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1.
Genet Med ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649276

RESUMO

PURPOSE: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly. METHODS: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish. RESULTS: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives. CONCLUSION: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.

2.
Genet Med ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31363182

RESUMO

PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

3.
Eur J Hum Genet ; 27(11): 1692-1700, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31285529

RESUMO

Early infantile epileptic encephalopathy (EIEE) is a heterogeneous group of severe forms of age-related developmental and epileptic encephalopathies with onset during the first weeks or months of life. The interictal electroencephalogram (EEG) shows a "suppression burst" (SB) pattern. The prognosis is usually poor and most children die within the first two years or survive with very severe intellectual disabilities. EIEE type 3 is caused by variants affecting function, in SLC25A22, which is also responsible for epilepsy of infancy with migrating focal seizures (EIMFS). We report a family with a less severe phenotype of EIEE type 3. We performed exome sequencing and identified two unreported variants in SLC25A22 in the compound heterozygous state: NM_024698.4: c.[813_814delTG];[818 G>A] (p.[Ala272Glnfs*144];[Arg273Lys]). Functional studies in cultured skin fibroblasts from a patient showed that glutamate oxidation was strongly defective, based on a literature review. We clustered the 18 published patients (including those from this family) into three groups according to the severity of the SLC25A22-related disorders. In an attempt to identify genotype-phenotype correlations, we compared the variants according to the location depending on the protein domains. We observed that patients with two variants located in helical transmembrane domains presented a severe phenotype, whereas patients with at least one variant outside helical transmembrane domains presented a milder phenotype. These data are suggestive of a continuum of disorders related to SLC25A22 that could be called SLC25A22-related disorders. This might be a first clue to enable geneticists to outline a prognosis based on genetic molecular data regarding the SLC25A22 gene.

4.
Neuroimage Clin ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30497982

RESUMO

Kabuki syndrome (KS) is a rare congenital disorder (1/32000 births) characterized by distinctive facial features, intellectual disability, short stature, and dermatoglyphic and skeletal abnormalities. In the last decade, mutations in KMT2D and KDM6A were identified as a major cause of kabuki syndrome. Although genetic abnormalities have been highlighted in KS, brain abnormalities have been little explored. Here, we have investigated brain abnormalities in 6 patients with KS (4 males; Mage = 10.96 years, SD = 2.97 years) with KMT2D mutation in comparison with 26 healthy controls (17 males; Mage = 10.31 years, SD = 2.96 years). We have used MRI to explore anatomical and functional brain abnormalities in patients with KS. Anatomical abnormalities in grey matter volume were assessed by cortical and subcortical analyses. Functional abnormalities were assessed by comparing rest cerebral blood flow measured with arterial spin labeling-MRI. When compared to healthy controls, KS patients had anatomical alterations characterized by grey matter decrease localized in the bilateral precentral gyrus and middle frontal gyrus. In addition, KS patients also presented functional alterations characterized by cerebral blood flow decrease in the left precentral gyrus and middle frontal gyrus. Moreover, subcortical analyses revealed significantly decreased grey matter volume in the bilateral hippocampus and dentate gyrus in patients with KS. Our results strongly indicate anatomical and functional brain abnormalities in KS. They suggest a possible neural basis of the cognitive symptoms observed in KS, such as fine motor impairment, and indicate the need to further explore the consequences of such brain abnormalities in this disorder. Finally, our results encourage further imaging-genetics studies investigating the link between genetics, anatomical and functional brain alterations in KS.

5.
Eur J Med Genet ; 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30006060

RESUMO

Alazami syndrome (AS) (MIM# 615071) is an autosomal recessive microcephalic primordial dwarfism (PD) with recognizable facial features and severe intellectual disability due to depletion or loss of function variants in LARP7. To date, 15 patients with AS have been reported. Here we describe two consanguineous Algerian sisters with Alazami PD due to LARP7 homozygous pathogenic variants detected by whole exome sequencing. By comparing these two additional cases with those previously reported, we strengthen the key features of AS: severe growth restriction, severe intellectual disability and some distinguishing facial features such as broad nose, malar hypoplasia, wide mouth, full lips and abnormally set teeth. We also report significant new findings enabling further delineation of this syndrome: disproportionately mild microcephaly, stereotypic hand wringing and severe anxiety, thickened skin over the hands and feet, and skeletal, eye and heart malformations. From previous reviews, we summarize the main etiologies of PD according to the involved mechanisms and cellular pathways, highlighting their clinical core features.

