Williams-Beuren Syndrome (WBS) is an autosomal dominant neurodevelopmental disorder caused by hemizygous deletion of a 1.5 Mb region on chromosome 7q11.23. Symptoms are numerous and include behavioural and cognitive components. One of the deleted genes, GTF2IRD1, a putative transcription factor, has been implicated in the neurological features of WBS by studying patients with atypical deletions of 7q11.23. Gtf2ird1-targeted mice have features consistent with the WBS phenotype, namely reduced innate fear and increased sociability. To identify neural targets of GTF2IRD1, microarray analyses were performed comparing gene expression in whole brains of Gtf2ird1-/- and wildtype (WT) mice at embryonic day 15.5 and at birth. Overall, the changes in gene expression in the mutant mice were not striking, with most falling in the range of 0.3 to 2 fold. qRT-PCR was used to verify the expression levels of candidate genes and examination of verified genes revealed that most were located on chromosome 5, within 50 Mb of Gtf2ird1. Expression of these candidate genes in Gtf2ird1-/- mice was found to be the same as in WT 129S1/SvImJ mice, indicating the differences were the result of flanking chromosomal material from the, 129-derived, R1 ES cells from which the Gtf2ird1-/- mice were generated, and that expression differences were unrelated to Gtf2ird1 dosage. Further analysis found that while many genes showed decreased expression using primers targeting the 3’ UTR, expression of upstream exons was not affected. Transcripts using alternative polyadenylation sites were identified using 3’ RACE, and qRT-PCR showed that expression of different 3’ UTR isoforms can occur in a strain specific manner. Expression analysis of previously identified GTF2IRD1 targets also failed to demonstrate an in vivo effect. In summary, I was unable to find any in vivo neuronal targets of this putative transcription factor, despite its robust expression in the developing rodent brain.

Williams-Beuren Syndrome (WBS) is an autosomal dominant neurodevelopmental disorder caused by hemizygous deletion of a 1.5 Mb region on chromosome 7q11.23. Symptoms are numerous and include behavioural and cognitive components. One of the deleted genes, GTF2IRD1, a putative transcription factor, has been implicated in the neurological features of WBS by studying patients with atypical deletions of 7q11.23. Gtf2ird1-targeted mice have features consistent with the WBS phenotype, namely reduced innate fear and increased sociability. To identify neural targets of GTF2IRD1, microarray analyses were performed comparing gene expression in whole brains of Gtf2ird1-/- and wildtype (WT) mice at embryonic day 15.5 and at birth. Overall, the changes in gene expression in the mutant mice were not striking, with most falling in the range of 0.3 to 2 fold. qRT-PCR was used to verify the expression levels of candidate genes and examination of verified genes revealed that most were located on chromosome 5, within 50 Mb of Gtf2ird1. Expression of these candidate genes in Gtf2ird1-/- mice was found to be the same as in WT 129S1/SvImJ mice, indicating the differences were the result of flanking chromosomal material from the, 129-derived, R1 ES cells from which the Gtf2ird1-/- mice were generated, and that expression differences were unrelated to Gtf2ird1 dosage. Further analysis found that while many genes showed decreased expression using primers targeting the 3’ UTR, expression of upstream exons was not affected. Transcripts using alternative polyadenylation sites were identified using 3’ RACE, and qRT-PCR showed that expression of different 3’ UTR isoforms can occur in a strain specific manner. Expression analysis of previously identified GTF2IRD1 targets also failed to demonstrate an in vivo effect. In summary, I was unable to find any in vivo neuronal targets of this putative transcription factor, despite its robust expression in the developing rodent brain.

Ulm, Univ., Diss., 2008.

Duplication and deletion of a common interval spanning 26 genes on chromosome 7q11.23 cause Dup7q11.23 Syndrome and Williams-Beuren Syndrome, neurodevelopmental disorders with contrasting anxiety phenotypes. The General Transcription Factor 2 I (GTF2I) gene has been implicated in separation anxiety, common in people with Dup7q11.23, and we studied the effects of commonly used anxiolytics on maternal separation-induced USV in mouse models with copy number changes in Gtf2i. Subcutaneous injection of saline affected both USV production and plasma corticosterone levels in a Gtf2i gene-dosage dependent manner. Drugs acting on the glutamate receptors were most effective at attenuating USVs in all genotypes, compared to GABAergic and serotonergic modulators. Brain c-fos expression after separation was reduced by a GABAA agonist, but not a glutamate antagonist. Collectively, these results suggest a potential difference in pain sensitivity based on Gtf2i copy number and implicate the glutamatergic and GABAergic systems in anxiety phenotypes in these two disorders.

