Breakpoint analysis of the recurrent constitutional t(8;22)(q24.13;q11.21) translocation

Abstract

BackgroundsThe t(8;22)(q24.13;q11.2) has been identified as one of several recurrent constitutional translocations mediated by palindromic AT-rich repeats (PATRRs). Although the breakage on 22q11 utilizes the same PATRR as that of the more prevalent constitutional t(11;22)(q23;q11.2), the breakpoint region on 8q24 has not been elucidated in detail since the analysis of palindromic sequence is technically challenging.ResultsIn this study, the entire 8q24 breakpoint region has been resolved by next generation sequencing. Eight polymorphic alleles were identified and compared with the junction sequences of previous and two recently identified t(8;22) cases . All of the breakpoints were found to be within the PATRRs on chromosomes 8 and 22 (PATRR8 and PATRR22), but the locations were different among cases at the level of nucleotide resolution. The translocations were always found to arise on symmetric PATRR8 alleles with breakpoints at the center of symmetry. The translocation junction is often accompanied by symmetric deletions at the center of both PATRRs. Rejoining occurs with minimal homology between the translocation partners. Remarkably, comparison of der (8) to der(22) sequences shows identical breakpoint junctions between them, which likely represent products of two independent events on the basis of a classical model.ConclusionsOur data suggest the hypothesis that interactions between the two PATRRs prior to the translocation event might trigger illegitimate recombination resulting in the recurrent palindrome-mediated translocation.

A Genome Model Linking Birth Defects to Infections

“…Data Sources. DNA sequences from acquired congenital disorders were from published whole genome sequences at chromosome breakpoints and rearrangement sites [1][2][3] . Comparison to multiple databases of microbial sequences determined whether there was significant human homology.…”

“…Emphasis was on cases with strong evidence that a particular human chromosome rearrangement was pathologic for the congenital disorder. Patients in the 3 major studies [1][2][3] used in this analysis were 98 females and 144 males.…”

“…Large amounts of foreign DNA present during human meiosis with its many double strand breaks during the most active period of recombination produce defective gametes. Errors in spermatogenesis underlie a prevalent and recurrent gene rearrangement that causes intellectual disability, and dysmorphism (Emanuel syndrome) 2 . In contrast, recombination in ova occurs in fetal life and then meiosis is arrested until puberty 51 .…”

“…As the nervous system develops, tion of the neurologic system. Based on DNA sequence analyses, some chromosome rearrangements have been identified as causing individual congenital disorders because they disrupt genes essential for normal development [1][2][3] . There is poor understanding and no effective treatment for many of these overwhelming abnormalities.…”

Parental infections disrupt clustered genes encoding related functions required for nervous system development in newborns

“…A significant advance in genome sequence level resolution of balanced cytogenetic abnormalities greatly improves the ability to document changes in regulation and dosage for genes critical to the function of the neurologic system. Based on DNA sequence analyses, some chromosome rearrangements have been identified as causing individual congenital disorders because they disrupt genes essential for normal development [1][2][3] .…”