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Iascone M.,Laboratorio Of Genetica Medica | Ciccone R.,University of Pavia | Marchetti D.,Laboratorio Of Genetica Medica | Lincesso A.R.,Laboratorio Of Genetica Medica | And 7 more authors.
Clinical Genetics | Year: 2012

Hypoplastic left heart syndrome (HLHS) is one of the most severe congenital heart malformations, characterized by underdevelopment of the structures in the left heart-aorta complex. The majority of cases are sporadic. Although multiple genetic loci have been tentatively implicated in HLHS, no gene or pathway seems to be specifically associated with the disease. To elucidate the genetic basis of HLHS, we analyzed 53 well-characterized patients with isolated HLHS using an integrated genomic approach that combined DNA sequencing of five candidate genes (NKX2-5, NOTCH1, HAND1, FOXC2 and FOXL1) and genome-wide screening by high-resolution array comparative genomic hybridization. In 30 patients, we identified two novel de novo mutations in NOTCH1, 23 rare patients inherited gene variants in NOTCH1, FOXC2 and FOXL1, and 33 rare patients mostly inherited copy-number variants. Some of the identified variations coexisted in the same patient. The biological significance of such rare variations is unknown, but our findings strengthen the role of NOTCH pathway in cardiac valve development, indicating that HLHS is, at least in part, a 'valve' disease. This is the first report of de novo mutations associated with isolated HLHS. Moreover, the coexistence of multiple rare variants suggests in some cases a cumulative effect, as shown for other complex disease. © 2011 John Wiley & Sons A/S.


Filippo P.D.,Electrophysiology and Pacing Unit | Ferrari P.,Electrophysiology and Pacing Unit | Iascone M.,Laboratorio Of Genetica Medica | Senni M.,Azienda Ospedaliera Papa Giovanni XXIII
Journal of Cardiovascular Electrophysiology | Year: 2015

A Tricky Case of Pediatric Overlap Syndrome We describe the case of 2-year-old baby with compound heterozygosity for paternal and maternal alleles mutation of α-subunit of the cardiac sodium channel (SCN5A), sinus node dysfunction, atrial flutter recurrences, and drug induced long-QT syndrome. In this setting, we chose at first to perform linear ablation of cavotricuspid isthmus resulting in a bidirectional isthmus block. As a second step, we decided to implant a miniaturized loop recorder that, with a minimally invasive procedure, permits us to follow the development of the disease in order to define the future strategy. After 8 months follow-up, automatic daily loop-recorder transmissions disclose the complete absence of any arrhythmia along with asymptomatic ventricular pauses due to sinus node dysfunction. Echocardiography shows normal findings, in particular no left ventricular dysfunction. © 2014 Wiley Periodicals, Inc.


PubMed | Unita Operativa Malattie Metaboliche Genetica Medica and Laboratorio Of Genetica Medica
Type: | Journal: Molecular cytogenetics | Year: 2015

The CHL1 gene codes for a member of the L1 family of neural cell adhesion molecules. It is highly expressed in the central and peripheral nervous system playing an important role in the building and functioning on the brain. CHL1 proteins are also involved in axonal migration, synaptic formation and plasticity. In mice, functional studies showed that the haploinsufficiency of Chl1 gene in the developing brain results in cognitive deficits suggesting that the CHL1 gene at 3p26.3 is a candidate for an autosomal form of intellectual disability. Furthermore, in humans deletions of CHL1 have been described in patients with neurodevelopmental delay characterized by learning and language difficulties, seizures. Less is known about the potential effect of CHL1 overexpression, and microduplications of CHL1 have been rarely identified.In this report, we describe a male patient with a phenotype characterized by developmental delay, symptoms of hyperactivity, short attention span and speech delay. In addition, minor facial dysmorphic features have been observed. Chromosomal microarray analysis revealed a rare de novo 0.85Mb microduplication on the short arm (p26.3) of chromosome 3, encompassing a single gene, CHL1. To the best of our knowledge, duplication of chromosome 3p26.3, including only the CHL1 gene, has been described in only one intellectually disabled girl with epilepsy. The duplication described here is the smallest reported so far. In addition, this is the first report describing a patient in which the CHL1 duplication is a de novo event.The clinical and molecular findings reported here are useful to provide further evidence that CHL1 is a dosage sensitive gene suggesting that not only the deletion but also its duplication can cause non-syndromic neurodevelopmental phenotypes.