Duplication and deletion of a common interval spanning 26 genes on chromosome 7q11.23 cause Dup7q11.23 Syndrome and Williams-Beuren Syndrome, neurodevelopmental disorders with contrasting anxiety phenotypes. The General Transcription Factor 2 I (GTF2I) gene has been implicated in separation anxiety, common in people with Dup7q11.23, and we studied the effects of commonly used anxiolytics on maternal separation-induced USV in mouse models with copy number changes in Gtf2i. Subcutaneous injection of saline affected both USV production and plasma corticosterone levels in a Gtf2i gene-dosage dependent manner. Drugs acting on the glutamate receptors were most effective at attenuating USVs in all genotypes, compared to GABAergic and serotonergic modulators. Brain c-fos expression after separation was reduced by a GABAA agonist, but not a glutamate antagonist. Collectively, these results suggest a potential difference in pain sensitivity based on Gtf2i copy number and implicate the glutamatergic and GABAergic systems in anxiety phenotypes in these two disorders.

Made available in DSpace on 2014-06-11T19:32:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-03-30Bitstream added on 2014-06-13T21:03:47Z : No. of bitstreams: 1 rossi_nf_dr_botib.pdf: 737377 bytes, checksum: c92ca8300b29818f0a7adbc439cdf03a (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / A síndrome de Williams-Beuren (SWB) é um distúrbio neurodesenvolvimental causado por uma deleção hemizigótica de 1.5Mb na região cromossômica 7q11.23. Essa síndrome é reconhecida pelo comportamento sociável com fala fluente e favorecimento das habilidades auditivas se comparadas às visuais. O objetivo deste estudo foi caracterizar o fenótipo comportamental e da linguagem na SWB. A casuística geral desta pesquisa foi formada por 40 indivíduos com diagnóstico da SWB, positivos para a deleção do gene da Elastina na região cromossômica 7q11.23 confirmado pela técnica de Hibridização in situ por Fluorescência (FISH), sendo 30 falantes do Português do Brasil e 10 falantes do Português de Portugal. Também foram avaliados 30 indivíduos controles falantes do Português do Brasil e 10 falantes do Português de Portugal. Para responder ao objetivo, a pesquisa foi dividida em 3 estudos. O objetivo do estudo 1 foi investigar problemas comportamentais de crianças e adolescentes com a SWB, identificados pelos pais e correlacioná-los ao desempenho intelectual e de linguagem. No estudo 2, o objetivo foi caracterizar o perfil da fluência da fala em indivíduos com a SWB na situação de narrativa, comparando-os com indivíduos com desenvolvimento típico de linguagem e idade mental. O objetivo do estudo 3 foi comparar o desempenho de indivíduos com SWB com controles semelhantes por idade mental e cronológica em tarefas auditivas e visuais, além de investigar o perfil de habilidades auditivas comparadas às visuais. Foi aplicado o inventário comportamental Child Behavior Checklist (CBCL/6-18 anos), provas e testes de linguagem para o estudo 1. Foram aplicadas tarefas em situação de narrativa, com apresentação de figura de ação e figuras sequenciais para análise da fluência no estudo 2. O Teste Illinois de Habilidades Psicolinguísticas foi utilizado... / Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a hemizygous deletion of 1.5Mb in chromosome region 7q11.23. WBS phenotype has been described as social behavior, fluent speech and superior auditory abilities despite visuospatial impairments. The purpose of this study was to characterize the WBS behavioral and language phenotype. The present study was composed of 40 WBS, positive for Elastin gene deletion on chrosome 7q11.23 confirmed by Fluorescent in Situ Hybridization (FISH), involving 30 Portuguese speakers from Brazil and 10 Portuguese speakers from Portugal. Thirty typically development Portuguese speakers' individuals from Brazil and 10 from Portugal were also involved. To meet the goal, three studies were conducted in this research. In the study 1 the purpose was to investigate behavioral problems according to WBS parents report and to correlate it with the intellectual and language performance. The purpose of the study 2 was to characterize the speech fluency profile of WBS individuals in narrative task and compare to typically development and finally in study 3, was to compare performance of individuals with WBS to chronological aged-matched and mental age matched group on auditory and visual processing. The Child Behavior Checklist (CBCL/6-18 years old) and language tests were applied for study 1. In the study 2, a single-picture and a picture-sequence were applied to assess narrative and speech fluency profile. The Illinois Test of Psycholinguistic Abilities was study 3. Results showed that social and attention problems were mentioned by WBS' parents. The correlation analysis suggested that behavioral problems identified by parents were more directly related to language performance (Study 1). Significant differences were observed in speech fluency profile, especially on common breakdowns (non-stuttered) and pauses often more frequently in the WBS group... (Complete abstract click electronic access below)

