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San Giovanni Rotondo, Italy

Redeker B.,University of Amsterdam | Jongejan A.,University of Amsterdam | Bradley T.E.J.,University of Amsterdam | Anselmi M.,University of Rome Tor Vergata | And 16 more authors.
Nature Genetics | Year: 2014

Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutations in ZBTB20, residing within the 3q13.31 microdeletion syndrome critical region, underlie Primrose syndrome. This finding establishes a genetic link between these disorders and delineates the impact of ZBTB20 dysregulation on development, growth and metabolism. © 2014 Nature America, Inc.

Parri V.,University of Siena | Katzaki E.,University of Siena | Uliana V.,University of Siena | Scionti F.,University of Siena | And 23 more authors.
European Journal of Human Genetics | Year: 2010

Cohen syndrome is a rare, clinically variable autosomal recessive disorder characterized by mental retardation, postnatal microcephaly, facial dysmorphisms, ocular abnormalities and intermittent neutropenia. Mutations in the COH1 gene have been found in patients from different ethnic origins. However, a high percentage of patients have only one or no mutated allele. To investigate whether COH1 copy number changes account for missed mutations, we used multiplex ligation-dependent probe amplification (MLPA) to test a group of 14 patients with Cohen syndrome. This analysis has allowed us to identify multi-exonic deletions in 11 alleles and duplications in 4 alleles. Considering our previous study, COH1 copy number variations represent 42% of total mutated alleles. To our knowledge, COH1 intragenic duplications have never been reported in Cohen syndrome. The three duplications encompassed exons 4-13, 20-30 and 57-60, respectively. Interestingly, four deletions showed the same exon coverage (exons 6-16) with respect to a deletion recently reported in a large Greek consanguineous family. Haplotype analysis suggested a possible founder effect in the Mediterranean basin. The use of MLPA was therefore crucial in identifying mutated alleles undetected by traditional techniques and in defining the extent of the deletions/duplications. Given the high percentage of identified copy number variations, we suggest that this technique could be used as the initial screening method for molecular diagnosis of Cohen syndrome. © 2010 Macmillan Publishers Limited All rights reserved.

Bukvic N.,University of Foggia | Delli Carri V.,OORR | Di Cosola M.L.,UOC Laboratorio Genetica Medica | Pustorino G.,OORR | And 10 more authors.
American Journal of Medical Genetics, Part A | Year: 2010

X;Y translocation is a relatively rare event in humans. Analyzed cytogenetically, the majority of these aberrations have breakpoints at Xp22 and Yq11. Females with t(X;Y)(p22;q11) are phenotypically normal except for short stature, while the males may have abnormalities. Aberrations that lead to nullisomy of the deleted region and complete loss of the respective genes have been recognized as a cause of variable contiguous gene syndromes in males. The phenotype depends on the extent and position of the deletion showing the variable association of apparently unrelated clinical manifestations such as ichthyosis, chondrodysplasia punctata, hypogonadotropic hypogonadism with anosmia, ocular albinism, short stature, and mental retardation. In addition, some patients have been reported with symptoms of attention deficit hyperactivity disorder. The extent of terminal Xp deletions is limited by the presence of male lethal genes in Xp22.2 at about 10-11 Mb from the telomere. The deletions in the majority of viable reported male patients extend to the STS (∼7.0 Mb) or to the KAL1 (∼8.5Mb) loci. We present a clinical, cytogenetic, FISH, and array CGH study of a family with an Xp;Yq translocation. The chromosomal status is also discussed in the light of their phenotypic traits. The final karyotypes of the patients were designated as: Patient 1: 46,Y,der(X),t(X;Y)(p22;q12).ish der(X)(Xpter-,DXZ1+, Xqter+)mat.arr cghXp22.31p22.33(RP11-60P14→RP13-391G2) x0;arr cgh Yq11.221qter (RP11-235I1→RP11-270H4)x2. Patient 2: 46,X,der(X),t(X;Y)(p22;q12).ish der(X)(Xpter-,DXZ1+, Xqter+)mat.arr cghXp22.31p22.33(RP11-60P14→RP13-391G2) x1;arr cgh Yq11.221qter (RP11-235I1→RP11-270H4)x1.

Jaiswal M.,Heinrich Heine University Dusseldorf | Strullu M.,Robert Debre Hospital | Strullu M.,University Paris Diderot | Fansa E.K.,Heinrich Heine University Dusseldorf | And 38 more authors.
Human Molecular Genetics | Year: 2014

RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identifiedmutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease. © The Author 2014. Published by Oxford University Press. All rights reserved.

Pannone L.,University of Rome La Sapienza | D'Agostino D.,McGill University | Consoli F.,University of Rome La Sapienza | Consoli F.,Laboratorio Mendel | And 14 more authors.
Human Mutation | Year: 2015

Noonan syndrome (NS) is a relatively common developmental disorder with a pleomorphic phenotype. Mutations causing NS alter genes encoding proteins involved in the RAS-MAPK pathway. We and others identified Casitas B-lineage lymphoma proto-oncogene (CBL), which encodes an E3-ubiquitin ligase acting as a tumor suppressor in myeloid malignancies, as a disease gene underlying a condition clinically related to NS. Here, we further explored the spectrum of germline CBL mutations and their associated phenotype. CBL mutation scanning performed on 349 affected subjects with features overlapping NS and no mutation in NS genes allowed the identification of five different variants with pathological significance. Among them, two splice-site changes, one in-frame deletion, and one missense mutation affected the RING domain and/or the adjacent linker region, overlapping cancer-associated defects. A novel nonsense mutation generating a v-Cbl-like protein able to enhance signal flow through RAS was also identified. Genotype-phenotype correlation analysis performed on available records indicated that germline CBL mutations cause a variable phenotype characterized by a relatively high frequency of neurological features, predisposition to juvenile myelomonocytic leukemia, and low prevalence of cardiac defects, reduced growth, and cryptorchidism. Finally, we excluded a major contribution of two additional members of the CBL family, CBLB and CBLC, to NS and related disorders. Germline mutations in CBL cause a leukemia-prone disorder clinically related to Noonan syndrome. Here, we explored the spectrum of CBL mutationsand their associated phenotype. Five different mutations are identified, including a novel nonsense change generating a v-Cbl-like protein able to enhance signaling through RAS. Genotype-phenotype correlation analysis indicate that germline CBL mutations cause a variable phenotype characterized by a relatively high frequency of neurological features, predisposition to JMML, and low prevalence of cardiac defects and reduced growth. © 2015 Wiley Periodicals, Inc.

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