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1.
Mol Med Rep ; 19(5): 4419-4424, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942463

RESUMO

Nance­Horan syndrome (NHS) is a rare X­linked disorder with various clinical manifestations. The present study aimed to identify the pathogenic mutation causing NHS in a three­generation Chinese family with 4 individuals presenting primarily with congenital cataracts. The genomic DNA of 5 individuals was collected, and family history and clinical information were recorded. Whole exome sequencing was performed on the proband, and candidate mutations were filtered by a series of screening processes and validated by Sanger sequencing. The identified pathogenic mutation was confirmed by co­segregation analysis. Finally, a novel frameshift mutation (NM_001291867.1: c.302dupA; p.Ala102fs) was identified in the NHS actin remodeling regulator (NHS) gene, which co­segregated with congenital cataracts in this family. Carrier females exhibited similar but milder clinical symptoms compared with the affected male. These clinical symptoms were consistent with the phenotypic features of the NHS­associated disease, NHS. In summary, the present study identified a novel NHS mutation in a Chinese family with atypical NHS; the results broaden the known pathogenic mutation spectrum of NHS and will aid in the genetic counseling of patients with NHS. The data from the present study also suggest that genetic analysis may be required for the diagnosis of this disease.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Catarata/congênito , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas Nucleares/genética , Anormalidades Dentárias/genética , Adulto , Catarata/genética , Catarata/patologia , Pré-Escolar , Feminino , Mutação da Fase de Leitura , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Linhagem , Anormalidades Dentárias/patologia , Sequenciamento Completo do Exoma
2.
Mol Genet Genomics ; 294(3): 773-787, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887145

RESUMO

The latent transforming growth factor-beta-binding protein 3 (LTBP3), encoding extracellular matrix proteins, plays a role in skeletal formation. Mutations in LTBP3 have been associated with various types of skeletal dysplasia. We aimed to characterize clinical and molecular features of more patients with mutations in the gene, which may help suggest genotype-phenotype correlation. The first two East Asian patients with short stature, heart defects, and orodental anomalies having LTBP3 mutations were identified. Whole exome and Sanger sequencing revealed that the one with a novel heterozygous missense (c.2017G>T, p.Gly673Cys) mutation in LTBP3 had clinical features consistent with acromicric dysplasia (ACMICD). The variant was located in the highly conserved EGF-like calcium-binding domain adjacent to the single reported LTBP3 variant associated with ACMICD. This finding supports that LTBP3 is a disease gene for ACMICD. Another patient with a novel homozygous splice site acceptor (c.1721-2A>G) mutation in LTBP3 was affected with dental anomalies and short stature (DASS). Previously undescribed orodental features included multiple unerupted teeth, high-arched palate, and microstomia found in our patient with ACMICD, and extensive dental infection, condensing osteitis, and deviated alveolar bone formation in our patient with DASS. Our results and comprehensive reviews suggest a genotype-phenotype correlation: biallelic loss-of-function mutations cause DASS, monoallelic missense gain-of-function mutations in the EGF-like domain cause ACMICD, and monoallelic missense gain-of-function mutations with more drastic effects on the protein functions cause geleophysic dysplasia (GPHYSD3). In summary, we expand the phenotypic and genotypic spectra of LTBP3-related disorders, support that LTBP3 is a disease gene for ACMICD, and propose the genotype-phenotype correlation of LTBP3 mutations.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Estudos de Associação Genética/métodos , Proteínas de Ligação a TGF-beta Latente/genética , Deformidades Congênitas dos Membros/genética , Mutação , Anormalidades Dentárias/genética , Adolescente , Sequência de Aminoácidos , Criança , Nanismo/genética , Feminino , Humanos , Masculino , Linhagem , Homologia de Sequência de Aminoácidos , Adulto Jovem
3.
Methods Mol Biol ; 1922: 407-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838594