6.
Genet Med ; 20(2): 269-274, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28771243

RESUMO

PurposeBased on prenatal suspicion of the combination of radioulnar or radiohumeral synostosis and a peculiar shape of the skull suggestive of craniosynostosis, we report on six patients from four unrelated consanguineous families in whom Antley-Bixler syndrome was suspected during the prenatal period without mutation in genes known to be associated with the syndrome.MethodsMolecular diagnosis involved whole-exome and gene-panel sequencing. RESULTS: All sequenced patients showed a unique homozygous mutation of c.667G>A, p.Gly223Ser (NM_012200) in the beta-1,3-glucuronyltransferase 3 (B3GAT3) gene known to be involved in linkeropathy syndrome. Linkeropathies correspond to a recently identified group of heterogeneous genetic syndromes along a spectrum of skeletal and connective tissue disorders. These patients featured mainly craniosynostosis, midface hypoplasia, bilateral radioulnar synostosis, multiple neonatal fractures, dislocated joints, joint contracture, long fingers, foot deformity, and cardiovascular abnormalities. All died before 1 year of age.ConclusionWe identified a novel B3GAT3-related disorder with craniosynostosis and bone fragility, due to a unique homozygous mutation in B3GAT3. This syndrome should be considered in the prenatal period in light of the severe outcome and as an alternative diagnosis to Antley-Bixler or Shprintzen-Goldberg syndrome.


Assuntos
Osso e Ossos/anormalidades , Osso e Ossos/metabolismo , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Glucuronosiltransferase/genética , Mutação , Osso e Ossos/patologia , Diagnóstico Diferencial , Humanos , Fenótipo , Análise de Sequência de DNA , Crânio/anormalidades , Crânio/diagnóstico por imagem , Síndrome , Ultrassonografia Pré-Natal , Sequenciamento Completo do Genoma
7.
Mol Genet Genomic Med ; 5(2): 110-116, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28361096

RESUMO

BACKGROUND: TNF receptor-associated syndrome (TRAPS) is a dominantly inherited autoinflammatory condition caused by mutations in the TNFRSF1A gene. The mechanism underlying the variable expressivity of the common variant R92Q (rs4149584; c.362G>A; p.Arg121Gln) is unclear and is of critical importance for patient care and genetic counseling. This study evaluated the impact of the number of R92Q mutations in two unique unrelated families. METHODS: Two patients with undefined but clear autoinflammatory symptoms were referred for genetic diagnosis. Blood samples were collected from the available family members to screen autoinflammatory genes and assess key steps of the TNFR1-mediated signaling pathway using flow cytometry and ex vivo culture. RESULTS: R92Q homozygosity was demonstrated for the two probands. In family 1, the segregation analysis revealed TRAPS-like symptoms in all carriers, with a more severe presentation in the proband, whereas in family 2, the heterozygous parents were totally asymptomatic, suggesting recessive transmission. Functional studies revealed a nonclassical pathogenesis of TRAPS in the two probands and suggested a compensatory mechanism without clear dose effect. CONCLUSION: We observed for the first time a possible clinical dose effect of R92Q. This work highlights the importance of familial studies to reconcile the contradictory reports published on the pathogenicity of this variant.

8.
Ann Rheum Dis ; 76(7): 1191-1198, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27965258

RESUMO

OBJECTIVES: Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in NLRP3 and NLRC4 are linked to hereditary autoinflammatory diseases, whereas polymorphisms in NLRP1 are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human NLRP1 mutation is associated with autoinflammation remains to be determined. METHODS: To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients. RESULTS: We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome. CONCLUSIONS: We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of NLRP1 in inflammation and immunity. TRIAL REGISTRATION NUMBER: NCT02067962; Results.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Artrite Juvenil/genética , Doenças Autoimunes/genética , Doenças Hereditárias Autoinflamatórias/genética , Dermatopatias/genética , Adolescente , Grupo com Ancestrais do Continente Africano , Argélia , Artrite Juvenil/complicações , Artrite Juvenil/imunologia , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Caspase 1/imunologia , Criança , Consanguinidade , Grupo com Ancestrais do Continente Europeu , Feminino , Doenças Hereditárias Autoinflamatórias/complicações , Doenças Hereditárias Autoinflamatórias/imunologia , Homozigoto , Humanos , Interleucina-18/imunologia , Masculino , Mutação , Países Baixos , Células Precursoras de Linfócitos B/imunologia , Dermatopatias/complicações , Dermatopatias/imunologia , Síndrome
9.
Hum Mutat ; 37(9): 847-64, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27302555

