Marcella Devoto

Sapienza University of Rome, Roma, Latium, Italy

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Publications (227)1729.23 Total impact

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    ABSTRACT: Background: Very early onset inflammatory bowel disease (VEO-IBD) occurs in children less than 5 years old and is frequently characterized by a more severe disease course than older onset IBD. The etiology likely includes a significant genetic contribution, particularly genes associated with immunodeficiency. The increased utilization of whole exome sequencing (WES) has identified several rare and novel variants in immune pathways that are associated with this phenotype. Methods: A 17-month-old boy with a family history of consanguinity and Crohn disease in his maternal grandmother initially presented with poor growth, recurrent fever, constipation, and intermittent blood in his stool. He was discovered to have a recurrent perianal fistula. Colonoscopy revealed multiple ulcerations in the distal 10cm of his colon and rectum. He was treated with azathioprine, corticosteroids, mesalamine enemas, and metronidazole and had resolution of his symptoms and fistula within 6 months. He developed serious infections as well, including multiple episodes of febrile pneumonia requiring hospitalization and IV antibiotics. Additionally he had 2 episodes of acute otitis media but no sinusitis or cellulitis. His growth remained poor. His physical exam was notable for hypertelorism, epicanthal folds, low set posteriorly rotated ears, and developmental delay. Results: Immune work up revealed combined immunodeficiency including total hypogammaglobulinemia, decreased production and maturation of B cells, decreased NK cells, and poor titer response to vaccines. WES detected a potential causative homozygous frameshift mutation, c.1492-1493delCA: p.Q498VfsX15, in ZBTB24, which is involved in B cell differentiation. The subject's mother and father are heterozygous for the same mutation. Homozygous and compound heterozygous mutations of ZBTB24 have been described in patients with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 (ICF2, OMIM 614069). Karyotype to confirm this diagnosis was performed. Conclusions: Underlying immunodeficiencies can present with phenotypic characteristics of VEO-IBD. Here whole exome sequencing together with immunophenotyping detected a novel variant in a known immunodeficiency gene presenting as recurrent pneumonia and inflammatory bowel disease.
    No preview · Article · Mar 2016 · Inflammatory Bowel Diseases
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    ABSTRACT: Background: Very early onset inflammatory bowel disease (VEO-IBD) is frequently considered a different disease process than older onset IBD. The severe phenotype and young age of onset suggest a more pronounced genetic susceptibility and dysregulated immune response. We hypothesized that rare or novel variants involving pathways in barrier defense, autoimmunity as well as both B and T cell development and activation, were enriched in patients with VEO-IBD. In turn, these variants result in altered gene expression, impaired immunological responses, and aberrant host-microbe interactions. Our primary aim is to identify dysregulation in the gene expression profiles of VEO-IBD patients, to determine the down-stream impact of candidate causal variants on the affected immune pathways and to delineate their role in disease pathogenesis. Methods: IBD patients 5 years and younger, and parents were recruited. Exome capture was performed by Agilent SureSelect V4, and sequencing was accomplished using the Illumina HiSeq platform. Following functional annotation, single base substitutions likely to alter protein function, such as missense and loss of function mutations, were kept for subsequent analysis. RNA isolated from whole blood collected in Tempus tubes was hybridized to Illumina HumanHT-12v4 arrays to evaluate the downstream effects of the variants on the mRNA product through changes in gene expression. Results: Three hundred eleven samples were analyzed, including 71 trios. Patients' age ranged from 3 weeks to 4 years. 4 trios were analyzed for gene expression. WES identified compound heterozygous mutations in FAT1, and a heterozygous variant in BIRC6 in a male diagnosed with severe VEO-IBD at age 2, unresponsive to medical and surgical therapy. FAT1 is an antagonist of caspase-8, and BIRC6 is a member of the Inhibitors of Apoptosis protein (IAP) family. Gene expression demonstrated upregulation of genes involved in leukocyte apoptosis, including CASP7 and CASP8. This increased apoptotic activity is similar to the mechanism seen in XIAP deficiency, a known primary immunodeficiency that can result in VEO-IBD. In addition, there was an upregulation of NAIP, and subsequent down-stream increased anti-microbial activity. NAIP is a component of the NLRC4 inflammasome. Conclusions: The association of candidate risk variants with gene expression provides a powerful method to mine WES identified variants. This case illustrates the ability to detect downstream effects of suspected causal variants. Currently there is a paucity of data utilizing this strategy in patients with VEO-IBD. This systems biology-based approach may provide further understanding of the interacting pathways responsible for a subset of disease in VEO-IBD.
