Publications by authors named "Monia Magliozzi"

17 Publications

  • Page 1 of 1

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.

J Clin Invest 2021 03;131(5)

Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.
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http://dx.doi.org/10.1172/JCI142148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919725PMC
March 2021

Clinical and molecular characterizations of 11 new patients with type 1 Feingold syndrome: Proposal for selecting diagnostic criteria and further genetic testing in patients with severe phenotype.

Am J Med Genet A 2021 04 14;185(4):1204-1210. Epub 2021 Jan 14.

Medical Genetics Unit, Santa Maria della Misericordia Hospital and University of Perugia, Perugia, Italy.

Feingold Syndrome type 1 (FS1) is an autosomal dominant disorder due to a loss of function mutations in the MYCN gene. FS1 is generally clinically characterized by mild learning disability, microcephaly, short palpebral fissures, short stature, brachymesophalangy, hypoplastic thumbs, as well as syndactyly of toes, variably associated with organ abnormalities, the most common being gastrointestinal atresia. In current literature, more than 120 FS1 patients have been described, but diagnostic criteria are not well agreed upon, likewise the genotype-phenotype correlations are not well understood. Here, we describe 11 FS1 patients, belonging to six distinct families, where we have identified three novel MYCN mutations along with three pathogenetic variants, the latter which have already been reported. Several patients presented a mild phenotype of the condition and they have been diagnosed as being affected only after segregation analyses of the MYCN mutation identified in the propositus. We also describe here the first ever FS1 patient with severe intellectual disability having a maternally inherited MYCN variant together with an additional GNAO1 mutation inherited paternally. Mutations in the GNAO1 gene are associated with a specific form of intellectual disability and epilepsy, thus the finding of two different rare diseases in the same patient could explain his severe phenotype. Therein, a thorough investigation is merited into the possibility that additional variants in patients with a MYCN mutation and severe phenotype do exist. Finally, in order to guarantee a more reliable diagnosis of FS1, we suggest using both major and minor clinical-molecular diagnostic criteria.
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http://dx.doi.org/10.1002/ajmg.a.62068DOI Listing
April 2021

Cardiovascular Involvement in Pediatric Laminopathies. Report of Six Patients and Literature Revision.

Front Pediatr 2020 24;8:374. Epub 2020 Jul 24.

The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, Rome, Italy.

Lamin A/C () encodes for two nuclear intermediate filament proteins. Mutations in cause a highly heterogeneous group of diseases predominantly leading to muscular or cardiac disease, lipodystrophy syndromes, peripheral neuropathy, and accelerated aging disorders. Cardiac involvement includes progressive arrhythmias (brady/tachyarrhythmias, sudden cardiac death). Furthermore, cardiomyocyte damage often progresses into dilated cardiomyopathy (DCM), rarely described in the pediatric age group. Neuromuscular manifestations are even rarer in children. We report on six pediatric patients with mutations: patient 1 was operated on for aortic coarctation, non-compact left ventricle, atrial fibrillation (AF) preceding the diagnosis of DCM; patient 2 was operated on for ventricular septal defect (VSD), developed after years malignant arrhythmias preceding the progression to DCM (left ventricular non-compaction with LV dysfunction); patient 3 had ectopic atrial tachycardia as first manifestation of a DCM; patients 4 and 5 had no major arrhythmic events but only dilated ascending aorta, mildly dilated LV with mild hypertrabeculation of the lateral wall and a normally functioning but dilated left ventricle, respectively; patient 6 showed aortic coarctation, supraventricular tachycardia. Paroxysmal AF occurred in patients 1, 2, and 3 (50% of cases). Our series highlight the coexistence of congenital heart defects (CHDs) and aortic involvement with laminopathies in four of our patients: consisting of aortic coarctation (two patients), aortic root dilatation (one patient), and VSD (one patient). Aortic changes in laminopathies have been reported only once in an adult patient. This is the first report in the pediatric setting, and no associations with CHD have been previously described.
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http://dx.doi.org/10.3389/fped.2020.00374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393225PMC
July 2020

What is the impact of a novel MED12 variant on syndromic conotruncal heart defects? Analysis of case report on two male sibs.

Ital J Pediatr 2020 Jul 18;46(1):98. Epub 2020 Jul 18.

Department of Neonatology and NICU, University Hospital Policlinico P. Giaccone, Palermo, Italy.

Background: Syndromic congenital heart disease accounts for 30% of cases and can be determined by genetic, environmental or multifactorial causes. In many cases the etiology remains uncertain. Many known genes are responsible for specific morphopathogenetic mechanisms during the development of the heart whose alteration can determine specific phenotypes of cardiac malformations.