Amato F.,CEINGE Biotecnologie avanzate | Amato F.,University of Naples Federico II | Seia M.,Laboratorio Of Genetica Medica | Giordano S.,CEINGE Biotecnologie avanzate | And 10 more authors.
PLoS ONE | Year: 2013

Cystic fibrosis (CF) is the most frequent lethal genetic disorder among Caucasians. It depends on alterations of a chloride channel expressed by most epithelial cells and encoded by CFTR gene. Also using scanning techniques to analyze the whole coding regions of CFTR gene, mutations are not identified in up to 10% of CF alleles, and such figure increases in CFTR-related disorders (CFTR-RD). Other gene regions may be the site of causing-disease mutations. We searched for genetic variants in the 1500 bp of CFTR 3′ untranslated region, typical target of microRNA (miRNA) posttranscriptional gene regulation, in either CF patients with the F508del homozygous genotype and different clinical expression (n = 20), CF (n = 32) and CFTR-RD (n = 43) patients with one or none mutation after CFTR scanning and in controls (n = 50). We identified three SNPs, one of which, the c.*1043A>C, was located in a region predicted to bind miR-433 and miR-509-3p. Such mutation was peculiar of a CFTR-RD patient that had Congenital Bilateral Absence of Vas Deferens (CBAVD), diffuse bronchiectasis, a borderline sweat chloride test and the heterozygous severe F508del mutation on the other allele. The expression analysis demonstrated that the c.*1043A>C increases the affinity for miR-509-3p and slightly decreases that for the miR-433. Both miRNAs cause in vitro a reduced expression of CFTR protein. Thus, the c.*1043A>C may act as a mild CFTR mutation enhancing the affinity for inhibitory miRNAs as a novel pathogenetic mechanism in CF. © 2013 Amato et al.


PubMed | Centro Regionale Toscano per la Fibrosi Cistica, Unita di Fibrosi Cistica, Laboratorio Genetica Medica, University Telematica Pegaso and 9 more.
Type: | Journal: Journal of medical genetics | Year: 2016

The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies.To describe the genotype-phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator (CFTR) complex alleles.We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p.[Arg74Trp;Val201Met;Asp1270Asn], n=8; p.[Ile148Thr;Ile1023_Val1024del], n=5; p.[Arg117Leu;Leu997Phe], n=6; c.[1210-34TG[12];1210-12T[5];2930C>T], n=3; p.[Arg74Trp;Asp1270Asn], n=4; p.Asp1270Asn, n=2; p.Ile148Thr, n=6; p.Leu997Phe, n=36. In 39 patients, we analysed the CFTR gating activity on NEC in comparison with patients with CF (n=8) and carriers (n=4). Finally, we analysed in vitro the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele.The p.[Ile148Thr;Ile1023_Val1024del] caused severe CF in five compound heterozygous with a class I-II mutation. Their CFTR activity on NEC was comparable with patients with two class I-II mutations (mean 7.3% vs 6.9%). The p.[Arg74Trp;Asp1270Asn] and the p.Asp1270Asn have scarce functional effects, while p.[Arg74Trp;Val201Met;Asp1270Asn] caused mild CF in four of five subjects carrying a class I-II mutation in trans, or CFTR-related disorders (CFTR-RD) in three having in trans a class IV-V mutation. The p.[Arg74Trp;Val201Met;Asp1270Asn] causes significantly (p<0.001) higher CFTR activity compared with compound heterozygous for class I-II mutations. Furthermore, five of six compounds heterozygous with the p.[Arg117Leu;Leu997Phe] had mild CF, whereas the p.Leu997Phe, in trans with a class I-II CFTR mutation, caused CFTR-RD or a healthy status (CFTR activity: 21.3-36.9%). Finally, compounds heterozygous for the c.[1210-34TG[12];1210-12T[5];2930C>T] and a class I-II mutation had mild CF or CFTR-RD (gating activity: 18.5-19.0%).The effect of complex alleles partially depends on the mutation in trans. Although larger studies are necessary, the CFTR activity on NEC is a rapid contributory tool to classify patients with CFTR dysfunction.