    No preview · Article · Feb 2016 · Inflammatory Bowel Diseases
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    ABSTRACT: Chronic intestinal pseudo-obstruction (CIPO) syndromes are heterogeneous gastrointestinal disorders, caused by either neuropathy or myopathy, resulting in compromised peristalsis and intestinal obstruction. CIPO can have a profound impact on quality of life, leading the most severely affected individuals to life-long parenteral nutrition and urinary catheterization. To search for disease causing gene(s), we performed the whole exome sequencing (WES) in both eight sporadic and two familial cases, followed by targeted sequencing in additional CIPO patients. After identifying a heterozygous missense variant in the ACTG2 gene in one of 10 patients undergone WES, targeted Sanger sequencing of this gene allowed to detect heterozygous missense variants in 9 of 23 further patients with either megacystis-microcolon-intestinal hypoperistalsis syndrome or intestinal pseudo-obstruction. Variants thus identified, one of which still unreported, affect highly conserved regions of the ACTG2 gene that encodes a protein crucial for correct enteric muscle contraction. These findings provided evidence for a correlation between the clinical phenotype and genotype at the ACTG2 locus, a first step to improve the diagnosis and prognosis of these severe conditions.European Journal of Human Genetics advance online publication, 27 January 2016; doi:10.1038/ejhg.2015.275.
    No preview · Article · Jan 2016 · European journal of human genetics: EJHG
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    ABSTRACT: The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS; MIM #192430; 188400) is the most common microdeletion syndrome. The phenotypic presentation of 22q11DS is highly variable; approximately 60-75 % of 22q11DS patients have been reported to have a congenital heart defect (CHD), mostly of the conotruncal type, and/or aortic arch defect. The etiology of the cardiac phenotypic variability is not currently known for the majority of patients. We hypothesized that rare copy number variants (CNVs) outside the 22q11.2 deleted region may modify the risk of being born with a CHD in this sensitized population. Rare CNV analysis was performed using Affymetrix SNP Array 6.0 data from 946 22q11DS subjects with CHDs (n = 607) or with normal cardiac anatomy (n = 339). Although there was no significant difference in the overall burden of rare CNVs, an overabundance of CNVs affecting cardiac-related genes was detected in 22q11DS individuals with CHDs. When the rare CNVs were examined with regard to gene interactions, specific cardiac networks, such as Wnt signaling, appear to be overrepresented in 22q11DS CHD cases but not 22q11DS controls with a normal heart. Collectively, these data suggest that CNVs outside the 22q11.2 region may contain genes that modify risk for CHDs in some 22q11DS patients.
    Full-text · Article · Jan 2016 · Human Genetics
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    ABSTRACT: We studied two brothers who presented in the newborn period with cardiac, renal, and hepatic anomalies that were initially suggestive of ALGS, although no mutations in JAG1 or NOTCH2 were identified. Exome sequencing demonstrated compound heterozygous mutations in the NEK8 gene (Never in mitosis A-related Kinase 8), a ciliary kinase indispensable for cardiac and renal development based on murine studies. The mutations included a c.2069_2070insC variant (p.Ter693LeufsTer86), and a c.1043C>T variant (p.Thr348Met) in the highly conserved RCC1 (Regulation of Chromosome Condensation 1) domain. The RCC1 domain is crucial for localization of the NEK8 protein to the centrosomes and cilia. Mutations in NEK8 have been previously reported in three fetuses (from a single family) with renal-hepatic-pancreatic dysplasia 2 (RHPD2), similar to Ivemark syndrome, and in three individuals with nephronophthisis (NPHP9). This is the third report of disease-causing mutations in the NEK8 gene in humans and only the second describing multi-organ involvement. The clinical features we describe differ from those in the previously published report in that (1) a pancreatic phenotype was not observed in the individuals reported here, (2) there were more prominent cardiac findings, (consistent with observations in murine models), and (3) we observed bile duct hypoplasia rather than ductal plate malformation. The patients reported here expand our understanding of the NEK8-associated phenotype. Our findings highlight the variable phenotypic expressivity and the spectrum of clinical manifestations due to mutations in the NEK8 gene. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Dec 2015 · American Journal of Medical Genetics Part A
