Evaluation of the distal 22q11 deletion syndrome. A highly variable phenotype
BULK, Saskia ; PIERQUIN, Geneviève ; GAILLEZ, Stephanie et al
Poster (2014, February 07)Detailed reference viewed: 30 (5 ULg)
Haematological and molecular responses in refractory anaemia with ring sideroblasts and thrombocytosis treated with lenalidomide
CAERS, Jo ; HAFRAOUI, Kaoutar ; KEUTGENS, Aurore et al
in European Journal of Haematology (2014), 92(2), 179-180Detailed reference viewed: 66 (30 ULg)
Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation.
; Daly, Adrian ; et al
in The New England journal of medicine (2014)
Background Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. Methods We performed ... [more ▼]
Background Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. Methods We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. Results We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells. Conclusions We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.). [less ▲]Detailed reference viewed: 20 (12 ULg)
Pattern of congenital heart diseases in Rwandan children with genetic defects.
; ; et al
in Pan African Medical Journal (The) (2014), 19
INTRODUCTION: Congenital heart diseases (CHD) are commonly associated with genetic defects. Our study aimed at determining the occurrence and pattern of CHD association with genetic defects among ... [more ▼]
INTRODUCTION: Congenital heart diseases (CHD) are commonly associated with genetic defects. Our study aimed at determining the occurrence and pattern of CHD association with genetic defects among pediatric patients in Rwanda. METHODS: A total of 125 patients with clinical features suggestive of genetic defects were recruited. Echocardiography and standard karyotype studies were performed in all patients. RESULTS: CHDs were detected in the majority of patients with genetic defects. The commonest isolated CHD was ventricular septal defect found in many cases of Down syndrome. In total, chromosomal abnormalities represented the majority of cases in our cohort and were associated with various types of CHDs. CONCLUSION: Our findings showed that CHDs are common in Rwandan pediatric patients with genetic defects. These results suggest that a routine echocardiography assessment combined with systematic genetic investigations including standard karyotype should be mandatory in patients presenting characteristic clinical features in whom CHD is suspected to be associated with genetic defect. [less ▲]Detailed reference viewed: 13 (2 ULg)
Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1.
; ; et al
in Orphanet journal of rare diseases (2014), 9(1), 174
BackgroundDystonia, cerebellar atrophy, and cardiomyopathy constitute a rare association.MethodsWe used homozygosity mapping and whole exome sequencing to determine the mutation, western blot and ... [more ▼]
BackgroundDystonia, cerebellar atrophy, and cardiomyopathy constitute a rare association.MethodsWe used homozygosity mapping and whole exome sequencing to determine the mutation, western blot and immunolabelling on cultured fibroblasts to demonstrate the lower expression and the mislocalization of the protein.ResultsWe report on a boy born from consanguineous healthy parents, who presented at three years of age with rapidly progressing dystonia, progressive cerebellar atrophy, and dilated cardiomyopathy. We identified regions of homozygosity and performed whole exome sequencing that revealed a homozygous missense mutation in TOR1AIP1. The mutation, absent in controls, results in a change of a highly conserved glutamic acid to alanine. TOR1AIP1 encodes lamina-associated polypeptide 1 (LAP1), a transmembrane protein ubiquitously expressed in the inner nuclear membrane. LAP1 interacts with torsinA, the protein mutated in DYT1-dystonia. In vitro studies in fibroblasts of the patient revealed reduced expression of LAP1 and its mislocalization and aggregation in the endoplasmic reticulum as underlying pathogenic mechanisms.Conclusions and relevanceThe pathogenic role of TOR1AIP1 mutation is supported by a) the involvement of a highly conserved amino acid, b) the absence of the mutation in controls, c) the functional interaction of LAP1 with torsinA, and d) mislocalization of LAP1 in patient cells. Of note, cardiomyopathy has been reported in LAP1-null mice and in patients with the TOR1AIP1 nonsense mutation. Other cases will help delineate the clinical spectrum of LAP1-related mutations. [less ▲]Detailed reference viewed: 10 (2 ULg)
Array-CGH analysis in Rwandan patients presenting development delay/intellectual disability with multiple congenital anomalies.