RESUMO

Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype-genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/genética , Histona Desmetilases/genética , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/patologia , Face/patologia , Feminino , Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Doenças Hematológicas/patologia , Humanos , Masculino , Herança Materna , Síndrome de Noonan/genética , Análise de Sequência de DNA , Doenças Vestibulares/patologia
10.
Oncotarget ; 6(30): 29034-47, 2015 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-26362269

RESUMO

The aim of this work was to understand whether the nature of breast cancer cells could modify the nature of the dialog of mesenchymal stem cells (MSCs) with cancer cells. By treating MSCs with the conditioned medium of metastatic Estrogen-receptor (ER)-negative MDA-MB-231, or non-metastatic ER-positive MCF-7 breast cancer cells, we observed that a number of chemokines were produced at higher levels by MSCs treated with MDA-MB-231 conditioned medium (CM). MDA-MB-231 cells were able to induce NF-κB signaling in MSC cells. This was shown by the use of a NF-kB chemical inhibitor or an IκB dominant negative mutant, nuclear translocation of p65 and induction of NF-κB signature. Our results suggest that MDA-MB-231 cells exert their effects on MSCs through the secretion of IL-1ß, that activates MSCs and induces the same chemokines as the MDA-MB-231CM. In addition, inhibition of IL-1ß secretion in the MDA-MB-231 cells reduces the induced production of a panel of chemokines by MSCs, as well the motility of MDA-MB-231 cells. Our data suggest that aggressive breast cancer cells secrete IL-1ß, which increases the production of chemokines by MSCs.


Assuntos
Neoplasias da Mama/metabolismo , Quimiocinas/metabolismo , Interleucina-1beta/metabolismo , Células-Tronco Mesenquimais/metabolismo , Comunicação Parácrina , Microambiente Tumoral , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Quimiocinas/genética , Meios de Cultivo Condicionados/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Interleucina-1beta/genética , Mutação , Invasividade Neoplásica , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Fator de Transcrição RelA/metabolismo , Transfecção
11.
Genet Med ; 16(9): 720-4, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24603435

RESUMO

PURPOSE: Treacher Collins syndrome is a mandibulofacial dysostosis caused by mutations in genes involved in ribosome biogenesis and synthesis. TCOF1 mutations are observed in ~80% of the patients and are inherited in an autosomal dominant manner. Recently, two other genes have been reported in <2% of patients--POLR1D in patients with autosomal dominant inheritance, and POLR1C in patients with autosomal recessive inheritance. METHODS: We performed direct sequencing of TCOF1, POLR1C, and POLR1D in two unrelated consanguineous families. RESULTS: The four affected children shared the same homozygous mutation in POLR1D (c.163C>G, p.Leu55Val). This mutation is localized in a region encoding the dimerization domain of the RNA polymerase. It is supposed that this mutation impairs RNA polymerase, resulting in a lower amount of mature dimeric ribosomes. A functional analysis of the transcripts of TCOF1 by real-time quantitative reverse transcription-polymerase chain reaction was performed in the first family, demonstrating a 50% reduction in the index case, compatible with this hypothesis. CONCLUSION: This is the first report of POLR1D mutation being responsible for an autosomal recessive inherited Treacher Collins syndrome. These results reinforce the concept of genetic heterogeneity of Treacher Collins syndrome and underline the importance of combining clinical expertise and familial molecular analyses for appropriate genetic counseling.


Assuntos
RNA Polimerases Dirigidas por DNA/genética , Genes Recessivos , Disostose Mandibulofacial/diagnóstico , Disostose Mandibulofacial/genética , Mutação , Proteínas Nucleares/genética , Fosfoproteínas/genética , RNA Mensageiro/genética , Adulto , Substituição de Aminoácidos , Criança , Pré-Escolar , Análise Mutacional de DNA , Facies , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Loci Gênicos , Haplótipos , Homozigoto , Humanos , Fenótipo
12.
Eur J Hum Genet ; 22(4): 471-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24129437

RESUMO

Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion.


