results:We identified an apparently balanced translocation t(3;5), later shown to be a G-CTH, in all individuals of a three-generation family. The G-CTH stably segregated without occurrence of additional rearrangements; however, several spontaneous abortions were reported, possibly due to unbalanced transmission. Although seven protein-coding genes are interrupted, no clinical features can be definitively attributed to the affected genes. However, it can be speculated that truncation of one of these genes, encoding ataxia-telangiectasia and Rad3-related protein kinase (ATR), a key component of the DNA damage response, may be related to G-CTH formation.Conclusion:G-CTH rearrangements are not always associated with abnormal phenotypes and may be misinterpreted as balanced two-way translocations, suggesting that G-CTH is an underdiagnosed phenomenon.",

author = "Birgitte Bertelsen and Lusine Nazaryan-Petersen and Wei Sun and Mehrjouy, {Mana M} and Gangcai Xie and Wei Chen and Hjermind, {Lena E} and Taschner, {Peter E M} and Zeynep T{\"u}mer",

year = "2016",

month = may,

day = "1",

doi = "10.1038/gim.2015.112",

language = "English",

volume = "18",

pages = "494--500",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "nature publishing group",

number = "5",

}

TY - JOUR

T1 - A germline chromothripsis event stably segregating in 11 individuals through three generations

AU - Bertelsen, Birgitte

AU - Nazaryan-Petersen, Lusine

AU - Sun, Wei

AU - Mehrjouy, Mana M

AU - Xie, Gangcai

AU - Chen, Wei

AU - Hjermind, Lena E

AU - Taschner, Peter E M

AU - Tümer, Zeynep

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Purpose:Parentally transmitted germ-line chromothripsis (G-CTH) has been identified in only a few cases. Most of these rearrangements were stably transmitted, in an unbalanced form, from a healthy mother to her child with congenital abnormalities probably caused by de novo copy-number changes of dosage sensitive genes. We describe a G-CTH transmitted through three generations in 11 healthy carriers.Methods:Conventional cytogenetic analysis, mate-pair sequencing, and polymerase chain reaction (PCR) were used to identify the chromosome rearrangement and characterize the breakpoints in all three generations.Results:We identified an apparently balanced translocation t(3;5), later shown to be a G-CTH, in all individuals of a three-generation family. The G-CTH stably segregated without occurrence of additional rearrangements; however, several spontaneous abortions were reported, possibly due to unbalanced transmission. Although seven protein-coding genes are interrupted, no clinical features can be definitively attributed to the affected genes. However, it can be speculated that truncation of one of these genes, encoding ataxia-telangiectasia and Rad3-related protein kinase (ATR), a key component of the DNA damage response, may be related to G-CTH formation.Conclusion:G-CTH rearrangements are not always associated with abnormal phenotypes and may be misinterpreted as balanced two-way translocations, suggesting that G-CTH is an underdiagnosed phenomenon.

AB - Purpose:Parentally transmitted germ-line chromothripsis (G-CTH) has been identified in only a few cases. Most of these rearrangements were stably transmitted, in an unbalanced form, from a healthy mother to her child with congenital abnormalities probably caused by de novo copy-number changes of dosage sensitive genes. We describe a G-CTH transmitted through three generations in 11 healthy carriers.Methods:Conventional cytogenetic analysis, mate-pair sequencing, and polymerase chain reaction (PCR) were used to identify the chromosome rearrangement and characterize the breakpoints in all three generations.Results:We identified an apparently balanced translocation t(3;5), later shown to be a G-CTH, in all individuals of a three-generation family. The G-CTH stably segregated without occurrence of additional rearrangements; however, several spontaneous abortions were reported, possibly due to unbalanced transmission. Although seven protein-coding genes are interrupted, no clinical features can be definitively attributed to the affected genes. However, it can be speculated that truncation of one of these genes, encoding ataxia-telangiectasia and Rad3-related protein kinase (ATR), a key component of the DNA damage response, may be related to G-CTH formation.Conclusion:G-CTH rearrangements are not always associated with abnormal phenotypes and may be misinterpreted as balanced two-way translocations, suggesting that G-CTH is an underdiagnosed phenomenon.

U2 - 10.1038/gim.2015.112

DO - 10.1038/gim.2015.112

M3 - Journal article

C2 - 26312826

SN - 1098-3600

VL - 18

SP - 494

EP - 500

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 5

ER -

A germline chromothripsis event stably segregating in 11 individuals through three generations

Abstract

Access to Document

Fingerprint

Cite this