@article {10765, title = {Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders.}, journal = {Epigenetics}, volume = {13}, year = {2018}, month = {2018}, pages = {897-909}, abstract = {

The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50\% of BWS and 29\% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Beckwith-Wiedemann Syndrome, Child, Child, Preschool, Chromosomes, Human, Pair 15, DNA Methylation, Female, Genomic Imprinting, Humans, Infant, Kruppel-Like Transcription Factors, Male, Mutation, Missense, Silver-Russell Syndrome, Young Adult}, issn = {1559-2308}, doi = {10.1080/15592294.2018.1514230}, author = {Fontana, L and Bedeschi, M F and Maitz, S and Cereda, A and Far{\'e}, C and Motta, S and Seresini, A and D{\textquoteright}Ursi, P and Orro, A and Pecile, V and Calvello, M and Selicorni, A and Lalatta, F and Milani, D and Sirchia, S M and Miozzo, M and Tabano, S} } @article {10515, title = {A complete duplication of X chromosome resulting in a tricentric isochromosome originated by centromere repositioning.}, journal = {Mol Cytogenet}, volume = {10}, year = {2017}, month = {2017}, pages = {22}, abstract = {

BACKGROUND: Neocentromeres are rare and considered chromosomal aberrations, because a non-centromeric region evolves in an active centromere by mutation. The literature reported several structural anomalies of X chromosome and they influence the female reproductive capacity or are associated to Turner syndrome in the presence of monosomy X cell line.

CASE PRESENTATION: We report a case of chromosome X complex rearrangement found in a prenatal diagnosis. The fetal karyotype showed a mosaicism with a 45,X cell line and a 46 chromosomes second line with a big marker, instead of a sex chromosome. The marker morphology and fluorescence in situ hybridization (FISH) characterization allowed us to identify a tricentric X chromosome constituted by two complete X chromosome fused at the p arms telomere and an active neocentromere in the middle, at the union of the two Xp arms, where usually are the telomeric regions. FISH also showed the presence of a paracentric inversion of both Xp arms. Furthermore, fragility figures were found in 56\% of metaphases from peripheral blood lymphocytes culture at birth: a shorter marker chromosome and an apparently acentric fragment frequently lost.

CONCLUSIONS: At our knowledge, this is the first isochromosome of an entire non-acrocentric chromosome. The neocentromere is constituted by canonical sequences but localized in an unusual position and the original centromeres are inactivated. We speculated that marker chromosome was the result of a double rearrangement: firstly, a paracentric inversion which involved the Xp arm, shifting a part of the centromere at the p end and subsequently a duplication of the entire X chromosome, which gave rise to an isochromosome. It is possible to suppose that the first event could be a result of a non-allelic homologous recombination mediated by inverted low-copy repeats. As expected, our case shows a Turner phenotype with mild facial features and no major skeletal deformity, normal psychomotor development and a spontaneous development of puberty and menarche, although with irregular menses since the last follow-up.

}, issn = {1755-8166}, doi = {10.1186/s13039-017-0323-7}, author = {Villa, N and Conconi, D and Benussi, D Gambel and Tornese, G and Crosti, F and Sala, E and Dalpr{\`a}, L and Pecile, V} }