Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.037
Filtrar
1.
Hum Genet ; 139(4): 531-543, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32030560

RESUMO

We present a comprehensive clinically oriented workflow for large-insert genome sequencing (liGS)-based nucleotide level resolution and interpretation of de novo (dn) apparently balanced chromosomal abnormalities (BCA) in prenatal diagnosis (PND). Retrospective or concomitant with conventional PND and liGS, molecular and newly developed clinically inspired bioinformatic tools (TAD-GConTool and CNV-ConTool) are applied to analyze and assess the functional and phenotypic outcome of dn structural variants (dnSVs). Retrospective analysis of four phenotype-associated dnSVs identified during conventional PND precisely reveal the genomic elements disrupted by the translocation breakpoints. Identification of autosomal dominant disease due to the disruption of ANKS1B and WDR26 by t(12;17)(q23.1;q21.33)dn and t(1;3)(q24.11;p25.3)dn breakpoints, respectively, substantiated the proposed workflow. We then applied this workflow to two ongoing prenatal cases with apparently balanced dnBCAs: 46,XX,t(16;17)(q24;q21.3)dn referred for increased risk on combined first trimester screening and 46,XY,t(2;19)(p13;q13.1)dn referred due to a previous trisomy 21 pregnancy. Translocation breakpoints in the t(16;17) involve ANKRD11 and WNT3 and disruption of ANKRD11 resulted in KBG syndrome confirmed in postnatal follow-up. Breakpoints in the t(2;19) are within ATP6V1B1 and the 3' UTR of CEP89, and are not interpreted to cause disease. Genotype-phenotype correlation confirms the causative role of WDR26 in the Skraban-Deardorff and 1q41q42 microdeletion phenocopy syndromes, and that disruption of ANKS1B causes ANKS1B haploinsufficiency syndrome. In sum, we show that an liGS-based approach can be realized in PND care providing additional information concerning clinical outcomes of dnBCAs in patients with such rearrangements.


Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Transtornos Cromossômicos , Cromossomos Humanos/genética , Facies , Genes Dominantes , Deficiência Intelectual , Diagnóstico Pré-Natal , Anormalidades Dentárias , Translocação Genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Gravidez , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Fluxo de Trabalho
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(12): 1191-1194, 2019 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-31813145

RESUMO

OBJECTIVE: To explore the genetic basis of a pedigree affected with oculodentodigital dysplasia. METHODS: Genomic DNA was extracted from peripheral blood or amniotic fluid samples derived from the pedigree. Exon 2 of the GJA1 gene was amplified for sequencing. RESULTS: Two pedigree members were found to carry heterozygous missense variation of the GJA1 gene, c.221A>C (p.H74P). CONCLUSION: The missense c.221A>C variation of the GJA1 gene probably underlies the oculodentodigital dysplasia in this pedigree.


Assuntos
Conexina 43/genética , Anormalidades Craniofaciais/genética , Anormalidades do Olho/genética , Deformidades Congênitas do Pé/genética , Sindactilia/genética , Anormalidades Dentárias/genética , Humanos , Mutação , Linhagem
3.
Genes (Basel) ; 10(10)2019 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615056

RESUMO

A single male domestic shorthair cat that did not complete puberty was reported. At four years of age, it still had primary dentition, testicular hypoplasia, and was relatively small for its age. We hypothesized that the phenotype might have been due to an inherited form of hypogonadotropic hypogonadism (HH). We sequenced the genome of the affected cat and compared the data to 38 genomes from control cats. A search for private variants in 40 candidate genes associated with human HH revealed a single protein-changing variant in the affected cat. It was located in the TAC3 gene encoding tachykinin 3, a precursor protein of the signaling molecule neurokinin B, which is known to play a role in sexual development. TAC3 variants have been reported in human patients with HH. The identified feline variant, TAC3:c.220G>A or p.(Val74Met), affects a moderately conserved region of the precursor protein, 11 residues away from the mature neurokinin B sequence. The affected cat was homozygous for the mutant allele. In a cohort of 171 randomly sampled cats, 169 were homozygous for the wildtype allele and 2 were heterozygous. These data tentatively suggest that the identified TAC3 variant might have caused the suppression of puberty in the affected cat.