Case Presentation: We report on two cases of association of conotruncal heart defect with facial dysmorphisms in sibs. In both cases the malformations' identification occurred by ultrasound in the prenatal period. It was followed by prenatal invasive diagnosis. The genetic analysis revealed no rearrangements in Array-CGH test, while gene panel sequencing identified a new hemizygous variant of uncertain significance (c.887G > A; p.Arg296Gln) in the MED12 gene, located on the X chromosome and inherited from the healthy mother.

Conclusion: No other reports about the involvement of MED12 gene in syndromic conotruncal heart defects are actually available from the literature and the international genomic databases. This novel variant is a likely pathogenic variant of uncertain significance and it could broaden the spectrum of genes involved in the development of congenital heart diseases and the phenotypic range of MED12-related disorders.
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http://dx.doi.org/10.1186/s13052-020-00865-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368728PMC
July 2020

Cantú syndrome versus Zimmermann-Laband syndrome: Report of nine individuals with ABCC9 variants.

Eur J Med Genet 2020 Sep 2;63(9):103996. Epub 2020 Jul 2.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Cantú syndrome (CS) is a rare developmental disorder characterized by a coarse facial appearance, macrocephaly, hypertrichosis, skeletal and cardiovascular anomalies and caused by heterozygous gain-of-function variants in ABCC9 and KCNJ8, encoding subunits of heterooctameric ATP-sensitive potassium (K) channels. CS shows considerable clinical overlap with Zimmermann-Laband syndrome (ZLS), a rare condition with coarse facial features, hypertrichosis, gingival overgrowth, intellectual disability of variable degree, and hypoplasia or aplasia of terminal phalanges and/or nails. ZLS is caused by heterozygous gain-of-function variants in KCNH1 or KCNN3, and gain-of-function KCNK4 variants underlie the clinically similar FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) syndrome; KCNH1, KCNN3 and KCNK4 encode potassium channels. Within our research project on ZLS, we performed targeted Sanger sequencing of ABCC9 in 15 individuals tested negative for a mutation in the ZLS-associated genes and found two individuals harboring a heterozygous pathogenic ABCC9 missense variant. Through a collaborative effort, we identified a total of nine individuals carrying a monoallelic ABCC9 variant: five sporadic patients and four members of two unrelated families. Among the six detected ABCC9 missense variants, four [p.(Pro252Leu), p.(Thr259Lys), p.(Ala1064Pro), and p.(Arg1197His)] were novel. Systematic assessment of the clinical features in the nine cases with an ABCC9 variant highlights the significant clinical overlap between ZLS and CS that includes early developmental delay, hypertrichosis, gingival overgrowth, joint laxity, and hypoplasia of terminal phalanges and nails. Gain of K channel activity possibly accounts for significant clinical similarities of CS, ZLS and FHEIG syndrome and defines a new subgroup of potassium channelopathies.
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http://dx.doi.org/10.1016/j.ejmg.2020.103996DOI Listing
September 2020

Delayed appearance of 3-methylglutaconic aciduria in neonates with early onset metabolic cardiomyopathies: A potential pitfall for the diagnosis.

Am J Med Genet A 2020 01 15;182(1):64-70. Epub 2019 Nov 15.

Metabolic Diseases Unit, Bambino Gesù Children Hospital and Research Institute, Rome, Italy.

Infantile onset cardiomyopathies are highly heterogeneous with several phenocopies compared with adult cardiomyopathies. Multidisciplinary management is essential in determining the underlying etiology in children's cardiomyopathy. Elevated urinary excretion of 3-methylglutaconic acid (3-MGA) is a useful tool in identifying the etiology in some metabolic cardiomyopathy. Here, we report the delayed appearance of 3-MGA-uria, between 6 and 18 months in three patients (out of 100 childhood onset cardiomyopathy) with neonatal onset cardiomyopathy, secondary to TMEM70 mutations and TAZ mutations (Barth syndrome), in whom extensive metabolic investigations, performed in the first weeks of life, did not display 3-MGA-uria. Serial retrospective evaluations showed full characteristic features of TMEM70 and TAZ mutations (Barth syndrome) in these three patients, including a clearly abnormal monolysocardiolipin/cardiolipin ratio in the two Barth syndrome patients. Serially repeated metabolic investigations finally discovered the 3-MGA-uria biomarker in all three patients between the age of 6 and 18 months. Our observation provides novel insights into the temporal appearance of 3-MGA-uria in TMEM70 and TAZ mutations (Barth syndrome) and focus the importance of multidisciplinary management and careful evaluation of family history and red flag signs for phenocopies in infantile onset cardiomyopathies.
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http://dx.doi.org/10.1002/ajmg.a.61383DOI Listing
January 2020

Familial aggregation of "apple peel" intestinal atresia and cardiac left-sided obstructive lesions: A possible causal relationship with NOTCH1 gene mutations.