RESUMO

Rare genetic disorders are often challenging to diagnose. Anomalies of tooth number, shape, size, mineralized tissue structure, eruption, and resorption may exist as isolated symptoms or diseases but are often part of the clinical synopsis of numerous syndromes (Bloch-Zupan A, Sedano H, Scully C. Dento/oro/craniofacial anomalies and genetics, 1st edn. Elsevier, Boston, MA, 2012). Concerning amelogenesis imperfecta (AI), for example, mutations in a number of genes have been reported to cause isolated AI, including AMELX, ENAM, KLK4, MMP20, FAM83H, WDR72, C4orf26, SLC24A4, and LAMB3. In addition, many other genes such as DLX3, CNNM4, ROGDI, FAM20A, STIM1, ORAI1, and LTBP3 have been shown to be involved in developmental syndromes with enamel defects. The clinical presentation of the enamel phenotype (hypoplastic, hypomineralized, hypomature, or a combination of severities) alone does not allow a reliable prediction of possible causative genetic mutations. Understanding the potential genetic cause(s) of rare diseases is critical for overall health management of affected patient. One effective strategy to reach a genetic diagnosis is to sequence a selected gene panel chosen for a determined range of phenotypes. Here we describe a laboratory protocol to set up a specific gene panel for orodental diseases.


Assuntos
Anormalidades Craniofaciais/genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Raras/genética , Anormalidades Dentárias/genética , Amelogênese Imperfeita/diagnóstico , Amelogênese Imperfeita/genética , Anormalidades Craniofaciais/diagnóstico , DNA/genética , Desenho de Equipamento , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Humanos , Doenças Raras/diagnóstico , Anormalidades Dentárias/diagnóstico
4.
Methods Mol Biol ; 1922: 453-492, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838595

RESUMO

This chapter describes methods related to the diagnosis of genetic dental diseases. Based on the present knowledge, clinical phenotyping and next-generation sequencing techniques are discussed. Methods necessary for Sanger sequencing, multiplex ligation-dependent probe amplification, and epigenetic modification methods are detailed. In addition, protocols for cell culture establishment and characterization from patients with inherited dental anomalies are described.


Assuntos
Epigênese Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Raras/genética , Odontopatias/genética , Amelogênese Imperfeita/genética , Técnicas de Cultura de Células/métodos , DNA/genética , DNA/isolamento & purificação , Humanos , Fenótipo , Reação em Cadeia da Polimerase/métodos , Anormalidades Dentárias/genética
5.
Genes Brain Behav ; 18(4): e12553, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30786142

RESUMO

KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD-symptoms and social-emotional impairments. In this study, the behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 patients with other genetic disorders with comparable intelligence levels, completed neuropsychological assessment. Age-appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen's d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cognição , Deficiência Intelectual/fisiopatologia , Fenótipo , Anormalidades Dentárias/fisiopatologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/psicologia , Adolescente , Adulto , Idoso , Atenção , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/psicologia , Criança , Função Executiva , Facies , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Inteligência , Masculino , Memória , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Comportamento Social , Anormalidades Dentárias/genética , Anormalidades Dentárias/psicologia , Percepção Visual
6.
BMC Med Genet ; 20(1): 16, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642272

RESUMO

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Epilepsia Generalizada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Convulsões Febris/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Alelos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Brasil , Eletroencefalografia , Epilepsia Generalizada/fisiopatologia , Facies , Feminino , Loci Gênicos , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Linhagem , Convulsões Febris/fisiopatologia , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/etiologia , Anormalidades Dentárias/fisiopatologia , Sequenciamento Completo do Exoma
7.
BMC Med Genet ; 20(1): 14, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642278