Assuntos
Cromossomos Humanos Par 2/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Deleção de Sequência , Fatores de Transcrição/genética , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hibridização in Situ Fluorescente , Masculino , Obesidade/complicações , Obesidade/diagnóstico , Fenótipo , Polimorfismo de Nucleotídeo Único , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Análise de Sequência de DNA
13.
Eur J Hum Genet ; 22(2): 289-92, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23674175

RESUMO

Intellectual disability (ID) is frequent in the general population, with 1 in 50 individuals directly affected worldwide. The multiple etiologies include X-linked ID (XLID). Among syndromic XLID, few syndromes present severe ID associated with postnatal microcephaly and midline stereotypic hand movements. We report on three male patients with ID, midline stereotypic hand movements, hypotonia, hyperkinesia, strabismus, as well as seizures (2/3), and non-inherited and postnatal onset microcephaly (2/3). Using array CGH and exome sequencing we characterised two truncating mutations in IQSEC2, namely two de novo intragenic duplication mapped to the Xp11.22 region and a nonsense mutation in exon 7. We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C.


Assuntos
Anormalidades Múltiplas/diagnóstico , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Pré-Escolar , Códon sem Sentido , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/classificação , Deficiência Intelectual/genética , Masculino , Fenótipo
14.
Eur J Hum Genet ; 22(1): 52-6, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23695276

RESUMO

Mandibulofacial dysostosis is part of a clinically and genetically heterogeneous group of disorders of craniofacial development, which lead to malar and mandibular hypoplasia. Treacher Collins syndrome is the major cause of mandibulofacial dysostosis and is due to mutations in the TCOF1 gene. Usually patients with Treacher Collins syndrome do not present with intellectual disability. Recently, the EFTUD2 gene was identified in patients with mandibulofacial dysostosis associated with microcephaly, intellectual disability and esophageal atresia. We report on two patients presenting with mandibulofacial dysostosis characteristic of Treacher Collins syndrome, but associated with unexpected intellectual disability, due to a large deletion encompassing several genes including the TCOF1 gene. We discuss the involvement of the other deleted genes such as CAMK2A or SLC6A7 in the cognitive development delay of the patients reported, and we propose the systematic investigation for 5q32 deletion when intellectual disability is associated with Treacher Collins syndrome.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Deficiência Intelectual/genética , Disostose Mandibulofacial/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Adolescente , Criança , Feminino , Deleção de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/etiologia , Deficiência Intelectual/patologia , Masculino , Disostose Mandibulofacial/etiologia , Disostose Mandibulofacial/patologia , Mutação
15.
Eur J Hum Genet ; 22(1): 136-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23572024

RESUMO

Trichorhinophalangeal syndrome type I (TRPSI) is a genetic disorder characterized by sparse hair, a bulbous nasal tip, short stature with severe generalized shortening of all phalanges, metacarpal and metatarsal bones and cone-shaped epiphyses. This syndrome is caused by autosomal dominant mutations in the TRPS1 gene. However, because recurrence has been observed in siblings from healthy parents, an autosomal recessive mode of inheritance has also been suggested. We report on a male patient, born to healthy unrelated parents, with TRPSI. Using Sanger sequencing, we identified a mutation in the TRPS1 gene (c.2735 G>A, P.Cys912Tyr). The same mutation was detected as a 10% mosaic mutation by Pyrosequencing in blood-derived DNA from his healthy mother. To our knowledge, this is the first time that somatic mosaicism has been identified in TRPSI. This data combined with the observations of recurrences in siblings from healthy parents modifies the genetic counseling for TRPSI, which should discuss a 5-10 percent recurrence risk for healthy parents with an affected child because of the possibility of germinal mosaicism.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Dedos/anormalidades , Aconselhamento Genético , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/genética , Nariz/anormalidades , Fatores de Transcrição/genética , Anormalidades Múltiplas/patologia , Criança , Dedos/patologia , Doenças do Cabelo/patologia , Humanos , Síndrome de Langer-Giedion/patologia , Masculino , Mosaicismo , Nariz/patologia
16.
Ann Rheum Dis ; 73(1): 290-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23505244