; CABERG, Jean-Hubert ; et al
in BMC medical genetics (2014), 15(1), 79
BACKGROUND: Array-CGH is considered as the first-tier investigation used to identify copy number variations. Right now, there is no available data about the genetic etiology of patients with development ... [more ▼]
BACKGROUND: Array-CGH is considered as the first-tier investigation used to identify copy number variations. Right now, there is no available data about the genetic etiology of patients with development delay/intellectual disability and congenital malformation in East Africa. METHODS: Array comparative genomic hybridization was performed in 50 Rwandan patients with development delay/intellectual disability and multiple congenital abnormalities, using the Agilent's 180 K microarray platform. RESULTS: Fourteen patients (28%) had a global development delay whereas 36 (72%) patients presented intellectual disability. All patients presented multiple congenital abnormalities. Clinically significant copy number variations were found in 13 patients (26%). Size of CNVs ranged from 0,9 Mb to 34 Mb. Six patients had CNVs associated with known syndromes, whereas 7 patients presented rare genomic imbalances. CONCLUSION: This study showed that CNVs are present in African population and show the importance to implement genetic testing in East-African countries. [less ▲]Detailed reference viewed: 14 (7 ULg)
Implementation of genomic arrays in prenatal diagnosis: the Belgian approach to meet the challenges.
; ; et al
in European journal of medical genetics (2014), 57(4), 151-6
After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have demonstrated the ... [more ▼]
After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have demonstrated the advantages of this method, we are confronted with difficulties regarding the technology and the ethical dilemmas inherent to genomic arrays. These include indication for testing, array design, interpretation of variants and how to deal with variants of unknown significance and incidental findings. The experiences with these issues reported in the literature are most often from single centres. Here, we report on a national consensus approach how microarray is implemented in all genetic centres in Belgium. These recommendations are subjected to constant re-evaluation based on our growing experience and can serve as a useful tool for those involved in prenatal diagnosis. [less ▲]Detailed reference viewed: 21 (4 ULg)
Femoral-facial syndrome: long term follow-up and associated array CGH abnormalities.
JACQUINET, Adeline ; VALDES SOCIN, Hernan Gonzalo ; LIBIOULLE, Cécile et al
Poster (2013, October 22)
The femoral-facial syndrome is usually sporadic and its aetiology remains unknown. Non-genetic factors as maternal diabetes mellitus have been associated. Reports of familial cases have otherwise ... [more ▼]
The femoral-facial syndrome is usually sporadic and its aetiology remains unknown. Non-genetic factors as maternal diabetes mellitus have been associated. Reports of familial cases have otherwise suggested autosomal dominant inheritance. We report the 20 years clinical follow-up of a girl with femoral-facial syndrome diagnosed at birth. Recently, array CGH investigation identified a 1400 kb duplication at 9q31.1, including the gene SMC2, and a 343 kb deletion at 12q24.33 including the genes CHFR, ZNF26, ZNF140, ZNF10 and ZNF268. Moreover, the patient presents a Mayer-Rokitansky-Kuster-Hauser syndrome diagnosed at puberty. Femoral-facial syndrome and Mullerian agenesis may reflect different defects in the primary axial mesodermal development, being the consequences of same environmental or/and genetic factors during blastogenesis. Among these genetic factors, we suggest the possible involvement of the two copy number variants reported here [less ▲]Detailed reference viewed: 66 (9 ULg)
Clinical, cytogenetic and molecular characterization of two cases of mosaic ring chromosome 13.
; PIERQUIN, Geneviève ; GAILLEZ, Stephanie et al
in Genetic counseling (Geneva, Switzerland) (2013), 24(2), 193-200
The occurrence of mosaic ring chromosome 13 is rare. The mechanism of ring chromosome formation is usually associated with loss of genetic material. We report 2 cases of mosaic ring chromosome 13 ... [more ▼]
The occurrence of mosaic ring chromosome 13 is rare. The mechanism of ring chromosome formation is usually associated with loss of genetic material. We report 2 cases of mosaic ring chromosome 13, resulting in deletion of 13qter. The first patient, a 15 year-old boy, presented a delayed psychomotor development, mental retardation, dysmorphic features and bleeding disorders associated with a de novo terminal 13q34 deletion. The second case was a foetus of 31 weeks with prenatal diagnosis of severe malformation such as holoprosencephaly, congenital cardiac defects, gastro-intestinal abnormalities with intrauterine growth retardation, the molecular analysis showed a de novo deletion encompassing the region 13q31.3-q34. [less ▲]Detailed reference viewed: 46 (7 ULg)
Genetic diagnosis of Duchenne and Becker muscular dystrophy using multiplex ligation-dependent probe amplification in Rwandan patients.
