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Sotto il Monte Giovanni XXIII, Italy

Milani D.,University of Milan | Bedeschi M.F.,University of Milan | Iascone M.,Ussd Laboratorio Of Genetica Medica | Chiarelli G.,University of Milan | And 2 more authors.
Cytogenetic and Genome Research | Year: 2012

We describe the case of a 6-year-old boy with a de novo deletion of the long arm of chromosome 1 encompassing band 1q31.1-q32.1, minor facial anomalies, mild developmental delay, and behavioral disorders. His postnatal karyotype was normal. Using array-comparative genomic hybridization, we identified and characterized a de novo 1q interstitial deletion of about 15.6 Mb, which partially overlaps those of other reported cases. We considered the gene content of the deleted region in an attempt to compare the clinical features of our patient with these other cases, even though they were not characterized molecularly in detail. The most remarkable difference was the absence of microcephaly. To the best of our knowledge, this is the first report of a de novo 1q31.1-q32.1 deletion. Moreover, it illustrates how molecular delineation associated with fine clinical characterization can improve the genotype-phenotype correlations of classical cytogenetic abnormalities. Copyright © 2012 S. Karger AG.

Sana M.E.,Ussd Laboratorio Of Genetica Medica | Pezzoli L.,Ussd Laboratorio Of Genetica Medica | Preda L.,Centro per la Diagnosi e il Trattamento delle Cardiopatie Congenite | Ferrazzi P.,The Surgical Center | Iascone M.,Ussd Laboratorio Of Genetica Medica
American Journal of Medical Genetics, Part A | Year: 2014

Biventricular hypertrophy (BVH) is a disease state characterized by the thickening of the ventricle walls. The differential diagnosis of BVH with other congenital and familial diseases in which increased ventricle wall thickness is a prominent clinical feature is fundamental due to its therapeutic and prognostic value, mainly during infancy. We describe a 2-month-old infant presenting BVH. Using exome sequencing, we identified a novel de novo 3-bp deletion in the RAF1 gene that is located in the binding active site for the 14-3-3 peptide. Based on docking calculations, we demonstrate that this novel mutation impairs protein/target binding, thus constitutively activating Ras signaling, which is a dysregulation associated with Noonan syndrome. Finally, our study underlines the importance of molecular modeling to understand the roles of novel mutations in pathogenesis. © 2014 Wiley Periodicals, Inc.

Vetro A.,Biotechnology Research Laboratories | Iascone M.,Ussd Laboratorio Of Genetica Medica | Limongelli I.,Fondazione IRCCS Policlinico San Matteo | Ameziane N.,VU University Amsterdam | And 16 more authors.
Human Mutation | Year: 2015

The diagnosis of VACTERL syndrome can be elusive, especially in the prenatal life, due to the presence of malformations that overlap those present in other genetic conditions, including the Fanconi anemia (FA). We report on three VACTERL cases within two families, where the two who arrived to be born died shortly after birth due to severe organs' malformations. The suspicion of VACTERL association was based on prenatal ultrasound assessment and postnatal features. Subsequent chromosome breakage analysis suggested the diagnosis of FA. Finally, by next-generation sequencing based on the analysis of the exome in one family and of a panel of Fanconi genes in the second one, we identified novel FANCL truncating mutations in both families. We used ectopic expression of wild-type FANCL to functionally correct the cellular FA phenotype for both mutations. Our study emphasizes that the diagnosis of FA should be considered when VACTERL association is suspected. Furthermore, we show that loss-of-function mutations in FANCL result in a severe clinical phenotype characterized by early postnatal death. © 2015 WILEY PERIODICALS, INC.

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