title: A germline chromothripsis event stably segregating in 11 individuals through three generations.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.Genet Med 18 5, 494-500.
authors: Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
authors: Birgitte
authors: B
authors: Bertelsen
authors: Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
authors: Lusine
authors: L
authors: Nazaryan-Petersen
authors: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin, Germany.
authors: Wei
authors: 0000-0001-9607-1361
authors: W
authors: Sun
authors: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
authors: Mana M
authors: MM
authors: Mehrjouy
authors: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin, Germany.
authors: Gangcai
authors: G
authors: Xie
authors: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin, Germany.
authors: Wei
authors: W
authors: Chen
authors: Neurogenetics Clinic, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, and Department of Cellular and Molecular Medicine, Section of Neurogenetics, University of Copenhagen, Copenhagen, Denmark.
authors: Lena E
authors: LE
authors: Hjermind
authors: Generade Center of Expertise Genomics; University of Applied Sciences Leiden, Leiden, The Netherlands.
authors: Peter E M
authors: 0000-0001-9621-465X
authors: PE
authors: Taschner
authors: Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
authors: Zeynep
authors: 0000-0002-4777-5802
authors: Z
authors: Tümer
mesh_terms: D000022:Abortion, Spontaneous / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D002648:Child; D000072837:Chromothripsis; D000013:Congenital Abnormalities / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D015321:Gene Rearrangement; D005854:Germ Cells / Q000166:cytology*; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic / Q000235:genetics*