Am J Med Genet A 2019 08 20;179(8):1570-1574. Epub 2019 May 20.

Medical Genetics Unit, Medical Genetics Laboratory, Neonatal Surgery Unit, Neonatal Intensive Care Unit, Scientific Rectorate, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy.

"Apple peel" intestinal atresia is a rare form of small bowel atresia, in which the duodenum or proximal jejunum ends in a blind pouch and the distal small bowel wraps around its vascular supply, in a spiral resembling an apple peel. The etiology of "apple peel" intestinal atresia is presently unknown, although a congenital or acquired intestinal vascular accident can have a role in the pathogenesis. We report a family in which the proband affected by "apple peel" intestinal atresia, had a sibling (an interrupted pregnancy), and a paternal cousin with cardiac left-sided obstructive lesions. Molecular testing for NOTCH1 gene was carried out in the proband, because pathogenic mutations in this gene have been associated with familial and sporadic cardiac left-sided obstructive lesions and vascular anomalies, both isolated or within the spectrum of the Adams-Oliver syndrome (AOS). The heterozygous c.2734C>T (p.Arg912Trp) NOTCH1 variant was found in the proband with "apple peel" intestinal atresia and in his father. This result argues for a possible causal relationship between NOTCH1 gene mutations and some forms of intestinal defects, through a vascular mechanism. The spectrum of NOTCH1-associated malformations is widened. Genetic counseling should take into account intrafamilial variable clinical expression and incomplete penetrance.
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http://dx.doi.org/10.1002/ajmg.a.61195DOI Listing
August 2019

Palmoplantar Keratoderma and Woolly Hair Revealing Asymptomatic Arrhythmogenic Cardiomyopathy.

Acta Derm Venereol 2019 Jul;99(9):831-832

Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Via dei Monti di Creta, 104, IT-00167 Rome, Italy.

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http://dx.doi.org/10.2340/00015555-3216DOI Listing
July 2019

Small 4p16.3 deletions: Three additional patients and review of the literature.

Am J Med Genet A 2018 11 23;176(11):2501-2508. Epub 2018 Sep 23.

Medical Genetics Unit and Laboratory of Medical Genetics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Wolf-Hirschhorn syndrome is a well-defined disorder due to 4p16.3 deletion, characterized by distinct facial features, intellectual disability, prenatal and postnatal growth retardation, and seizures. Genotype-phenotype correlations based on differently sized deletions have been attempted, and some candidate genes have been suggested. We report on clinical characteristics of three patients with pure interstitial submicroscopic 4p16.3 deletions, ranging in size from 68 to 166 kb, involving WHSCR1 and/or part of WHSCR2, and review published cases with overlapping 4p16.3 losses. The present study highlights a major role of NSD2 gene in the pathogenesis of the WHS main features and predicts that loss-of-function mutations affecting NSD2 gene could result in microcephaly, prenatal and postnatal growth retardation, psychomotor and language delay, and craniofacial features. Absent seizures in all subjects corroborate the suggestion that this specific feature is causally linked with at least one additional causative gene. Finally, we suggest that mir-943 could play a role in the pathogenesis of CHD in some of these patients.
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http://dx.doi.org/10.1002/ajmg.a.40512DOI Listing
November 2018

First evidence of maternally inherited mosaicism in TGFBR1 and subtle primary myocardial changes in Loeys-Dietz syndrome: a case report.

BMC Med Genet 2018 09 15;19(1):170. Epub 2018 Sep 15.

Mechanical Assistance Device and Artificial Heart Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.

Background: Loeys-Dietz syndrome (LDS) is a rare multisystemic disorder characterized by vascular and skeletal abnormalities, with considerable intra- and interfamilial variability.