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    ABSTRACT: Background Children with very early-onset inflammatory bowel disease (VEO-IBD), those diagnosed at less than 5 years of age, are a unique population. A subset of these patients present with a distinct phenotype and more severe disease than older children and adults. Host genetics is thought to play a more prominent role in this young population, and monogenic defects in genes related to primary immunodeficiencies are responsible for the disease in a small subset of patients with VEO-IBD. Case Presentation We report a child who presented at 3 weeks of life with very early-onset inflammatory bowel disease (VEO-IBD). He had a complicated disease course and remained unresponsive to medical and surgical therapy. The refractory nature of his disease, together with his young age of presentation, prompted utilization of whole exome sequencing (WES) to detect an underlying monogenic primary immunodeficiency and potentially target therapy to the identified defect. Copy number variation analysis (CNV) was performed using the eXome-Hidden Markov Model. Whole exome sequencing revealed 1,380 nonsense and missense variants in the patient. Plausible candidate variants were not detected following analysis of filtered variants, therefore, we performed CNV analysis of the WES data, which led us to identify a de novo whole gene deletion in XIAP. Conclusion This is the first reported whole gene deletion in XIAP, the causal gene responsible for XLP2 (X-linked lymphoproliferative Disease 2). XLP2 is a syndrome resulting in VEO-IBD and can increase susceptibility to hemophagocytic lymphohistocytosis (HLH). This identification allowed the patient to be referred for bone marrow transplantation, potentially curative for his disease and critical to prevent the catastrophic sequela of HLH. This illustrates the unique etiology of VEO-IBD, and the subsequent effects on therapeutic options. This cohort requires careful and thorough evaluation for monogenic defects and primary immunodeficiencies.
    Full-text · Article · Nov 2015 · BMC Gastroenterology
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    ABSTRACT: STUDY HYPOTHESIS Susceptibility to inherited cryptorchidism in the LE/orl rat may be associated with genetic loci that influence developmental patterning of the gubernaculum by the fetal testis.
    No preview · Article · Oct 2015 · Molecular Human Reproduction
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    ABSTRACT: What are the genetic loci that increase susceptibility to nonsyndromic cryptorchidism, or undescended testis? A genome-wide association study (GWAS) suggests that susceptibility to cryptorchidism is heterogeneous, with a subset of suggestive signals linked to cytoskeleton-dependent functions and syndromic forms of the disease. Population studies suggest moderate genetic risk of cryptorchidism and possible maternal and environmental contributions to risk. Previous candidate gene analyses have failed to identify a major associated locus, although variants in insulin-like 3 (INSL3), relaxin/insulin-like family peptide receptor 2 (RXFP2) and other hormonal pathway genes may increase risk in a small percentage of patients. This is a case-control GWAS of 844 boys with nonsyndromic cryptorchidism and 2718 control subjects without syndromes or genital anomalies, all of European ancestry. All boys with cryptorchidism were diagnosed and treated by a pediatric specialist. In the discovery phase, DNA was extracted from tissue or blood samples and genotyping performed using the Illumina HumanHap550 and Human610-Quad (Group 1) or OmniExpress (Group 2) platform. We imputed genotypes genome-wide, and combined single marker association results in meta-analyses for all cases and for secondary subphenotype analyses based on testis position, laterality and age, and defined genome-wide significance as P = 7 × 10(-9) to correct for multiple testing. Selected markers were genotyped in an independent replication group of European cases (n = 298) and controls (n = 324). We used several bioinformatics tools to analyze top (P < 10(-5)) and suggestive (P < 10(-3)) signals for significant enrichment of signaling pathways, cellular functions and custom gene lists after multiple testing correction. In the full analysis, we identified 20 top loci, none reaching genome-wide significance, but one passing this threshold in a subphenotype analysis of proximal testis position (rs55867206, near SH3PXD2B, odds ratio = 2.2 (95% confidence interval 1.7, 2.9), P = 2 × 10(-9)). An additional 127 top loci emerged in at least one secondary analysis, particularly of more severe phenotypes. Cytoskeleton-dependent molecular and cellular functions were prevalent in pathway analysis of suggestive signals, and may implicate loci encoding cytoskeletal proteins that participate in androgen receptor signaling. Genes linked to human syndromic cryptorchidism, including hypogonadotropic hypogonadism, and to hormone-responsive and/or differentially expressed genes in normal and cryptorchid rat gubernaculum, were also significantly