Lalatta F.,UOSD di Genetica Medica | Folliero E.,UNITA di GENETICA CLINICA | Cavallari U.,Servizio di Genetica | Di Segni M.,Laboratorio Of Genetica Medica | And 6 more authors.
Italian Journal of Pediatrics | Year: 2012

Background: An increasing number of foetuses are recognized as having double Y because of the widespread use of prenatal screening using chorionic villus sampling and amniocentesis. 47, XYY karyotype occurs in about one out of 1,000 newborn males, but it is not often detected unless it is diagnosed during prenatal testing. Despite the fact that unbiased follow-up studies demonstrate largely normal post-natal development of young men with 47, XYY, there is a scarcity of controlled studies about the neurological, cognitive and behavioural phenotype which remains the main reason for anxiety and anticipatory negative attitudes of parents. Furthermore, prejudices still exist among professionals and the general population concerning the relationship between this sex chromosome aneuploidy and aggressive and antisocial behaviours. Methods. We report on the clinical follow-up of children diagnosed prenatally with a 47,XYY karyotype, whose parents received multidisciplinary counselling and support at time of diagnosis. The specific focus of our study is on auxology, facial features, developmental milestones, behaviour, detection of aggressiveness as well as the evaluation of parental attitudes toward prenatal counselling. Clinical evaluations including auxological measurements and dysmorphological descriptions were as conducted on 13 boys aged 9 month -7 years. The Child Behavior Check List test specific for age and a 15 item questionnaire were administered to both parents. An update of ongoing problems was carried out by means of a telephone interview two years later. Results: Our results show that, from birth, weight, height and head circumference were above average values while some facial features such mild hypertelorism are overrepresented when compared to parents' facial features. Language delay was detected in 8 out of 11 children older than 20 months. Parental attitudes were found to be favourable toward prenatal diagnoses of sexual chromosome aneuploidies. Conclusions: Our data, although limited, is similar to other observational studies, and serves to alert clinicians about opportunities to delineate new and appropriate educational interventions that target the specific learning challenges of XYY boys. Our experience better defines the early manifestation of XYY and should aid those involved in prenatal counselling and paediatric surveillance. © 2012 Lalatta et al.; licensee BioMed Central Ltd.


PubMed | Laboratorio Of Genetica Medica and University of Bari
Type: | Journal: Molecular cytogenetics | Year: 2016

Structural rearrangements of chromosome 19p13.3 are a rare condition, and their phenotypic consequences remain not well defined, because of the variability of clinical manifestations. Increasing knowledge of new 19p13.3 microdeletion is useful to clarify the phenotypic variability observed in some patients. In a small number of recent papers, patients with intellectual disabilities, multiple congenital anomalies and microdeletion of the chromosome band 19p13.3 have been described. However, little is known about genes responsible for clinical features in patients carriers of 19p13.3 microdeletion; thus, increasing number of reported cases will be helpful to investigate the contribution of candidate genes, providing bases for future investigations.Here, we report on a 10-years-old girl referred to our genetics clinic due to intellectual disability, attention deficit, behavioral and speech delay, hypotonia, facial dysmorphisms, eye anomalies and congenital malformations. Using an high resolution SNP array, we identified a de novo microdeletion of chromosome 19p13.3, resulting in the heterozygous loss of 27 RefSeq genes and a miRNA, partially overlapping with three others deletions already reported in literature, but extending downstream (centromeric) for additional 386 Kb. This chromosomal region includes 13 genes amongst of which we suggest for the first time the APC2, PLK5 and MBD3 genes as potential functional candidates for neurodevelopmental and behavioral phenotypes observed.Here we describe a patient with a 19p13.3 microdeletion that spans to the downstream chromosomal region with respect to the overlapping deletions previously reported in several other cases. The neurobehavioral features observed in our case has extended the phenotypic spectrum associated with the 19p13.3 microdeletion. New candidate genes are proposed for the neurobehavioral phenotype observed in our case.