; ; et al
in Journal of tropical pediatrics (2013)
Duchenne and Becker muscular dystrophies are the most common clinical forms of muscular dystrophies. They are genetically X-linked diseases caused by a mutation in the dystrophin (DMD) gene. A genetic ... [more ▼]
Duchenne and Becker muscular dystrophies are the most common clinical forms of muscular dystrophies. They are genetically X-linked diseases caused by a mutation in the dystrophin (DMD) gene. A genetic diagnosis was carried out in six Rwandan patients presenting a phenotype of Duchenne and Becker muscular dystrophies and six asymptomatic female carrier relatives using multiplex ligation-dependent probe amplification (MLPA). Our results revealed deletion of the exons 48-51 in one patient, an inherited deletion of the exons 8-21 in two brothers and a de novo deletion of the exons 46-50 in the fourth patient. No copy number variation was found in two patients. Only one female carrier presented exon deletion in the DMD gene. This is the first cohort of genetic analysis in Rwandan patients affected by Duchenne and Becker muscular dystrophies. This report confirmed that MLPA assay can be easily implemented in low-income countries. [less ▲]Detailed reference viewed: 36 (14 ULg)
Partial trisomy 4q associated with young-onset dopa-responsive parkinsonism.
Garraux, Gaëtan ; CABERG, Jean-Hubert ; et al
in Archives of Neurology (2012), 69(3), 398-400
OBJECTIVE: To describe a patient who developed a young-onset, dopa-responsive parkinsonism linked to a de novo heterozygous interstitial duplication 4q. DESIGN: Case report. SETTING: Movement Disorder ... [more ▼]
OBJECTIVE: To describe a patient who developed a young-onset, dopa-responsive parkinsonism linked to a de novo heterozygous interstitial duplication 4q. DESIGN: Case report. SETTING: Movement Disorder Outpatient Clinic at the University Hospital Centre, Liege, Belgium. Patient A 31-year-old woman. MAIN OUTCOME MEASURES: Clinical, neuroimaging, and genetic data. RESULTS: The duplicated region contains 150 known genes, including the alpha-synuclein (SNCA) gene locus. Motor and 6-[(18)F]fluoro-L-dopa positron emission tomography features are similar to those previously reported in heterozygote SNCA duplication carriers. Altered expression of other genes contained in the duplicated region may contribute to clinical features that are uncommon in the phenotypic spectrum of SNCA multiplications such as delayed developmental psychomotor milestones during infancy and musculoskeletal abnormalities. CONCLUSION: This case report provides new insights on the genetic basis of parkinsonism. [less ▲]Detailed reference viewed: 35 (10 ULg)
Surface Mucin-1 does not play a role in dendritic cell migration
; Caberg, Jean-Hubert ; et al
in Molecular Immunology (2009), 46(4), 738-742Detailed reference viewed: 29 (3 ULg)
Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: role of CCL20
Caberg, Jean-Hubert ; Hubert, Pascale ; Herman, Ludivine et al
in Cancer Immunology, Immunotherapy (2009), 58(1), 39-47Detailed reference viewed: 72 (7 ULg)
Silencing of E7 oncogene restores functional E-cadherin expression in human papillomavirus 16-transformed keratinocytes
Caberg, Jean-Hubert ; Hubert, Pascale ; Begon, Dominique et al
in Carcinogenesis (2008), 29(7), 1441-7Detailed reference viewed: 46 (11 ULg)
Transforming growth factor-beta1-mediated Slug and Snail transcription factor up-regulation reduces the density of Langerhans cells in epithelial metaplasia by affecting E-cadherin expression
Herfs, Michael ; Hubert, Pascale ; et al
in American Journal of Pathology (2008), 172(5), 1391-402
Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is ... [more ▼]
Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is associated with an increased frequency of (pre)cancerous lesions. We propose that EpM is involved in cancer development by altering the expression of adhesion molecules important for cell-mediated antitumor immunity. Langerhans cells (LCs) are intraepithelial dendritic cells that initiate immune responses against viral or tumor antigens on both skin and mucosal surfaces. In the present study, we showed by immunohistology that the density of CD1a LCs is reduced in EpM of the uterine cervix compared with native squamous epithelium and that the low number of LCs observed in EpM correlates with the down-regulation of cell-surface E-cadherin. We also demonstrated that transforming growth factor- 1 is not only overexpressed in metaplastic tissues but also reduces E-cadherin expression in keratinocytes in vitro by inducing the promoter activity of Slug and Snail transcription factors. Finally, we showed that in vitro-generated LCs adhere poorly to keratinocytes transfected with either Slug or Snail DNA. These data suggest that transforming growth factor- 1 indirectly reduces antigenpresenting cell density in EpM by affecting E-cadherin expression, which might explain the increased susceptibility of abnormal tissue differentiation to the development of cancer by the establishment of local immunodeficiency responsible for EpM tumorigenesis. [less ▲]Detailed reference viewed: 71 (20 ULg)
The cross-talk between dendritic and regulatory T cells: good or evil?
