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

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

Molecular cloning of the 5;15 translocation in case 1.

<p>A, magnified view of the chromosome 5 breakpoint boundary detected by array-CGH using a 244 K oligonucleotide-based whole-genome microarray. The shaded area indicates a loss in DNA copy number (deletion) detected by three oligonucleotide probes (green dots). Black dots represent probes with no changes in copy number (non-deleted region). B, whole chromosome view (left) and magnified view (right) of the chromosome 15 breakpoint boundaries detected by custom oligonucleotide-based 15q11-q13 microarray. The shaded areas indicate a deletion (majority of green dots) and a gain in DNA copy number (duplication) detected by red dots (see arrow). The area containing few widely spaced probes represents BP3, a large region containing paralogous sequences. The last deleted oligomer is at 26,210,153 bp within <i>HERC2</i>, corresponding to BP3; the duplicated region is between 26,996,914 (first duplicated) and 27,106,557 bp (last duplicated) with first normal oligomer at 27,108,882 bp just distal to BP3, within the <i>APBA2</i> gene. An arrowhead points to the two black spots possibly indicating a single copy region between the deletion and the duplication. C, schematic representation of the rearrangement showing the two chromosomes involved, the position and orientation of the duplicated region, and the location of the two junctions (arrows). D, DNA sequences spanning the chromosome 5 deletion/15 duplication junction (Jc1) aligned with the reference sequences. E, dot-plot diagram, made with PipMaker software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039180#pone.0039180-Schwartz1" target="_blank">[45]</a>, showing the relative location of the inverted chromosome 15 duplication boundaries (Jc1 and Jc2, arrows) and of the <i>GOLGA8E</i>-associated inverted low copy repeat. The duplicated portion is represented by an orange arrow box.</p

Physical map of the 15q11.2-q14 region.

<p>The six segmental duplication sites responsible for specific recurrent rearrangements in this region, known as BP1-6, are represented by black boxes. All genes in the region are shown. The position of the chromosome 15 breakpoints of the five translocation cases we have examined are represented by thin arrows. The positions of the eight translocation cases (MR1-8) described by Mignon-Ravix <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039180#pone.0039180-MignonRavix1" target="_blank">[10]</a> are indicated by thick arrows.</p

Phenotype, karyotype and molecular characterization of the five cases with unbalanced translocations.

*<p>The minor cell line has been confirmed, by classical cytogenetics, in fibroblasts, with a similar mosaicism percentage (45, XX, der(15;18)(q13;q23)[83]-15/45, X, der (X;15)(q28;q13),-15<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039180#pone.0039180-Carrozzo1" target="_blank">[3]</a>*).</p

Clinical characteristics and predictors of death among hospitalized patients infected with SARS-CoV-2 in Sicily, Italy: A retrospective observational study

Since late December 2019, severe acute respiratory syndrome coronavirus 2 has spread across the world, which resulted in the World Health Organization declaring a global pandemic. Coronavirus disease 2019 (COVID-19) presents a highly variable spectrum with regard to the severity of illness. Most infected individuals exhibit a mild to moderate illness (81%); however, 14% have a serious disease and 5% develop severe acute respiratory distress syndrome (ARDS), requiring intensive care support. The mortality rate of COVID-19 continues to rise across the world. Data regarding predictors of mortality in patients with COVID 19 are still scarce but are being actively investigated. The present multicenter retrospective observational study provides a complete description of the demographic and clinical characteristics, comorbidities and laboratory abnormalities in a population of 421 hospitalized patients recruited across eight infectious disease units in Southern Italy (Sicily) with the aim of identifying the baseline characteristics predisposing COVID-19 patients to critical illness or death. In this study, older age, pre-existing comorbidities and certain changes in laboratory markers (such as neutrophilia, lymphocytopenia and increased C-reactive protein levels) at the time of admission were associated with a higher risk of mortality. Male sex, on the other hand, was not significantly associated with increased risk of mortality. Symptoms such as fatigue, older age, a number of co-pathologies and use of continuous positive airway pressure were the most significant contributors in the estimation of clinical prognosis. Further research is required to better characterize the epidemiological features of COVID-19, to understand the related predictors of death and to develop new effective therapeutic strategies