Case Presentation: We report the case of an 8-year-old male with clinical features of two distinct genetic disorders, namely LDS, manifesting in the first months by progressive aortic root dilatation, arterial tortuosity, bifid uvula, and inguinal hernias and oculocutaneous albinism (OCA) manifesting by white hair and skin that does not tan, nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment). We identified previously reported, homozygous mutations of TYR, c.1A > G (p.Met1Val) and heterozygous, missense mutation of TGFBR1, c.1460G > A (p.Arg487Gln). Family history revealed that his mother underwent multiple surgical repairs for recurrent hemorrhage originating from the buccal artery. Molecular studies confirmed a maternally inherited low grade TGFBR1 mutation somatic mosaicism (18% in peripheral blood leukocytes, 18% in buccal cells and 10% in hair root cells). Maternal cardiac investigations revealed peculiar cardiovascular features: mild tortuosity at the aortic arch, dilatation of the proximal abdominal aorta, multiple deep left ventricular myocardial crypts, and dysplastic mitral valve. TGFBR2 germline mosaicism has been described in three fathers of children carrying TGFBR2 mutations but, to the best of our knowledge, no case of maternally inherited TGFBR1 mutation mosaicism has been reported so far.

Conclusions: This case report suggests that individuals with somatic mosaicism might be at risk for mild and unusual forms of LDS but germline mosaicism can lead to full blown picture of the disease in offspring.
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http://dx.doi.org/10.1186/s12881-018-0661-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139163PMC
September 2018

Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome.

Hum Mutat 2017 04 7;38(4):451-459. Epub 2017 Feb 7.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu , Leu , and Arg in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu and Arg exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu , with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features.
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http://dx.doi.org/10.1002/humu.23175DOI Listing
April 2017

Myoclonic status and central fever in Angelman syndrome due to paternal uniparental disomy.

J Neurogenet 2015 11;29(4):178-82. Epub 2015 Nov 11.

a Department of Pediatrics and Child Neuropsychiatry, Division of Child Neurology , Policlinico Hospital, Sapienza University , Roma , Italy.

Myoclonic status in nonprogressive encephalopathy (MSNE) is an early-onset, drug-resistant epileptic syndrome characterized by occurrence of continuous diffuse epileptiform abnormalities, associated with positive and/or negative phenomena and accompanied by transient and recurring motor, cognitive, and behavioral impairment. MSNE has been reported in Angelman syndrome (AS) secondary to 15q11-13 deletions or UBE3A mutations but not to paternal uniparental disomy (UPD). We describe the case of a male patient with AS caused by UPD who developed a myoclonic status (MS) associated with long-lasting fever of central origin, both promptly regressed with introduction of levetiracetam. Only three descriptions of thermal dysregulation in AS exist, and none of the previously reported cases were associated with MS or with UPD. Association of MS and central fever expands the spectrum of epileptic and non-epileptic features in UPD-related AS and provides a further evidence of hypothalamus involvement in the pathogenesis of this neurodevelopmental disorder.
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http://dx.doi.org/10.3109/01677063.2015.1091452DOI Listing
October 2016

Defining the epsilon-sarcoglycan (SGCE) gene phenotypic signature in myoclonus-dystonia: a reappraisal of genetic testing criteria.

Mov Disord 2013 Jun 15;28(6):787-94. Epub 2013 May 15.

Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom.

Mutations or exon deletions of the epsilon-sarcoglycan (SGCE) gene cause myoclonus-dystonia (M-D), but a subset of M-D patients are mutation-negative and the sensitivity and specificity of current genetic testing criteria are unknown. We screened 46 newly enrolled M-D patients for SGCE mutations and deletions; moreover, 24 subjects previously testing negative for SGCE mutations underwent gene dosage analysis. In our combined cohorts, we calculated sensitivity, specificity, positive and negative predictive values, and area under the curve of 2 published sets of M-D diagnostic criteria. A stepwise logistic regression was used to assess which patients' characteristics best discriminated mutation carriers and to calculate a new mutation predictive score ("new score"), which we validated in previously published cohorts. Nine of 46 (19.5%) patients of the new cohort carried SCGE mutations, including 5 novel point mutations and 1 whole-gene deletion; in the old cohort, 1 patient with a complex phenotype carried a 5.9-Mb deletion encompassing SGCE. Current diagnostic criteria had a poor ability to discriminate SGCE-positive from SGCE-negative patients in our cohort; conversely, age of onset, especially if associated with psychiatric features (as included in the new score), showed the best discriminatory power to individuate SGCE mutation carriers, both in our cohort and in the validation cohort. Our results suggest that young age at onset of motor symptoms, especially in association with psychiatric disturbance, are strongly predictive for SGCE positivity. We suggest performing gene dosage analysis by multiple ligation-dependent probe amplification (MLPA) to individuate large SGCE deletions that can be responsible for complex phenotypes.
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http://dx.doi.org/10.1002/mds.25506DOI Listing
June 2013

Novel and recurrent EVC and EVC2 mutations in Ellis-van Creveld syndrome and Weyers acrofacial dyostosis.