Orientador: Célia Maria Giacheti / Banca: Cláudia Aparecida Rainho / Banca: Niura Aparecida de Moura Ribeiro Padula / Banca: Antônia Paula Marques de Faria / Banca: Suelly Cecilia Olivan Limongi / Resumo: A síndrome de Williams-Beuren (SWB) é um distúrbio neurodesenvolvimental causado por uma deleção hemizigótica de 1.5Mb na região cromossômica 7q11.23. Essa síndrome é reconhecida pelo comportamento sociável com fala fluente e favorecimento das habilidades auditivas se comparadas às visuais. O objetivo deste estudo foi caracterizar o fenótipo comportamental e da linguagem na SWB. A casuística geral desta pesquisa foi formada por 40 indivíduos com diagnóstico da SWB, positivos para a deleção do gene da Elastina na região cromossômica 7q11.23 confirmado pela técnica de Hibridização in situ por Fluorescência (FISH), sendo 30 falantes do Português do Brasil e 10 falantes do Português de Portugal. Também foram avaliados 30 indivíduos controles falantes do Português do Brasil e 10 falantes do Português de Portugal. Para responder ao objetivo, a pesquisa foi dividida em 3 estudos. O objetivo do estudo 1 foi investigar problemas comportamentais de crianças e adolescentes com a SWB, identificados pelos pais e correlacioná-los ao desempenho intelectual e de linguagem. No estudo 2, o objetivo foi caracterizar o perfil da fluência da fala em indivíduos com a SWB na situação de narrativa, comparando-os com indivíduos com desenvolvimento típico de linguagem e idade mental. O objetivo do estudo 3 foi comparar o desempenho de indivíduos com SWB com controles semelhantes por idade mental e cronológica em tarefas auditivas e visuais, além de investigar o perfil de habilidades auditivas comparadas às visuais. Foi aplicado o inventário comportamental Child Behavior Checklist (CBCL/6-18 anos), provas e testes de linguagem para o estudo 1. Foram aplicadas tarefas em situação de narrativa, com apresentação de figura de ação e figuras sequenciais para análise da fluência no estudo 2. O Teste Illinois de Habilidades Psicolinguísticas foi utilizado... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a hemizygous deletion of 1.5Mb in chromosome region 7q11.23. WBS phenotype has been described as social behavior, fluent speech and superior auditory abilities despite visuospatial impairments. The purpose of this study was to characterize the WBS behavioral and language phenotype. The present study was composed of 40 WBS, positive for Elastin gene deletion on chrosome 7q11.23 confirmed by Fluorescent in Situ Hybridization (FISH), involving 30 Portuguese speakers from Brazil and 10 Portuguese speakers from Portugal. Thirty typically development Portuguese speakers' individuals from Brazil and 10 from Portugal were also involved. To meet the goal, three studies were conducted in this research. In the study 1 the purpose was to investigate behavioral problems according to WBS parents report and to correlate it with the intellectual and language performance. The purpose of the study 2 was to characterize the speech fluency profile of WBS individuals in narrative task and compare to typically development and finally in study 3, was to compare performance of individuals with WBS to chronological aged-matched and mental age matched group on auditory and visual processing. The Child Behavior Checklist (CBCL/6-18 years old) and language tests were applied for study 1. In the study 2, a single-picture and a picture-sequence were applied to assess narrative and speech fluency profile. The Illinois Test of Psycholinguistic Abilities was study 3. Results showed that social and attention problems were mentioned by WBS' parents. The correlation analysis suggested that behavioral problems identified by parents were more directly related to language performance (Study 1). Significant differences were observed in speech fluency profile, especially on common breakdowns (non-stuttered) and pauses often more frequently in the WBS group... (Complete abstract click electronic access below) / Doutor