overrepresented. No tested marker showed significant replication in an independent population. The results suggest heterogeneous, multilocus and potentially multifactorial susceptibility to nonsyndromic cryptorchidism. The present study failed to identify genome-wide significant markers associated with cryptorchidism that could be replicated in an independent population, so further studies are required to define true positive signals among suggestive loci. As the only GWAS to date of nonsyndromic cryptorchidism, these data will provide a basis for future efforts to understand genetic susceptibility to this common reproductive anomaly and the potential for additive risk from environmental exposures. This work was supported by R01HD060769 (the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD)), P20RR20173 (the National Center for Research Resources (NCRR), currently P20GM103464 from the National Institute of General Medical Sciences (NIGMS)), an Institute Development Fund to the Center for Applied Genomics at The Children's Hospital of Philadelphia, and Nemours Biomedical Research. The authors have no competing interests to declare. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
    No preview · Article · Jul 2015 · Human Reproduction
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    ABSTRACT: Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed ≤5 y of age, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development. Patients with VEO-IBD and parents (when available) were recruited from the Children's Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (ages 3 weeks to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by post-processing and variant calling. Following functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency <0.1%, and scaled combined annotation dependent depletion scores ≤10. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n=45) or adult-onset Crohn's disease (n=20) and healthy individuals (controls, n=145) were obtained from the University of Kiel, Germany and used as control groups. Four-hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling > 1 Mbp of coding sequence, were selected from the whole exome data. Our analysis revealed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19. In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Gastroenterology
  • Emmanuelle Génin · Marcella Devoto

    No preview · Article · Jul 2015 · Human Heredity
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    ABSTRACT: New genomic strategies can now be applied to identify a diagnosis in patients and families with previously undiagnosed rare genetic conditions. The large family evaluated in the present study was described in 1966 and now expands the phenotype of a known neuromuscular gene. To determine the genetic cause of a slowly progressive, autosomal dominant, scapuloperoneal neuromuscular disorder by using linkage and exome sequencing. Fourteen affected individuals in a 6-generation family with a progressive scapuloperoneal disorder were evaluated. Participants were examined at pediatric, neuromuscular, and research clinics from March 1, 2005, to May 31, 2014. Exome and linkage were performed in genetics laboratories of research institutions. Examination and evaluation by magnetic resonance imaging, ultrasonography, electrodiagnostic studies, and muscle biopsies (n = 3). Genetic analysis included linkage analysis (n = 17) with exome sequencing (n = 7). Clinical findings included progressive muscle weakness in an initially scapuloperoneal and distal distribution, including wrist extensor weakness, finger and foot drop, scapular winging, mild facial weakness, Achilles tendon contractures, and diminished or absent deep tendon reflexes. Both age at onset and progression of the disease showed clinical variability within the family. Muscle biopsy specimens demonstrated type I fiber atrophy and trabeculated fibers without nemaline rods. Analysis of exome sequences within the linkage region (4.8 megabases) revealed missense mutation c.591C>A p.Glu197Asp in a highly conserved residue in exon 4 of ACTA1. The mutation cosegregated with disease in all tested individuals and was not present in unaffected individuals. This family defines a new scapuloperoneal phenotype associated with an ACTA1 mutation. A highly conserved protein, ACTA1 is implicated in multiple muscle diseases, including nemaline myopathy, actin aggregate myopathy, fiber-type disproportion, and rod-core myopathy. To our knowledge, mutations in Glu197 have not been reported previously. This residue is highly conserved and located in an exposed position in the protein; the mutation affects the intermolecular and intramolecular electrostatic interactions as shown by structural modeling. The mutation in this residue does not appear to lead to rod formation or actin accumulation in vitro or in vivo, suggesting a different molecular mechanism from that of other ACTA1 diseases.
