Article

A Palindrome-Mediated Recurrent Translocation with 3:1 Meiotic Nondisjunction: The t(8;22)(q24.13;q11.21)

The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 08/2010; 87(2):209-18. DOI: 10.1016/j.ajhg.2010.07.002
Source: PubMed

ABSTRACT Palindrome-mediated genomic instability has been associated with chromosomal translocations, including the recurrent t(11;22)(q23;q11). We report a syndrome characterized by extremity anomalies, mild dysmorphia, and intellectual impairment caused by 3:1 meiotic segregation of a previously unrecognized recurrent palindrome-mediated rearrangement, the t(8;22)(q24.13;q11.21). There are at least ten prior reports of this translocation, and nearly identical PATRR8 and PATRR22 breakpoints were validated in several of these published cases. PCR analysis of sperm DNA from healthy males indicates that the t(8;22) arises de novo during gametogenesis in some, but not all, individuals. Furthermore, demonstration that de novo PATRR8-to-PATRR11 translocations occur in sperm suggests that palindrome-mediated translocation is a universal mechanism producing chromosomal rearrangements.

Full-text

Available from: April Hacker, Aug 24, 2014
0 Followers
 · 
214 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The 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. In 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. Our 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.
    Molecular Cytogenetics 08/2014; 7(1):55. DOI:10.1186/s13039-014-0055-x · 2.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Constitutional t(11;22)(q23;q11) is the most frequent recurrent non-Robertsonian translocation in humans. Balanced carriers of t(11;22) usually manifest no clinical symptoms, and are often identified after the birth of offspring with an unbalanced form of this translocation, known as Emanuel syndrome. To determine the prevalence of the disorder, we sent surveillance questionnaires to 735 core hospitals in Japan. The observed number of Emanuel syndrome cases was 36 and of t(11;22) balanced translocation carriers was 40. On the basis of the de novo t(11;22) translocation frequency in sperm from healthy males, we calculated the frequency of the translocations in the general population. Accordingly, the prevalence of Emanuel syndrome was estimated at 1 in 110,000. Based on this calculation, the estimated number of Emanuel syndrome cases in Japan is 1,063 and of t(11;22) balanced translocation carriers is 16,604, which are much higher numbers than those calculated from our questionnaire responses. It is possible that this discordance is partly attributable to a lack of disease identification. Further efforts should be made to increase the awareness of Emanuel syndrome to ensure a better quality of life for affected patients and their families.
    Pediatrics International 07/2014; 56(4). DOI:10.1111/ped.12437 · 0.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The mechanisms underlying these non-recurrent copy number changes have not yet been fully elucidated. Results We analyze large NF1 deletions with non-recurrent breakpoints as a model to investigate the full spectrum of causative mechanisms, and observe that they are mediated by various DNA double strand break repair mechanisms, as well as aberrant replication. Further, two of the 17 NF1 deletions with non-recurrent breakpoints, identified in unrelated patients, occur in association with the concomitant insertion of SINE/variable number of tandem repeats/Alu (SVA) retrotransposons at the deletion breakpoints. The respective breakpoints are refractory to analysis by standard breakpoint-spanning PCRs and are only identified by means of optimized PCR protocols designed to amplify across GC-rich sequences. The SVA elements are integrated within SUZ12P intron 8 in both patients, and were mediated by target-primed reverse transcription of SVA mRNA intermediates derived from retrotranspositionally active source elements. Both SVA insertions occurred during early postzygotic development and are uniquely associated with large deletions of 1 Mb and 867 kb, respectively, at the insertion sites. Conclusions Since active SVA elements are abundant in the human genome and the retrotranspositional activity of many SVA source elements is high, SVA insertion-associated large genomic deletions encompassing many hundreds of kilobases could constitute a novel and as yet under-appreciated mechanism underlying large-scale copy number changes in the human genome.
    Genome Biology 06/2014; 15(6):R80. DOI:10.1186/gb-2014-15-6-r80 · 10.47 Impact Factor