RESUMO

BACKGROUND: Mutations in the TNFRSF1A gene encoding the tumour necrosis factor α cell surface receptor, TNFR1, cause TNFR-associated periodic syndrome (TRAPS) and polymorphisms in TNFRSF1A, including rs4149570, rs767455 and rs1800692, are associated with inflammatory diseases. OBJECTIVES: To describe a new exon 2-spliced transcript-TNFR1-d2-and the impact of these three single nucleotide polymorphisms on exon 2 splicing, transcriptional activity of TNFRSF1A and TRAPS phenotype. METHODS: Expression of TNFRSF1A transcripts was performed by reverse-transcription-PCR in a range of human cells and tissues. Exon 2 splicing and transcriptional activity were analysed in HEK293T and SW480 cells by in vitro alternative splicing and luciferase assays, respectively. We constructed haplotypes containing rs4149570, rs767455 and rs1800692 in controls (n=72), patients with TRAPS (n=111) and in TRAPS-like patients (n=450) to compare their distribution and association with clinical features of TRAPS. RESULTS: TNFR1-d2 was expressed in a tissue-specific manner, whereas TNFR1 expression was ubiquitous. Alternative splicing assays showed that the T-A-T haplotype at rs4149570-rs767455-rs1800692 had a significantly higher expression of exon 2-skipping product (p=0.02) compared with the G-G-C haplotype. Transcriptional activity from the T-T haplotype at rs4149570-rs1800692 was increased compared with the G-C haplotype (p=0.03). In patients with TRAPS, rs1800692 T/T homozygotes were excessively rare (p<10(-4)) and TRAPS-like patients with this genotype experienced less fever. CONCLUSIONS: Our study provides a new mechanism of TNFRSF1A regulation whereby three polymorphisms in the promoter, exon 1 and intron 4 have a functional and combined effect on exon 2 splicing, via a coupling mechanism between transcription and splicing. These polymorphisms may affect the phenotype of TRAPS and TRAPS-like patients.


Assuntos
Regulação da Expressão Gênica/genética , Doenças Hereditárias Autoinflamatórias/genética , Polimorfismo Genético , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Adenocarcinoma , Processamento Alternativo/genética , Neoplasias do Colo , Éxons/genética , Febre , Teste de Complementação Genética , Células HEK293 , Haplótipos , Humanos , Íntrons/genética , Fenótipo , Regiões Promotoras Genéticas/genética
17.
Eur J Med Genet ; 56(10): 556-60, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23933090

RESUMO

Kabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS.


Assuntos
Anormalidades Múltiplas/diagnóstico , Face/anormalidades , Dedos/anormalidades , Doenças Hematológicas/diagnóstico , Doenças Vestibulares/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino
18.
J Pediatr ; 163(3): 742-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23535010

RESUMO

OBJECTIVE: To determine the frequency and types of renal malformations, and to evaluate renal function in a cohort of patients with Kabuki syndrome (KS). STUDY DESIGN: Renal ultrasound scans and plasma creatinine measurements were collected from a French cohort of 94 patients with genotyped KS. Renal function was evaluated based on the estimated glomerular filtration rate. A genotype-phenotype study was conducted for renal and urinary tract malformations. RESULTS: Renal malformations were present in 22% of cases, and urinary tract anomalies were present in 15%. Renal malformations were observed in 28% of the MLL2 mutation-positive group and in 0% of the MLL2 mutation-negative group (P = .015). No correlation was found between the presence or absence of renal or urinary tract malformations and the location or type of MLL2 mutation. Renal function was normal except for 1 patient with a MLL2 mutation diagnosed in the first days of life and severe renal disease due to unilateral renal agenesia and controlateral severe hypoplasia that progressed to the terminal stage at age 2 years. CONCLUSION: Our study emphasizes the need for ultrasound and renal function screening in children diagnosed with KS.


Assuntos
Anormalidades Múltiplas/diagnóstico , Doenças Hematológicas/diagnóstico , Rim/anormalidades , Doenças Vestibulares/diagnóstico , Anormalidades Múltiplas/sangue , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Biomarcadores/sangue , Criança , Pré-Escolar , Estudos de Coortes , Creatinina/sangue , Proteínas de Ligação a DNA/genética , Face/anormalidades , Face/fisiopatologia , Feminino , França , Estudos de Associação Genética , Marcadores Genéticos , Técnicas de Genotipagem , Taxa de Filtração Glomerular , Doenças Hematológicas/sangue , Doenças Hematológicas/genética , Doenças Hematológicas/fisiopatologia , Histona Desmetilases/genética , Humanos , Lactente , Rim/diagnóstico por imagem , Rim/metabolismo , Rim/fisiopatologia , Masculino , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Estudos Retrospectivos , Ultrassonografia , Doenças Vestibulares/sangue , Doenças Vestibulares/genética , Doenças Vestibulares/fisiopatologia , Adulto Jovem
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