Assuntos
Doenças do Gato/genética , Hipogonadismo/veterinária , Mutação de Sentido Incorreto , Taquicininas/genética , Dente Decíduo/metabolismo , Animais , Doenças do Gato/metabolismo , Gatos/genética , Hipogonadismo/genética , Hipogonadismo/patologia , Masculino , Neurocinina B/genética , Receptores da Neurocinina-3/genética , Maturidade Sexual/genética , Taquicininas/metabolismo , Testículo/patologia , Anormalidades Dentárias/genética , Anormalidades Dentárias/veterinária , Dente Decíduo/anormalidades
4.
BMC Oral Health ; 19(1): 164, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345197

RESUMO

BACKGROUND: Otodental syndrome is an exceptionally rare autosomal dominant condition characterized by a delayed eruption of posterior teeth, globodontia, lisping, and sensorineural hearing loss. In this case report, we reported a 3-year-old Chinese boy with the otodental syndrome. CASE PRESENTATION: A 3-year-old Chinese boy was referred to our hospital with complaint of no eruption of primary canines and molars. Three years follow-up showed lately erupted bulbous primary canines with hypoplastic enamel spot, globe-shaped primary molars and sensorineural hearing loss at 4 and a half-year-old age. We diagnosed otodental syndrome in the patient's mother with hearing loss at 16-year-old age. Gene sequencing and analysis of deafness-related genes GJB2, GJB3, SLC26A4, and mtDNA did not reveal any mutation or SNPs in the patient and his mother. CONCLUSIONS: This case report highlights the importance of detailed medical, dental, and family history examination, as well as multi-disciplinary teamwork for diagnosis and treatment of otodental syndrome.


Assuntos
Transtornos Cromossômicos/diagnóstico , Coloboma/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Anormalidades Dentárias/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Grupo com Ancestrais do Continente Asiático , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 11 , Coloboma/genética , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Mutação , Odontoma/diagnóstico , Odontoma/genética , Anormalidades Dentárias/genética
5.
Genes (Basel) ; 10(7)2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336982

RESUMO

Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel's aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations.


Assuntos
Microtia Congênita/genética , Microtia Congênita/patologia , Orelha Interna/anormalidades , Fator 3 de Crescimento de Fibroblastos/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Anormalidades Dentárias/genética , Anormalidades Dentárias/patologia , Adulto , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Surdez/congênito , Orelha Interna/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Fenótipo
6.
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
7.
AJNR Am J Neuroradiol ; 40(5): 788-791, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31023660

RESUMO

Oculodentodigital dysplasia is an autosomal dominant disorder due to GJA1 variants characterized by dysmorphic features. Neurologic symptoms have been described in some patients but without a clear neuroimaging pattern. To understand the pathophysiology underlying neurologic deficits in oculodentodigital dysplasia, we studied 8 consecutive patients presenting with hereditary spastic paraplegia due to GJA1 variants. Clinical disease severity was highly variable. Cerebral MR imaging revealed variable white matter abnormalities, consistent with a hypomyelination pattern, and bilateral hypointense signal of the basal ganglia on T2-weighted images and/or magnetic susceptibility sequences, as seen in neurodegeneration with brain iron accumulation diseases. Patients with the more prominent basal ganglia abnormalities were the most disabled ones. This study suggests that GJA1-related hereditary spastic paraplegia is a complex neurodegenerative disease affecting both the myelin and the basal ganglia. GJA1 variants should be considered in patients with hereditary spastic paraplegia presenting with brain hypomyelination, especially if associated with neurodegeneration and a brain iron accumulation pattern.