    No preview · Article · May 2015
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    ABSTRACT: The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS) is the most common microdeletion syndrome and the phenotypic presentation is highly variable. Approximately 65% of individuals with 22q11DS have a congenital heart defect (CHD), mostly of the conotruncal type, and/or an aortic arch defect. The etiology of this phenotypic variability is not currently known. We hypothesized that copy-number variants (CNVs) outside the 22q11.2 deleted region might increase the risk of being born with a CHD in this sensitized population. Genotyping with Affymetrix SNP Array 6.0 was performed on two groups of subjects with 22q11DS separated by time of ascertainment and processing. CNV analysis was completed on a total of 949 subjects (cohort 1, n = 562; cohort 2, n = 387), 603 with CHDs (cohort 1, n = 363; cohort 2, n = 240) and 346 with normal cardiac anatomy (cohort 1, n = 199; cohort 2, n = 147). Our analysis revealed that a duplication of SLC2A3 was the most frequent CNV identified in the first cohort. It was present in 18 subjects with CHDs and 1 subject without (p = 3.12 × 10(-3), two-tailed Fisher's exact test). In the second cohort, the SLC2A3 duplication was also significantly enriched in subjects with CHDs (p = 3.30 × 10(-2), two-tailed Fisher's exact test). The SLC2A3 duplication was the most frequent CNV detected and the only significant finding in our combined analysis (p = 2.68 × 10(-4), two-tailed Fisher's exact test), indicating that the SLC2A3 duplication might serve as a genetic modifier of CHDs and/or aortic arch anomalies in individuals with 22q11DS. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · The American Journal of Human Genetics

  • No preview · Article · Apr 2015 · Gastroenterology
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    ABSTRACT: Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277kb heterozygous deletion on chromosome 20 which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Mar 2015 · Human Mutation

  • No preview · Article · Mar 2015 · American Journal of Medical Genetics Part A
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    ABSTRACT: Purpose: Based on a genome-wide association study of testicular dysgenesis syndrome showing a possible association with TGFBR3, we analyzed data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal. Materials and methods: We excluded samples based on strict quality control criteria, leaving 844 cases and 2,718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform (ie Illumina® HumanHap550, version 1 or 3, or Human610-Quad, version 1 BeadChip in group 1 and Human OmniExpress 12, version 1 BeadChip platform in group 2). Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of data for groups 1 and 2, and selective genotyping of independent cases (330) and controls (324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum. Results: We identified suggestive (p ≤ 1× 10(-4)) association of markers in/near TGFBR3, including rs9661103 (OR 1.40; 95% CI 1.20, 1.64; p = 2.71 × 10(-5)) and rs10782968 (OR 1.58; 95% CI 1.26, 1.98; p = 9.36 × 10(-5)) in groups 1 and 2, respectively. In subgroup analyses we observed strongest association of rs17576372 (OR 1.42; 95% CI 1.24, 1.60; p = 1.67 × 10(-4)) with proximal and rs11165059 (OR 1.32; 95% CI 1.15, 1.38; p = 9.42 × 10(-4)) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior genome-wide association study signal (rs12082710) was marginal (OR 1.13; 95% CI 0.99, 1.28; p = 0.09 for group 1), and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild-type and cryptorchid rat fetal gubernaculum. Conclusions: These data suggest complex or phenotype specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFβ signaling.
    Full-text · Article · Oct 2014 · The Journal of Urology
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    ABSTRACT: The genetic etiology of sporadic neuroblastoma is still largely obscure. In a genome-wide association study, we identified single nucleotide polymorphisms (SNP) associated with neuroblastoma at the LINC00340, BARD1, LMO1, DUSP12, HSD17B12, HACE1 and LIN28B gene loci, but these explain only a small fraction of neuroblastoma heritability. Other neuroblastoma susceptibility genes are likely hidden among signals discarded by the multiple testing corrections. In this study, we evaluated 8 additional genes selected as candidates for further study based on proven involvement in neuroblastoma differentiation. SNP at these candidate genes were tested for association with disease susceptibility in 2101 cases and 4202 controls, with the associations found replicated in an independent cohort of 459 cases and 809 controls. Replicated associations were further studied for cis-effect using gene expression, transient overexpression, silencing and cellular differentiation assays. The neurofilament gene NEFL harbored three SNP associated with neuroblastoma (rs11994014; Pcombined=0.0050; OR=0.88, rs2979704; Pcombined=0.0072; OR=0.87, rs105911; Pcombined=0.0049; OR=0.86). The protective allele of rs1059111 correlated with increased NEFL expression. Biological investigations showed that ectopic overexpression of NEFL inhibited cell growth specifically in neuroblastoma cells carrying the protective allele. NEFL overexpression also enhanced differentiation and impaired the proliferation and anchorage-independent growth of cells with protective allele and basal NEFL expression, while impairing invasiveness and proliferation of cells homozygous for the risk genotype. Clinically, high levels of NEFL expression in primary neuroblastoma specimens was associated with better overall survival (P=0.03; HR=0.68). Our results show that common variants of NEFL influence neuroblastoma susceptibility and they establish that NEFL expression influences disease initiation and progression.