Morelli M.B.,University of Camerino | Offidani M.,Clinica di Ematologia | Alesiani F.,Unita di Oncoematologia | Discepoli G.,Laboratorio Of Genetica Medica | And 6 more authors.
International Journal of Cancer | Year: 2014

Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the accumulation of a monoclonal PC population in the bone marrow (BM). Cannabidiol (CBD) is a non-psychoactive cannabinoid with antitumoural activities, and the transient receptor potential vanilloid type-2 (TRPV2) channel has been reported as a potential CBD receptor. TRPV2 activation by CBD decreases proliferation and increases susceptibility to drug-induced cell death in human cancer cells. However, no functional role has been ascribed to CBD and TRPV2 in MM. In this study, we identified the presence of heterogeneous CD138+TRPV2+ and CD138+TRPV2- PC populations in MM patients, whereas only the CD138+ TRPV2- population was present in RPMI8226 and U266 MM cell lines. Because bortezomib (BORT) is commonly used in MM treatment, we investigated the effects of CBD and BORT in CD138+TRPV2- MM cells and in MM cell lines transfected with TRPV2 (CD138+TRPV2+). These results showed that CBD by itself or in synergy with BORT strongly inhibited growth, arrested cell cycle progression and induced MM cells death by regulating the ERK, AKT and NF-κB pathways with major effects in TRPV2+ cells. These data provide a rationale for using CBD to increase the activity of proteasome inhibitors in MM. What's new Cannabidiol, a non-psychoactive component of Cannabis, has antitumor properties. This study investigated whether cannabidiol could assist another drug, bortezomib, in fighting multiple myeloma. Although patients respond well to bortezomib at first, most develop resistance to it over time. The authors looked in myeloma cell lines and patient samples for a protein, TRPV2, which interacts with cannabidiol. They found that cannabidiol, working alone or in concert with bortezomib, kills multiple myeloma cells, particularly when TRPV2 was expressed. These data suggest that treatment with cannabidiol may help sidestep the problem of patients developing resistance to bortezomib. © 2013 UICC.


PubMed | Unita di Audiologia e Foniatria Universitaria and Laboratorio Of Genetica Medica
Type: Case Reports | Journal: Journal of human genetics | Year: 2015

Here, we report on a patient with a 625 kb duplication in Xp22.12, detected by array comparative genomic hybridization (CGH). The duplicated region contains only one gene, RPS6KA3, that results in partial duplication. The same duplication was present in his mother and his maternal uncle. This partial duplication inhibits the RPS6KA3 expression, mimicking the effect of loss-of-function mutations associated with Coffin-Lowry syndrome (CLS). The phenotype of the patient here presented is not fully evocative of this syndrome because he does not present some of the facial, digital and skeletal abnormalities that are considered the main diagnostic features of CLS. This case is one of the few examples where RPS6KA3 mutations are associated with a non-specific X-linked mental retardation.


PubMed | U.O.C Anatomia Patologica and Laboratorio Of Genetica Medica
Type: | Journal: Molecular cytogenetics | Year: 2015

Pure interstitial duplications of chromosome band 4p16.3 represent an infrequent chromosomal finding with, to the best of our knowledge, only two patients to date reported.We report on a 13-year-old boy showing a set of dysmorphic facial features, attention deficit hyperactivity disorders, learning difficulties, speech and cognitive delays, overgrowth and musculoskeletal anomalies in whom an interstitial duplication of about 400kb in 4p16.3 was detected by SNP-array analysis. The duplication includes the complete coding sequence of FAM53A, SLBP, TMEM129 and TACC3 genes and the first exon of the FGFR3 gene. Phenotypic comparison with previously described patients harboring a microduplication of similar size and position contributes to better define the clinical correlation of 4p16.3 microduplications, suggesting the existence of a novel distinct and phenotypically recognizable syndrome. In addition, being the duplication identified in our case the smallest so far reported, it allowed us to refine the smallest region of overlap among patients to 222kb, enabling a more accurate genotype-phenotype correlation for 4p16.3 microduplications.Our case report provide clinical and molecular evidences supporting the existence of a novel 4p16.3 microduplication syndrome. The genes FAM53A, TACC3 and FGFR3 seems to play a key role in the etiology of the clinical phenotype. Interestingly, our patient is the oldest described so far and for this reason useful to delineate the long-term prognosis of these patients.

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