RESUMO

BACKGROUND: Nance-Horan syndrome (NHS) is an X-linked inheritance disorder characterized by bilateral congenital cataracts, and facial and dental dysmorphism. This disorder is caused by mutations in the NHS gene. However, NHS may be difficult to detect in individuals with subtle facial dysmorphism and dental abnormalities in whom congenital cataracts are the primary clinical manifestations. METHODS: In this study, we present a three-generation family with NHS. Whole exome sequencing was performed to determine the potential pathogenic variant in the proband. Further validation was explored with Sanger sequencing in 9 of the available individuals of the family and additional 200 controls. RESULTS: A novel truncation mutation in gene NHS (c.C4449G, p.Tyr1483Ter) was found in the proband, who presented with a long-narrow face, prominent nose and large anteverted pinnae ear, screw-driver like incisors, mild mulberry like molars, one missing maxillary second molar and malocclusion. We found this mutation was detected in 2 male patients and 4 female carriers in the family. However, the mutation was never detected in the control subjects. CONCLUSIONS: In conclusion, we identified a novel truncation mutation in the NHS gene, which might associate with NHS. Our review on the NHS studies illustrated that NHS has significantly clinical heterogeneity. And NHS mutations in the NHS-affected individuals typically result in premature truncation of the protein. And the new mutation revealed in this study would highlight the understanding of the causative mutations of NHS.


Assuntos
Catarata/congênito , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença , Mutação , Proteínas Nucleares/genética , Anormalidades Dentárias/genética , Sequenciamento Completo do Exoma , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Catarata/diagnóstico por imagem , Catarata/genética , Catarata/fisiopatologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/fisiopatologia
8.
Medicine (Baltimore) ; 97(49): e13444, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30544426

RESUMO

RATIONALE: Oculofaciocardiodental syndrome (OFCD) patients who show radiculomegaly are very rare. We treated a new OFCD patient orthodontically, and performed longitudinal observation for 30 years. New findings, termed calcified-dental-papillae (CDPs) beneath open-apices (OAs) of developing radiculomegalies, pulp-stone-like-calcifications (PSLCs) and the process of radiculomegaly development were observed. A novel mutation of BCL-6 interacting corepressor (BCOR) was identified. Cone-beam-computed-tomography (CBCT) images of the radiculomegalies clarified their morphology. PATIENT CONCERNS: A female patient and her parents were referred to orthodontic clinic for alignment of the teeth. DIAGNOSIS: A CDP that harbored bulbous-round-calcified-tissue in the dental papilla beneath the OA of a developing radiculomegaly was found radiographically. PSLCs were observed in the dental pulp. Genetic analysis revealed a novel mutation c.265G>A on Exon 4 and diagnosed as OFCD. CBCT images confirmed round-calcified-tissue and PSLC and that the length of an affected canine was 38.0 mm and calculated as +14.8SD. These novel findings were not observed in lateral incisors and molars. INTERVENTIONS: Observation was performed for 29 years and 3 months including orthodontic treatment for 2 years and 9 months. OUTCOME: Longitudinal follow-up for 26 years and 7 months after the treatment revealed that the development of radiculomegaly every few months or years, CDPs beneath OAs and PSLCs were observed. CDPs, PSLCs, and OAs were associated with radiculomegaly. The patient and the affected teeth including aligned teeth showed no particular change after the completion of the radiculomegaly. CBCT images showed bulbous-calcified-tissue and PSLCs in the mature dental pulp associated with radiculomegaly. LESSONS: The radiographical findings of CDP, OA and PSLC help early diagnose of OFCD and have importance for initiating orthodontic treatment until radiculomegaly completion.


Assuntos
Catarata/congênito , Defeitos dos Septos Cardíacos/diagnóstico por imagem , Defeitos dos Septos Cardíacos/genética , Microftalmia/diagnóstico por imagem , Microftalmia/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/genética , Catarata/diagnóstico por imagem , Catarata/genética , Catarata/reabilitação , Criança , Feminino , Defeitos dos Septos Cardíacos/reabilitação , Humanos , Incisivo/diagnóstico por imagem , Incisivo/crescimento & desenvolvimento , Microftalmia/reabilitação , Ortodontia Corretiva , Anormalidades Dentárias/reabilitação , Raiz Dentária/diagnóstico por imagem , Raiz Dentária/crescimento & desenvolvimento , Resultado do Tratamento
9.
Cytogenet Genome Res ; 154(4): 181-186, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29902798