    Full-text · Article · Oct 2014 · Cancer Research

  • No preview · Article · May 2014 · Gastroenterology
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    ABSTRACT: TP53 is the most frequently mutated gene in human malignancies; however, de novo somatic mutations in childhood embryonal cancers such as neuroblastoma are rare. We report on the analysis of three independent case-control cohorts comprising 10290 individuals and demonstrate that rs78378222 and rs35850753, rare germline variants in linkage disequilibrium that map to the 3' untranslated region (UTR) of TP53 and 5' UTR of the Δ133 isoform of TP53, respectively, are robustly associated with neuroblastoma (rs35850753: odds ratio [OR] = 2.7, 95% confidence interval [CI] = 2.0 to 3.6, P combined = 3.43×10(-12); rs78378222: OR = 2.3, 95% CI = 1.8 to 2.9, P combined = 2.03×10(-11)). All statistical tests were two-sided. These findings add neuroblastoma to the complex repertoire of human cancers influenced by the rs78378222 hypomorphic allele, which impairs proper termination and polyadenylation of TP53 transcripts. Future studies using whole-genome sequencing data are likely to reveal additional rare variants with large effect sizes contributing to neuroblastoma tumorigenesis.
    Full-text · Article · Mar 2014 · Journal of the National Cancer Institute
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    ABSTRACT: Collagen VI-related myopathies are disorders of connective tissue presenting with an overlap phenotype combining clinical involvement from the muscle and from the connective tissue. Not all patients displaying related overlap phenotypes between muscle and connective tissue have mutations in collagen VI. Here, we report a homozygous recessive loss of function mutation and a de novo dominant mutation in collagen XII (COL12A1) as underlying a novel overlap syndrome involving muscle and connective tissue. Two siblings homozygous for a loss of function mutation showed widespread joint hyperlaxity combined with weakness precluding independent ambulation, while the patient with the de novo missense mutation was more mildly affected, showing improvement including the acquisition of walking. A mouse model with inactivation of the Col12a1 gene showed decreased grip strength, a delay in fiber-type transition and a deficiency in passive force generation while the muscle seems more resistant to eccentric contraction induced force drop, indicating a role for a matrix-based passive force-transducing elastic element in the generation of the weakness. This new muscle connective tissue overlap syndrome expands on the emerging importance of the muscle extracellular matrix in the pathogenesis of muscle disease.
    Full-text · Article · Dec 2013 · Human Molecular Genetics

Publication Stats

10k Citations
1,729.23 Total Impact Points


  • 2005-2016
    • Sapienza University of Rome
      • • Department of Molecular Medicine
      • • Department of Experimental Medicine
      • • Laboratory of Experimental Medicine and Pathology Environmental
      Roma, Latium, Italy
  • 2006-2015
    • The Children's Hospital of Philadelphia
      • • Department of Neurology
      • • Department of Pediatrics
      • • Center for Applied Genomics
      • • Department of Ophthalmology
      Filadelfia, Pennsylvania, United States
  • 2013
    • University of Pennsylvania
      • Department of Biostatistics and Epidemiology
      Philadelphia, Pennsylvania, United States
  • 2008-2011
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 1990-2005
    • Università degli Studi di Genova
      • Dipartimento di Medicina sperimentale (DIMES)
      Genova, Liguria, Italy
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 2001
    • CRO Centro di Riferimento Oncologico di Aviano
      Aviano, Friuli Venezia Giulia, Italy
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Università degli studi di Foggia
      Foggia, Apulia, Italy
  • 1994-2001
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1997-2000
    • The Rockefeller University
      New York, New York, United States
  • 1996
    • Columbia University
      • Department of Psychiatry
      New York City, New York, United States
  • 1995
    • Universität Heidelberg
      • Department of Nephrology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 1988-1995
    • National Institute of Molecular Genetics (INGM)
      Milano, Lombardy, Italy
    • Istituto di Genetica Molecolare
      Ticinum, Lombardy, Italy
  • 1993-1994
    • New York State Psychiatric Institute
      New York City, New York, United States
    • Massachusetts General Hospital
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1989-1994
    • IRCCS Istituto G. Gaslini
      Genova, Liguria, Italy
  • 1992
    • Institute of Molecular Biology, SAS
      Presburg, Bratislavský, Slovakia
  • 1991
    • Istituti Clinici di Perfezionamento
      Milano, Lombardy, Italy
    • University of Milan
      Milano, Lombardy, Italy
  • 1985-1986
    • University of Bologna
      • Urology Clinic
      Bolonia, Emilia-Romagna, Italy