Eur J Med Genet 2013 Feb 7;56(2):80-7. Epub 2012 Dec 7.

Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy.

Ellis van Creveld syndrome and Weyers acrofacial dysostosis are allelic disorders caused by mutations in EVC or EVC2 genes. We illustrate the results of direct analysis of whole EVC and EVC2 genes' coding regions in 32 unrelated families with clinical diagnosis of Ellis van Creveld syndrome and in 2 families with Weyers acrofacial dysostosis. We identified mutations in 27/32 (84%) cases with Ellis van Creveld syndrome and 2/2 cases with Weyers acrofacial dysostosis. Of the Ellis van Creveld syndrome cases, 20/27 (74%) had a mutation in EVC and 7/27 (26%) in EVC2 genes. The two subjects with Weyers acrofacial dysostosis had a heterozygous mutation in the last exon of EVC2. In total, we detected 25 independent EVC and 11 independent EVC2 mutations. Nineteen EVC mutations (19/25, 76%) and 4 EVC2 mutations (4/11, 36%) were novel. Also one EVC2 gene mutation found in Weyers acrofacial dysostosis was novel. In 5 unrelated cases with a clinical diagnosis of Ellis van Creveld syndrome, we did not find any mutation in either EVC or EVC2 genes. Current findings expand the Ellis van Creveld syndrome and Weyers acrofacial dysostosis mutation spectra, and provide further evidence that the last exon of EVC2 gene is a hot spot for Weyers acrofacial dysostosis mutations. Accordingly, EVC2 exon 22 should be analyzed with priority by mutation screening in individuals with a suspected diagnosis of Weyers acrofacial dysostosis.
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http://dx.doi.org/10.1016/j.ejmg.2012.11.005DOI Listing
February 2013

ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression.

Haematologica 2012 Jan 11;97(1):47-55. Epub 2011 Oct 11.

Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.

Background: The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease.

Design And Methods: Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval.

Results: Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations.

Conclusions: ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.
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http://dx.doi.org/10.3324/haematol.2011.049270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248930PMC
January 2012

Founder effects for ATM gene mutations in Italian Ataxia Telangiectasia families.

Ann Hum Genet 2009 Sep;73(Pt 5):532-9

II School of Medicine, University La Sapienza, I-00189 Roma, Italy.

We screened ATM gene mutations in 104 Italian Ataxia-Telangiectasia patients from 91 unrelated families (detection rate 90%) and found 21 recurrent mutations in 63 families. The majority (67%) of patients were compound heterozygotes, while 33% were homozygotes. To determine the existence of common haplotypes and potential founder effects, we analyzed five microsatellite markers within and flanking the ATM gene. Haplotype analysis was carried out in 48/63 families harbouring 16 of the 21 recurrent mutations. Forty different haplotypes were detected in the 48 A-T families studied. We found that the majority of patients with the same recurrent mutation originated from the same geographical area. All but one recurrent mutation analyzed displayed a common haplotype suggesting a single origin that then spread to different geographical areas. The high number of different haplotypes does not allow the screening of ATM mutations by haplotype analysis alone in the Italian population. The finding of recurrent public mutations without founder effect suggests the existence of 'mild' hot spots of mutation located along the sequence of the ATM gene.
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http://dx.doi.org/10.1111/j.1469-1809.2009.00535.xDOI Listing
September 2009

DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: fourteen novel ATM mutations.

Dis Markers 2006 ;22(4):257-64

IRCCS-CSS Mendel Institute, Rome, Italy.

The gene for ataxia-telangiectasia (A-T:MIM: #208900), ATM, spans about 150 kb of genomic DNA and is composed of 62 coding exons. ATM mutations are found along the entire coding sequence of the gene, without evidence of mutational hot spots. Using DNA as the starting material, we used denaturing high performance liquid chromatography (DHPLC) technique to search for ATM gene mutations. Initially, DHPLC was validated in a retrospective study of 16 positive control samples that included 19 known mutations; 100% of mutations were detected. Subsequently, DHPLC was used to screen for mutations a cohort of 22 patients with the classical form of A-T. A total of 27 different mutations were identified on 38 of the 44 alleles, corresponding to a 86% detection rate. Fourteen of the mutations were novel. In addition, 15 different variants and polymorphisms of unknown functional significance were found. The high incidence of new and individual A-T mutations in our cohort of patients demonstrates marked mutational heterogeneity of A-T in Italy and corroborate the efficiency of DHPLC as a method for the mutation screening of A-T patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862285PMC
http://dx.doi.org/10.1155/2006/740493DOI Listing
January 2007