Submitted by admin tede (tede@pucgoias.edu.br) on 2016-09-13T13:52:57Z No. of bitstreams: 1 MARINA MACHADO SANTOS.pdf: 3084828 bytes, checksum: 7da6c5d67d268a88f71826629557e0c5 (MD5) / Made available in DSpace on 2016-09-13T13:52:58Z (GMT). No. of bitstreams: 1 MARINA MACHADO SANTOS.pdf: 3084828 bytes, checksum: 7da6c5d67d268a88f71826629557e0c5 (MD5) Previous issue date: 2016-05-16 / Chromosomal abnormalities cause specific and complex phenotypes due to imbalance in the normal dosage of genes located in a specific chromosomal segment. They account for 60% or even more of all the identifiable genetic syndromes. Williams-Beuren syndrome (WBS) is related to a group of multiple defects and intellectual disabilities, described independently by Williams et al. (1961) and Beuren et al. (1962). The WBS is a genetic disease characterized by a microdeletion of the 7q11.23 region, which delay the physical and intellectual development and it is associated with congenital cardiac abnormalities, facial dimorphism, mental retardation and occasionally infantile hypercalcemia.The existing phenotypic variation in this syndrome hinders clinical diagnosis.Through the development of new cytomolecular technologies and the increased number of studies regarding the clinical features of this syndrome, seeks a better understanding of the genotype-phenotype correlation in WBS. The present study reports some of these techniques used for the diagnosis of WBS, such as Karyotype, MLPA, PCR, with emphasis on FISH and CMA. Additionally, we described four patients who were referred to LaGene/SES and NPR/PUC by the public health service. Three of them had clinical suggestion of WBS and the fourth patient of ID. The confirmation was unsuccessful regarding the diagnostic through techniques of conventional cytogenetics for all of the patinets. FISH technique was useful in the diagnostic investigation of a patient while CMA was used to study the other 3 cases. Chromosomal microarray analysis detected long stretches of homozygosity of uncertain clinical significance at the Xq11.1q13.1 region and a microduplication at the 7q11.23 region, the latter is defined as a critical region of WBS. The study of genotype-phenotype correlation in WBS has been established for some genes detected by CMA. But other genes did not show a strong relation to the syndrome, thus requiring further investigation. / As anomalias cromossômicas causam fenótipos específicos e complexos resultantes de desequilíbrios na dose normal de genes localizados em um segmento cromossômico específico, sendo responsáveis por 60 % ou mais das síndromes genéticas identificáveis. A Síndrome de Williams-Beuren (SWB) caracteriza-se por anomalias múltiplas e deficiência intelectual, descrita independentemente por Williams et al. (1961) e por Beuren et al. (1962). A SWB consiste em uma doença genética causada pela microdeleção em 7q11.23, que ocasiona o atraso no desenvolvimento físico e intelectual associado com alterações cardíacas congênitas, dimorfismos faciais, retardo mental e ocasionalmente hipercalcemia infantil. A variação fenotípica existente nesta síndrome dificulta o seu diagnóstico clínico. Com o desenvolvimento de novas tecnologias citomoleculares e o aumento de estudos voltados para o conhecimento das características clínicas desta síndrome, busca-se explicar melhor a correlação genótipo-fenótipo na SWB. O presente estudo relata algumas técnicas utilizadas para o diagnóstico da SWB, como Cariótipo, MLPA e PCR, dando ênfase em FISH e CMA. Adicionalmente, são descritos quatro pacientes encaminhados ao LaGene/SES e NPR/PUC pelo serviço público de saúde, onde três destes pacientes apresentavam hipótese diagnóstica para a SWB e um paciente para a DI. Para os quatro pacientes não houve êxito no diagnóstico pela citogenética convencional. A técnica de FISH foi útil na elucidação diagnóstica para um paciente, enquanto que a CMA foi utilizada no estudo dos outros 3 casos. A análise cromossômica por microarranjo detectou longos trechos contínuos de homozigose de significado clínico incerto em Xq11.1q13.1 e um caso de microduplicação na região 7q11.23, que é definida como região crítica da SWB. O estudo da correlação genótipo-fenótipo na Síndrome de Williams-Beuren foi estabelecido para alguns dos genes detectados pelo CMA. Entretanto outros genes detectados não tiveram sua relação estabelecida, necessitando assim de estudos posteriores.