Assuntos
Encéfalo/patologia , Conexina 43/genética , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/patologia , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/patologia , Sindactilia/genética , Sindactilia/patologia , Anormalidades Dentárias/genética , Anormalidades Dentárias/patologia , Adolescente , Adulto , Anormalidades Craniofaciais/complicações , Anormalidades do Olho/complicações , Feminino , Deformidades Congênitas do Pé/complicações , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Sindactilia/complicações , Anormalidades Dentárias/complicações
8.
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
9.
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 , Doenças Dentárias/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
10.
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
11.
Am J Med Genet A ; 179(4): 668-673, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30811827

RESUMO

In 2011, biallelic loss-of-function variants in the interleukin receptor 11 alpha gene IL11RA were found to be associated with a Crouzon-like craniosynostosis syndrome with associated dental anomalies (CRSDA). Since then, a total of 41 similar patients have been reported with IL11RA variants. We report two adult brothers diagnosed with Crouzon syndrome as children, in which the clinical diagnosis of CRSDA was made on reevaluation. Laboratory testing detected biallelic IL11RA variants, c.916_924dup (p.Thr306_Ser308dup) and c.781C > T (p.Arg261Cys), both of which have now been reported in other families. Protein modeling and conservation analysis show that these two mutation sites cluster together near a WSXWS motif that likely plays a significant role in regulating IL11RA protein function. Population analysis from gnomAD shows that Non-Finnish Europeans (similar to ethnicity of this family), have an allele frequency for p.Thr306_Ser308dup of 0.014% and p.Arg261Cys of 0.008%. We found other ethnicities have functional IL11RA missense variants at higher frequencies. With this report, we provide a summary of the clinical findings including details of middle ear anomalies associated with conductive hearing loss. We also provide data supporting the populations at risk for this condition to increase recognition and diagnosis of this rare autosomal recessive craniosynostosis syndrome.


Assuntos
Craniossinostoses/genética , Craniossinostoses/patologia , Subunidade alfa de Receptor de Interleucina-11/genética , Mutação , Fenótipo , Anormalidades Dentárias/genética , Anormalidades Dentárias/patologia , Adulto , Craniossinostoses/complicações , Frequência do Gene , Genes Recessivos , Humanos , Subunidade alfa de Receptor de Interleucina-11/química , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Masculino , Prognóstico , Anormalidades Dentárias/complicações
12.
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
13.
Ophthalmic Genet ; 40(1): 54-59, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30767687

RESUMO

BACKGROUND: Oculodentodigitaldysplasia (ODDD; MIM no. 164200) is a rare hereditary disorder caused by mutations in the gene GJA1.Ocular disorders included microcornea, cornea opacity and glaucoma. However, few studies described fundus findings. MATERIALS AND METHODS: Ophthalmic examination included visual acuity measurement, intraocular pressure (IOP) measurements, slit-lamp biomicroscopy, B-scan ultrasonography, Ultrasound biomicroscopy (UBM), spectral-domain optical coherence tomography (SD-OCT), ERG and retcam fluorescein angiogram. In addition, blood samples were taken from this patient for mutation analyze of GJA1. RESULT: The ophthalmic features of this patient were microcornea, cornea opacity, glaucoma as expected. Interestingly, the patient had a normal axial length with refractive status of emmetropia, but extremely retinal dysplasia and severe choroid thinning was noted. Flash electroretinogram (ERG) was extinguished in both eyes. This study identified a novel mutation c.91A>T in the GJA1 gene associated with fundus abnormalities. Bioinformatics and structural modeling suggested the mutation to be pathogenic. CONCLUSION: Our research expanded not only the mutation spectrum, but also the clinical characteristics of ODDD. To the best of our knowledge, this is the first report on anatomical and functional chorioretinal changes in ODDD patients. These novel ocular features highlight the importance of fundus morphological and functional evaluation in ODDD. ABBREVIATIONS: ODDD: oculodentodigital dysplasia; OCT: optical coherence tomography; ERG: electroretinogram; TACT: teller acuity card test; UBM: ultrasound biomicroscopy; MW: molecular weights; AL: axial length; Cx43: connexin 43; RPE: retinal pigment epithelium; RGCs: retinal ganglion cells; FEVR: familial exudative vitreoretinopathy; ROP: retinopathy of prematurity.