RESUMO

Oculodentodigital dysplasia (ODDD) is a rare condition characterized by a typical facial appearance and variable findings of the eyes, teeth, and fingers. ODDD is caused by mutations in the GJA1 gene in chromosome 6q22 and inherited in an autosomal dominant manner in the majority of the patients. However, in recent clinical reports, autosomal recessive ODDD cases due to by GJA1 mutations were also described. Here, we report on a 14-year-old boy with microphthalmia, microcornea, narrow nasal bridge, hypoplastic alae nasi, prominent columnella, hypodontia, dental caries, and partial syndactyly of the 2nd and 3rd toes. These clinical findings were concordant with the diagnosis of ODDD, and a novel homozygous mutation (c.442C>T, p.Arg148Ter) was determined in the GJA1 gene leading to a premature stop codon. His phenotypically normal parents were found to be carriers of the same mutation. This is the third family in the literature in which ODDD segregates in an autosomal recessive manner.


Assuntos
Anormalidades Craniofaciais/genética , Anormalidades do Olho/genética , Deformidades Congênitas do Pé/genética , Genes Recessivos , Sindactilia/genética , Anormalidades Dentárias/genética , Adolescente , Códon de Terminação/genética , Conexina 43/genética , Homozigoto , Humanos , Masculino , Mutação
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(2): 268-271, 2018 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-29653008

RESUMO

OBJECTIVE: To explore the genetic basis for a patient with oculodentodigital dysplasia. METHODS: Genomic DNA was extracted from peripheral blood samples from the patient and his parents. Whole-exome sequencing was carried out for the trio family. Suspected mutation was verified by Sanger sequencing. RESULTS: A de novo c.412G>A mutation of the GJA1 gene was identified in the patient, which was validated by Sanger sequencing. CONCLUSION: The c.412G>A mutation of the GJA1 gene probably underlies the disease in the patient.


Assuntos
Conexina 43/genética , Anormalidades Craniofaciais/genética , Exoma , Anormalidades do Olho/genética , Deformidades Congênitas do Pé/genética , Mutação , Sindactilia/genética , Anormalidades Dentárias/genética , Adulto , Humanos , Masculino , Análise de Sequência de DNA
12.
Dev Biol ; 435(2): 176-184, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29409769

RESUMO

The capacity to fully replace teeth continuously makes zebrafish an attractive model to explore regeneration and tooth development. The requirement of attachment bone for the appearance of replacement teeth has been hypothesized but not yet investigated. The transcription factor sp7 (osterix) is known in mammals to play an important role during odontoblast differentiation and root formation. Here we study tooth replacement in the absence of attachment bone using sp7 zebrafish mutants. We analysed the pattern of tooth replacement at different stages of development and demonstrated that in zebrafish lacking sp7, attachment bone is never present, independent of the stage of tooth development or fish age, yet replacement is not interrupted. Without bone of attachment we observed abnormal orientation of teeth, and abnormal connection of pulp cavities of predecessor and replacement teeth. Mutants lacking sp7 show arrested dentinogenesis, with non-polarization of odontoblasts and only a thin layer of dentin deposited. Osteoclast activity was observed in sp7 mutants; due to the lack of bone of attachment, remodelling was diminished but nevertheless present along the pharyngeal bone. We conclude that tooth replacement is ongoing in the sp7 mutant despite poor differentiation and defective attachment. Without bone of attachment tooth orientation and pulp organization are compromised.


