title: Catastrophic cellular events leading to complex chromosomal rearrangements in the germline.
abstract: Although complex chromosomal rearrangements were thought to reflect the accumulation of DNA damage over time, recent studies have shown that such rearrangements frequently arise from 'all-at-once' catastrophic cellular events. These events, designated chromothripsis, chromoanasynthesis, and chromoanagenesis, were first documented in the cancer genome and subsequently observed in the germline. These events likely result from micronucleus-mediated chromosomal shattering and subsequent random reassembly of DNA fragments, although several other mechanisms have also been proposed. Typically, only one or a few chromosomes of paternal origin are affected per event. These events can produce intrachromosomal deletions, duplications, inversions, and translocations, as well as interchromosomal translocations. Germline complex rearrangements of autosomes often result in developmental delay and dysmorphic features, whereas X chromosomal rearrangements are usually associated with relatively mild clinical manifestations. The concept of these catastrophic events provides novel insights into the etiology of human genomic disorders. This review introduces the molecular characteristics and phenotypic outcomes of catastrophic cellular events in the germline.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fukami
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shima
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Department of Pediatrics, Shizuoka City Shimizu Hospital, Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kamimaki
mesh_terms: D002869:Chromosome Aberrations; D000072837:Chromothripsis; D053903:DNA Breaks, Double-Stranded; D005260:Female; D015321:Gene Rearrangement; D015894:Genome, Human; D005854:Germ Cells; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D011247:Pregnancy
keywords: chromoanagenesis; chromoanasynthesis; chromosomal rearrangement; chromothripsis; congenital disorder; germline mutation