What Is a Complex Chromosome Rearrangement?

Abstract

No single definition of a complex chromosome rearrangement (CCR) can adequately cover the whole range of possible structural rearrangements. There are highly complex CCRs with multiple breaks that involve three, four or more chromosomes, but there are also CCRs that involve just two chromosomes or even a single chromosome. Although one of the first so-called ‘‘complex’’ translocations in humans was reported in 1970 [Fredga and Hall, 1970], it was Pai et al. [1980] who first described what they meant by a complex chromosome translocation. Pai et al. had reviewed nine cases of translocations involving three or more chromosomes and three or more breakpoints. They began their discussion with ‘‘complex chromosome translocations (i.e., those involving more than a reciprocal exchange of segments between two chromosomes), resulting in multiple derivative chromosomes, are rare.’’ This article by Pai et al. has become the most frequently quoted article for a definition of a CCR. Among the articles quoted in the review article on balanced CCRs by Madan [2012], 50 gave a definition of a CCR and of these 30 referred to Pai et al., [1980] as the source of their definition (Table I). At the time, I interpreted the statement by Pai et al. [1980] who referred to translocations (and not rearrangements), as ‘‘translocations that are more complex than the well described reciprocal translocations.’’ However, examination of the 30 papers that refer to Pai et al. shows that there is considerable variation in the interpretation of the statement of Pai et al., some of which may be far removed from the intended interpretation. A critical look at the various versions (see comments in Table I) shows that definition nos. 1 and 2 not only include most of the reported CCRs but also cover the extensive complexity (multiple breaks with translocations, inversions and insertions) found in some balanced and unbalanced rearrangements [Gardner et al., 2012]. The drawback of these two is that they do not cover CCRs involving one or two chromosomes. All the other definitions in Table I are confusing, limiting or incorrect because they include rearrangements that are not complex, such as interchromosomal insertions of single segments. With the steadily increasing number of CCRs that are being reported, new interpretations of Pai et al. emerge, for example: ‘‘CCRs are rare structural chromosome aberrations characterized by more than two breakpoints located in one or more chromosomes [Pai et al., 1980]’’ [Schwarzbraun et al., 2006]. This definition would include inter-chromosomal as well as intra-chromosomal insertions of single segments. The first question that arises is: How could the statement by Pai et al. [1980] have been interpreted in so many different ways? The wording of their statement is not clear and leaves plenty of room for various interpretations. This may be because Pai et al. never intended their statement to be used as an all-encompassing definition for all complex rearrangements more than 30 years later. Also, worth noting is that some interpretations of the statement are quoted by several authors. For example, definitions nos. 8 and 9 in Table I, each with its own drawback, are quoted in four and eight publications respectively, giving Pai et al. [1980] as the reference. This would mean either that several authors have interpreted the original statement independently in exactly the same way, or that an interpretation has been passed from one publication to the next along with the reference. There may be yet another factor at play, that is, errors in transcription. The words ‘‘at least three chromosomes’’ of definition 1 in Table I have changed to ‘‘more than two chromosomes’’ in definitions 7 and 8, which mean the same thing. However, these words have changed again to ‘‘two or more chromosomes’’ in definition 9, thus changing the meaning from minimum three to minimum two chromosomes. In a recent article [Kirkpatrick and Ma, 2012] the definition in the introduction has changed to ‘‘. . .involving two or more chromosomes and two or more breakpoints.’’, again referring to the Pai et al. paper, whereas in the abstract it is ‘‘. . . more than two chromosomes and more than two breakpoints. . .’’ The definition in the introduction implies a minimum of two chromosomes and a minimum of two breaks, which includes nearly all common structural changes except