Assuntos
Dentinogênese/genética , Odontogênese/genética , Fator de Transcrição Sp7/fisiologia , Anormalidades Dentárias/genética , Proteínas de Peixe-Zebra/fisiologia , Peixe-Zebra/genética , Processo Alveolar/patologia , Animais , Animais Geneticamente Modificados , Polpa Dentária/patologia , Dentina/anormalidades , Dentinogênese/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Odontoblastos/patologia , Odontogênese/fisiologia , Osteoclastos/metabolismo , Regeneração , Fator de Transcrição Sp7/deficiência , Fator de Transcrição Sp7/genética , Raiz Dentária/patologia , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética
13.
Indian J Ophthalmol ; 66(2): 334-336, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29380799

RESUMO

Here, we report a patient with oculodentodigital dysplasia (ODDD) caused by the c. 413G>A, p.Gly138Asp mutation in the gap junction protein alpha-1 gene. The patient suffered from characteristic dysmorphic features of ODDD. Ophthalmological investigation disclosed microcornea and a shallow anterior chamber, as expected. Surprisingly, the patient had a normal axial length and moderate myopia on both eyes. To the best of our knowledge, this is the first report on ODDD associated with relative anterior microphthalmos and myopia.


Assuntos
Anormalidades Múltiplas , Conexina 43/genética , Anormalidades Craniofaciais/diagnóstico , DNA/genética , Anormalidades do Olho/diagnóstico , Deformidades Congênitas do Pé/diagnóstico , Microftalmia/diagnóstico , Sindactilia/diagnóstico , Anormalidades Dentárias/diagnóstico , Adulto , Conexina 43/metabolismo , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Análise Mutacional de DNA , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/metabolismo , Humanos , Masculino , Microftalmia/genética , Microftalmia/metabolismo , Sindactilia/genética , Sindactilia/metabolismo , Tomografia de Coerência Óptica , Anormalidades Dentárias/genética , Anormalidades Dentárias/metabolismo
14.
Eur J Med Genet ; 61(2): 72-78, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29100920

RESUMO

Axenfeld-Rieger syndrome (ARS) is a heterogeneous clinical entity transmitted in an autosomal dominant manner. The main feature, Axenfeld-Rieger Anomaly (ARA), is a malformation of the anterior segment of the eye that can lead to glaucoma and impair vision. Extra-ocular defects have also been reported. Point mutations of FOXC1 and PITX2 are responsible for about 40% of the ARS cases. We describe the phenotype of a patient carrying a deletion encompassing the 4q25 locus containing PITX2 gene. This child presented with a congenital heart defect (Tetralogy of Fallot, TOF) and no signs of ARA. He is the first patient described with TOF and a complete deletion of PITX2 (arr[GRCh37]4q25(110843057-112077858)x1, involving PITX2, EGF, ELOVL6 and ENPEP) inherited from his ARS affected mother. In addition, to our knowledge, he is the first patient reported with no ocular phenotype associated with haploinsufficiency of PITX2. We compare the phenotype and genotype of this patient to those of five other patients carrying 4q25 deletions. Two of these patients were enrolled in the university hospital in Toulouse, while the other three were already documented in DECIPHER. This comparative study suggests both an incomplete penetrance of the ocular malformation pattern in patients carrying PITX2 deletions and a putative association between TOF and PITX2 haploinsufficiency.


Assuntos
Segmento Anterior do Olho/anormalidades , Deleção Cromossômica , Cromossomos Humanos Par 4/genética , Anormalidades do Olho/genética , Tetralogia de Fallot/genética , Anormalidades Dentárias/genética , Acetiltransferases/genética , Adulto , Segmento Anterior do Olho/patologia , Criança , Fator de Crescimento Epidérmico/genética , Anormalidades do Olho/patologia , Oftalmopatias Hereditárias , Feminino , Glutamil Aminopeptidase/genética , Haploinsuficiência , Proteínas de Homeodomínio/genética , Humanos , Masculino , Linhagem , Fenótipo , Tetralogia de Fallot/patologia , Anormalidades Dentárias/patologia , Fatores de Transcrição/genética
15.
Ophthalmic Genet ; 39(1): 56-62, 2018 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28922055

