De Novo Unbalanced Translocations in Prader-Willi and Angelman Syndrome Might Be the Reciprocal Product of inv dup(15)s

Abstract

The 15q11-q13 region is characterized by high instability, caused by the presence of several paralogous segmental duplications. Although most mechanisms dealing with cryptic deletions and amplifications have been at least partly characterized, little is known about the rare translocations involving this region. We characterized at the molecular level five unbalanced translocations, including a jumping one, having most of 15q transposed to the end of another chromosome, whereas the der(15)(pter->q11-q13) was missing. Imbalances were associated either with Prader-Willi or Angelman syndrome. Array-CGH demonstrated the absence of any copy number changes in the recipient chromosome in three cases, while one carried a cryptic terminal deletion and another a large terminal deletion, already diagnosed by classical cytogenetics. We cloned the breakpoint junctions in two cases, whereas cloning was impaired by complex regional genomic architecture and mosaicism in the others. Our results strongly indicate that some of our translocations originated through a prezygotic/postzygotic two-hit mechanism starting with the formation of an acentric 15qter->q1::q1->qter representing the reciprocal product of the inv dup(15) supernumerary marker chromosome. An embryo with such an acentric chromosome plus a normal chromosome 15 inherited from the other parent could survive only if partial trisomy 15 rescue would occur through elimination of part of the acentric chromosome, stabilization of the remaining portion with telomere capture, and formation of a derivative chromosome. All these events likely do not happen concurrently in a single cell but are rather the result of successive stabilization attempts occurring in different cells of which only the fittest will finally survive. Accordingly, jumping translocations might represent successful rescue attempts in different cells rather than transfer of the same 15q portion to different chromosomes. We also hypothesize that neocentromerization of the original acentric chromosome during early embryogenesis may be required to avoid its loss before cell survival is finally assured.

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

“…21 To clone case 3 breakpoint junctions, we used pooled long-range PCR reactions (for details, see Supplementary Material). Target sequences for qPCR analysis were selected using the Primer Express 3.0 software (Applied Biosystems, Foster City, CA, USA).…”

No evidence for mosaic pathogenic copy number variations in cardiac tissue from patients with congenital heart malformations

“…The Utype exchange mechanism cannot alone explain the rearrangement in the patient, and it is possible that an initially formed isodicentric marker underwent a subsequent rearrangement including non-homologous end-joining of the isodicentric marker and 15p to result in the observed karyotype. A similar mechanism has been described to explain the occurrence of translocations of 15q, believed to be the reciprocal products of the inv dup(15) chromosome (141). Further determination of the mechanism in patient P24(V) is dependent on microsatellite marker analysis in parents and proband.…”

Chromosomal aberrations in patients with suspected Prader Willi syndrome

“…La ausencia de expresión de genes paternos se produce por 3 mecanismos: deleción paterna 15q11-q13 (75 % de los casos), ausencia del cromosoma paterno por disomía uniparental materna (DUPmat) (25 %), o mutaciones del sitio de la impronta en el cromosoma 15 paterno El 1 % de los casos es causado por un desarreglo cromosómico como una translocación o inversión que puede causar deleción de alguno de los genes de la región crítica del PW. (5,6,7,8,9,10) Los criterios diagnósticos del SPW propuestos por Holm et al en 1993 fueron actualizados por Aygun et al en 2001 en base a las características clínicas según las edades en pacientes con diagnóstico molecular confirmado del SPW. El diagnóstico clínico muchas veces resulta difícil por la presencia de signos inespecíficos que involucran diferentes sistemas y su variación, de manera que algunos signos desaparecen y aparecen otros secuencialmente con la edad.…”