A síndrome de Williams Beuren (SWB), doença congênita causada pela microdeleção do cromossomo 7, incluindo o gene da elastina, pode conferir às pessoas afetadas, facies típico, retardo mental, cardiopatia congênita, hipertensão, alterações gástricas, distúrbios de desenvolvimento de dentes, dentre outras alterações. O objetivo desse estudo foi conhecer as alterações faciais e bucais, a condição de saúde bucal, características oclusais e aspectos da ATM, bem como as alterações sistêmicas e condições médicas que afetam o manejo odontológico em uma amostra significativa de indivíduos brasileiros com a SWB. Para tanto, examinamos 25 indivíduos com SWB, com média de idade de 13 anos (4 a 26 anos). Os resultados mostraram que todos os participantes exibiam algum grau de retardo mental. A hiperacusia foi encontrada em 88% (22/25), cardiopatia congênita, em 76% (19/25); especialmente estenose aórtica supravalvar), hiperatividade em 68% (17/25) e hipertensão arterial em 40% (10/25) dos participantes. Distúrbios de desenvolvimento de dente foram encontrados em todos os participantes sendo que o mais frequente foi a retenção prolongada de dentes decíduos (64% - 16/25), seguido do diastemas generalizados (60% - 15/25), anodontia parcial (42% - 9/21), hipoplasia de esmalte (28% - 7/25), incisivos em forma de chave de fenda (24% - 6/25), microdontia (8% - 2/25). Em iguais porcentagens (4% - 1/25), foram encontrados casos de geminação, taurodontismo e dente conóide. Quanto à presença de alterações oclusais, todos os pacientes examinados apresentaram maloclusão. A maioria exibiu maloclusão classe III dentária de Angle (11/19,57 %) e mordida cruzada (11/25, 44%). Setenta e dois por cento dos pacientes exibiam algum hábito parafuncional. A experiência presente e passada de cárie, entre os 25 pacientes examinados, foi classificada como muito baixa, de acordo com o índice CPO-D e ceo-d, e 76% apresentaram gengivite. Os pacientes exibiram alteração da amplitude dos movimentos excursivos de mandíbula (abertura máxima - 12/22, 54%; lateralidade - 6/9, 66%; e protrusão - 7/9; 77%), bem como alterações nas ATMs, como dor à palpação (3/22, 13%) e ruídos articulares (4/25, 16%). Concluímos que distúrbios de desenvolvimento de dentes e maloclusão são frequentes em pessoas brasileiras afetadas pela SWB, e que a maioria delas apresenta alterações sistêmicas e comportamentais que podem interferir no manejo clínico odontológico. / The Williams Beuren syndrome (WBS), congenital disease caused by micro deletion of chromosome 7, including the elastin gene, is characterized by typical facies, mental retardation, congenital heart disease, hypertension, gastric alterations, teeth development disorders, among other changes. The aim of this study was to know facial and oral abnormalities, the oral health condition, occlusal features and aspects of temporomandibular joint, as well as systemic and medical conditions that affect the dental management on a significant sample of Brazilian individuals with WBS. For this, we examined 25 patients with SWB, with a mean age of 13 years (4-26 years). The results showed that all participants had some degree of mental retardation. The hyperacusis was found in 88% (22/25), congenital heart disease in 76% (19/25; especially supravalvular aortic stenosis), hyperactivity in 68% (17/25) and hypertension in 40% (10/25) of participants. Tooth development disorders were found in all participants with the most frequent was prolonged retention of the deciduous teeth (64% - 16/25), followed by generalized diastema (60% - 15/25), hypodontia (42% - 9/21), enamel hypoplasia (28% - 7/25), incisor-shaped screwdriver (24%- 6/25), microdontia (8% - 2/25). In equal percentages (4% - 1/25) were found cases of gemination, taurodontism and conoid tooth. For the presence of occlusal changes, all the patients examined presented malocclusion. Most showed malocclusion class III dental malocclusion (11/19, 57%) and crossbite (11/25, 44%). Seventy-two percent of patients had some parafunctional habit. Present and past caries experience among the 25 patients examined was classified as very low, according to the DMFT, and 76% had gingivitis. The patients exhibited change in amplitude of excursive movements of the jaw (maximun mouth opening - 12/22, 54%; laterality - 6/9, 66%; e protrusion - 7/9; 77%), as well as changes in ATMs, such as pain on palpation (3/22,13%) and joint sounds (4/25, 16%). We conclude that teeth and malocclusion development disorders are common in Brazilian people affected by WBS, and most of them have systemic and behavioral changes that can interfere with dental clinical management.