RESUMO

The Nance-Horan syndrome is an X-linked disorder characterized by congenital cataract, facial features, microcornea, microphthalmia, and dental anomalies; most of the cases are due to NHS gene mutations on Xp22.13. Heterozygous carrier females generally present less severe features, and up to 30% of the affected males have intellectual disability. We describe two patients, mother and daughter, manifesting Nance-Horan syndrome. The cytogenetic and molecular analyses demonstrated a 46,X,t(X;1)(p22.13;q22) karyotype in each of them. No copy-number genomic imbalances were detected by high-density microarray analysis. The mother had a preferential inactivation of the normal X chromosome; expression analysis did not detect any mRNA isoform of NHS. This is the first report of Nance-Horan syndrome due to a skewed X chromosome inactivation resulting from a balanced translocation t(X;1) that disrupts the NHS gene expression, with important implications for clinical presentation and genetic counseling.


Assuntos
Catarata/congênito , Cromossomos Humanos Par 1/genética , Cromossomos Humanos X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas Nucleares/genética , Anormalidades Dentárias/genética , Translocação Genética/genética , Inativação do Cromossomo X/genética , Anormalidades Múltiplas/genética , Adulto , Catarata/genética , Pré-Escolar , Mapeamento Cromossômico , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Reação em Cadeia da Polimerase em Tempo Real
16.
Radiol Clin North Am ; 56(1): 125-140, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29157542

RESUMO

A variety of factors can affect the normal development of tissues and may lead to variation in the normal compliment of teeth and development of alterations in the shape and size of teeth. These anomalies can be congenital, developmental, or acquired. Dental anomalies can present as isolated traits or be associated with systemic conditions and syndromes for which early diagnosis and genetic testing may result in better treatment outcomes and quality of life. Dentists play an essential role in the multidisciplinary management of these abnormalities. This article discusses some of these tooth alterations and associated systemic and genetic conditions.


Assuntos
Predisposição Genética para Doença/genética , Radiografia Dentária/métodos , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/genética , Dente/diagnóstico por imagem , Diagnóstico Diferencial , Humanos
17.
Oral Dis ; 24(4): 611-618, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29121437

RESUMO

OBJECTIVE: To identify orodental characteristics and genetic aetiology of a family affected with non-syndromic orodental anomalies. SUBJECTS AND METHODS: Physical and oral features were characterised. DNA was collected from an affected Thai family. Whole-exome sequencing was employed to identify the pathogenic variants associated with inherited orodental anomalies. The presence of the identified mutation was confirmed by Sanger sequencing. RESULTS: We observed unique orodental manifestations including oligodontia, retained primary teeth, taurodont molars, peg-shaped maxillary central incisors, high attached frenum with nodule and midline diastema in the proband and her mother. Mutation analyses revealed a novel heterozygous frameshift deletion, c.573_574delCA, p.L193QfsX5, in exon 5 of PITX2A in affected family members. The amino acid alterations, localised in the transcriptional activation domain 2 in the C-terminus of PITX2, were evolutionarily conserved. Mutations in PITX2 have been associated with autosomal-dominant Axenfeld-Rieger syndrome and non-syndromic eye abnormalities, but never been found to cause isolated oral anomalies. CONCLUSIONS: This study for the first time demonstrates that the PITX2 mutation could lead to non-syndromic orodental anomalies in humans. We propose that the specific location in the C-terminal domain of PITX2 is exclusively necessary for tooth development.


Assuntos
Proteínas de Homeodomínio/genética , Anormalidades da Boca/genética , Anormalidades Dentárias/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Lactente , Masculino , Linhagem
18.
Int J Dermatol ; 57(2): 223-226, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29265343

RESUMO

Ectodermal dysplasias (EDs) are a group of hereditary disorders defined by alterations in two or more ectodermal structures. One recently described rare entity is the autosomal recessive inherited ectodermal dysplasia-syndactyly syndrome 1 (EDSS1). Homozygous and compound heterozygous missense and nonsense mutations in the poliovirus receptor related-4 (PVRL4) gene, encoding cell adhesion molecule nectin-4, have been identified as causal for EDSS1. We here report a consanguineous family with a 2-year-old girl featuring EDSS1, including slowly progressive alopecia on the head, pili torti-like twisted hairs in trichoscopy, widely spaced, peg-shaped and conical teeth, proximal syndactyly with fusion of the 2nd to 4th toes, and generalized dry skin. There was no palmoplantar hyperkeratosis and sweating appeared normal to slightly enhanced, especially on the head. Using exome sequencing, we identified the novel homozygous nonsense mutation c.229C>T (p.Gln77Ter) in PVRL4.