Hubert, Pascale ; Jacobs, Nathalie ; Caberg, Jean-Hubert et al
in Journal of Leukocyte Biology (2007), 82(4), 781-94
Immune responses against pathogens require fine regulation in order to avoid excessive inflammation, which could be harmful to the host. Moreover, the immune system must be tolerant to non-pathogenic ... [more ▼]
Immune responses against pathogens require fine regulation in order to avoid excessive inflammation, which could be harmful to the host. Moreover, the immune system must be tolerant to non-pathogenic antigens in order to prevent allergy, autoimmunity and transplant rejection. There is accumulating evidence that interactions between dendritic cells (DC) and regulatory T (Treg) cells play a crucial role in the balance between immune response and tolerance. Communications between these cells are complex, bi-directional and mediated by soluble or cell surface molecules. The maturation status of DC, which may be influenced by different microenvironmental factors, is considered as an important checkpoint for the induction of peripheral tolerance through modifications of the activation status of T cells. Moreover, several lines of experimental evidence suggest that different subsets or the functional status of DC are also involved in the promotion of Treg cell differentiation. A better knowledge of the regulatory mechanisms of the immune response induced or inhibited by DC via their interactions with Treg cells could be relevant for the development of new immunotherapeutic approaches. [less ▲]Detailed reference viewed: 74 (13 ULg)
MIP3 alpha stimulates the migration of Langerhans cells in models of human papillomavirus (HPV)-associated (pre)neoplastic epithelium
Herman, Ludivine ; Hubert, Pascale ; Caberg, Jean-Hubert et al
in Cancer Immunology, Immunotherapy (2007), 56(7), 1087-1096Detailed reference viewed: 50 (5 ULg)
Le cancer du col de l'utérus: du virus au traitement
Delvenne, Philippe ; Goffin, Frédéric ; Kridelka, Frédéric et al
in Revue Médicale de Liège (2007), 62(S1)
Squamous cell cancer of the uterine cervix is associated with a high morbidity and mortality worldwide and in Belgium. New therapeutic approaches have been recently proposed. The development of this ... [more ▼]
Squamous cell cancer of the uterine cervix is associated with a high morbidity and mortality worldwide and in Belgium. New therapeutic approaches have been recently proposed. The development of this cancer is related to the infection by oncogenic human papillomavirus (HPV) types. The link between cervical cancer and HPV has, in recent years, generated, a great interest for studies aiming to better understand the role of the immune system in the control of these infections and for the development of prophylactic anti-HPV vaccines. [less ▲]Detailed reference viewed: 178 (25 ULg)
Role of hormone cofactors in the human papillomavirus-induced carcinogenesis of the uterine cervix
Delvenne, Philippe ; Herman, Ludivine ; et al
in Molecular & Cellular Endocrinology (2007), 264(1-2), 1-5
If human papillomavirus (HPV) is necessary for the development of (pre)neoplastic lesions of the uterine cervix, it is not sufficient. Among the cofactors involved in the malignant transformation of cells ... [more ▼]
If human papillomavirus (HPV) is necessary for the development of (pre)neoplastic lesions of the uterine cervix, it is not sufficient. Among the cofactors involved in the malignant transformation of cells infected by HPV, sex hormones may facilitate the cervical carcinogenesis by different mechanisms, including the induction of squamous metaplasia in the transformation zone of the cervix, interactions between steroid hormones and HPV gene expression and alterations of the local immune microenvironment. [less ▲]Detailed reference viewed: 55 (10 ULg)