Le syndrome de Williams-Beuren (SWB} est une maladie génétique rare causée par une microdélétion de la région 7q11.23. A la suite de l'observation clinique d'une jeune fille atteinte du SWB ayant développé un lymphome de Burkitt à l'âge de 7 ans, nous nous sommes intéressé au lien génétique entre SWB et cancer. L'étude d'une série de cas de cancers survenus chez des enfants atteints de SWB a montré que les lymphomes non-hodgkiniens de type B étaient surreprésentés dans cette population puisque 73% des cancers chez les enfants atteints du SWB étaient des LNH-B. La région critique du SWB a été explorée par CGH-array et séquencage haut-débit dans les échantillons sains et tumoraux de 2 patients atteints de SWB. Aucune perte d'hétérozygotie de la région 7q11.23 n'a été trouvé. En outre, une délétion somatique de la région 7q11.23 a été identifiée dans un lymphome de Burkitt sporadique (Guenat D et al., J Hematol Oncol, 2014). Nous avons ensuite exploré les mécanismes de réponses aux dommages à l'ADN dans des lignées de fibroblastes primaires dérivées de patients atteints du SWB ainsi que dans des lignées 293T traitées avec des siRNA ciblant RFC2, BAZ1B et GTF2/, 3 gènes localisés en 7q11.23 et codant des protéines de réparation de l'ADN. Les cellules dérivées de patients SWB ont montré un défaut de signalisation dans les voies ATM/ATR-dépendantes en réponse aux dommages à l'ADN (Guenat D et al., DNA repair, article soumis). L'haploinsuffisance de la région 7q11.23 associée au SWB pourrait donc jouer un rôle dans la lymphomagenèse B par l'altération de voies de réponse aux dommages à l'ADN ATM/ATR-dépendantes. Cependant, ces résultats mériteraient d'être confirmés dans des modèles murins reproduisant le génotype complet du SWB. Enfin, des données épidémiologiques exhaustives sur l'incidence des pathologies tumorales chez les individus atteints du SWB sont indispensables pour affirmer qu'une prédisposition au cancer existe chez ces patients / Williams-Beuren syndrome (WBS) is a genetic disorder caused by a microdeletion at 7q11.23. The case of a young girl with WBS who developed a Burkitt lymphoma at the age of 7 leads us to explore the genetic link between WBS and cancer. The study of a series of cancers occurred in WBS patients during childhood have shown that B-cell non hodgkin lymphoma are over-represented in this population since 73% cancer cases in WBS were B-NHL. The critical region of WBS was explored by array-CGH and high-throughput sequencing in normal and tumor samples from WBS patients. No loss of heterozygosity at 7q11.23 was found. ln addition, a somatic deletion at 7q11.23 was observed in a sporadic case of Burkitt lymphoma (Guenat D et al., J Hematol Oncol, 2014). DNA damage response mechanisms were then explored in primary fibroblast cell lines derived from WBS patients as well as in 293T cell line treated with siRNA targeting RFC2, GTF2/ and BAZ1 B, 3 genes mapping at 7q11.23 that encode proteins involved in DNA damage response. WBS patients cell lines have shown a defect in ATM/ ATR-dependent DNA damage response pathways (Guenat D et al., DNA Repair, article submitted). Haploinsufficiency of the 7q11.23 region associated with WBS might play a role in B-cell lymphomagenesis through the alteration of ATM/ATR-dependent DNA damage response pathways. However, these results deserve to be confirmed in mouse models that reproduce the complete genotype of human WBS. Finally, strong epidemiological data would be required to confirm the predisposition to cancer in WBS patients.