Assuntos
Moléculas de Adesão Celular/genética , Displasia Ectodérmica/genética , Sindactilia/genética , Anormalidades Dentárias/genética , Pré-Escolar , Consanguinidade , Feminino , Homozigoto , Humanos , Mutação , Síndrome
19.
Ann Clin Lab Sci ; 48(6): 776-781, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30610049

RESUMO

Oculodentodigital dysplasia (ODDD; MIM #164200), a rare genetic disorder characterized by abnormal craniofacial, dental, ocular, and digital features, is caused by mutations in the gap junction alpha-1 (GJA1) gene. We report a case of a 6-year-old male who presented with dysmorphic facial features (short palpebral fissure, thin nose with hypoplastic alae nasi, and flat face), bilateral syndactyly, abnormal dentition, and proportionate short stature with growth hormone deficiency. A novel de novo heterozygous missense mutation (c.221A>C, p.H74P) in GJA1 was identified by targeted gene panel sequencing. This is the first case report of a novel ODDD-causing mutation in GJA1 confirmed by genetic analysis in Korea.


Assuntos
Conexina 43/genética , Anormalidades Craniofaciais/genética , Anormalidades do Olho/genética , Deformidades Congênitas do Pé/genética , Mutação/genética , Sindactilia/genética , Anormalidades Dentárias/genética , Criança , Anormalidades Craniofaciais/diagnóstico por imagem , Análise Mutacional de DNA , Anormalidades do Olho/diagnóstico por imagem , Deformidades Congênitas do Pé/diagnóstico por imagem , Junções Comunicantes/patologia , Humanos , Masculino , Sindactilia/diagnóstico por imagem , Anormalidades Dentárias/diagnóstico por imagem
20.
Orphanet J Rare Dis ; 12(1): 183, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258554

RESUMO

CLINICAL DESCRIPTION: KBG syndrome is characterized by macrodontia of upper central incisors, distinctive craniofacial features such as triangular face, prominent nasal bridge, thin upper lip and synophrys; skeletal findings including short stature, delayed bone age, and costovertebral anomalies; and developmental delay/intellectual disability sometimes associated with seizures and EEG abnormalities. The condition was named KBG syndrome after the initials of the last names of three original families reported in 1975. EPIDEMIOLOGY: The prevalence of KBG syndrome is not established. There are over 100 patients reported in the literature. It is likely that KBG syndrome is underreported due to incomplete recognition and very mild presentations of the disorder in some individuals. KBG syndrome is typically milder in females. ETIOLOGY: Causative variants in ANKRD11 have been identified in affected individuals. The vast majority of identified variants are loss of function, which include nonsense and frameshift variants and larger deletions at 16q24.3. Haploinsufficiency appears to be the mechanism of pathogenicity. GENETIC COUNSELING: Familial and de novo cases have been reported. Causative de novo variants occur approximately one third of the time. Transmission follows an autosomal dominant pattern. The syndrome displays inter- and intra-familial variability.


Assuntos
Anormalidades Múltiplas/metabolismo , Doenças do Desenvolvimento Ósseo/metabolismo , Deficiência Intelectual/metabolismo , Anormalidades Dentárias/metabolismo , Anormalidades Múltiplas/genética , Animais , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Hibridização Genômica Comparativa , Facies , Feminino , Haploinsuficiência/genética , Haploinsuficiência/fisiologia , Humanos , Deficiência Intelectual/genética , Masculino , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Convulsões/genética , Convulsões/metabolismo , Anormalidades Dentárias/genética
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