Assuntos
Conexina 43/genética , Anormalidades Craniofaciais/patologia , Anormalidades do Olho/patologia , Deformidades Congênitas do Pé/patologia , Mutação , Sindactilia/patologia , Anormalidades Dentárias/patologia , Anormalidades Craniofaciais/genética , Anormalidades do Olho/genética , Deformidades Congênitas do Pé/genética , Humanos , Lactente , Masculino , Microscopia Acústica , Prognóstico , Sindactilia/genética , Tomografia de Coerência Óptica , Anormalidades Dentárias/genética
14.
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
15.
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
16.
J Glaucoma ; 28(4): 357-362, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30628995

RESUMO

PURPOSE: We aimed to present a comprehensive assessment of the ophthalmic characteristics of genetically confirmed oculodentodigital dysplasia (ODDD) in 4 members of a single Korean family across 3 generations. PATIENTS AND METHODS: The characteristics of 4 affected ODDD patients were evaluated. Comprehensive ophthalmic and medical examinations were performed in 3 patients including the proband, together with genetic analysis, and retrospective chart review was conducted for an affected ancestor. For genetic analysis, targeted gene panel sequencing was conducted using genomic DNA extracted from peripheral blood. RESULTS: All affected individuals in this family showed shared ophthalmic abnormalities of microcornea, microphthalmia, elevated intraocular pressure, and shallow anterior chamber, all of which have been reported as typical ocular features of ODDD. Myopic refractive error despite short axial length and thick cornea were highlighted as new findings of ODDD. Facial abnormalities were common in all affected members, but their fingers were normal. Severity of glaucoma was different among the affected individuals and seemed to depend on elevation of intraocular pressure, which occurred in narrow, but open-angle. Genetic analysis revealed the presence of c.119C>T (p.Ala40Val) in GJA1, which is responsible for ODDD, but not found in the control population. CONCLUSIONS: This report describes detailed ocular characteristics in a genetically confirmed ODDD family, including unreported findings of thick cornea and myopic refractive error despite short axial length. The ocular features derived from the A40V mutation in GJA1 showed complete penetrance, suggesting a possible role of Cx43 in regulation of IOP and pathogenesis of glaucoma.


Assuntos
Conexina 43/genética , Córnea/anormalidades , Anormalidades Craniofaciais/genética , Anormalidades do Olho/genética , Deformidades Congênitas do Pé/genética , Glaucoma/genética , Microftalmia/genética , Mutação de Sentido Incorreto , Sindactilia/genética , Anormalidades Dentárias/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Criança , Anormalidades Craniofaciais/diagnóstico , Anormalidades do Olho/diagnóstico , Feminino , Deformidades Congênitas do Pé/diagnóstico , Humanos , Pressão Intraocular , Masculino , República da Coreia/epidemiologia , Estudos Retrospectivos , Sindactilia/diagnóstico , Anormalidades Dentárias/diagnóstico
17.
Genesis ; 57(1): e23252, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30253032

RESUMO

The skeletal structure of the mammalian middle ear, which is composed of three endochondral ossicles suspended within a membranous air-filled capsule, plays a critical role in conducting sound. Gene mutations that alter skeletal development in the middle ear result in auditory impairment. Mutations in fibroblast growth factor receptor 2 (FGFR2), an important regulator of endochondral and intramembranous bone formation, cause a spectrum of congenital skeletal disorders featuring conductive hearing loss. Although the middle ear malformations in multiple FGFR2 gain-of-function disorders are clinically characterized, those in the FGFR2 loss-of-function disorder lacrimo-auriculo-dento-digital (LADD) syndrome are relatively undescribed. To better understand conductive hearing loss in LADD, we examined the middle ear skeleton of mice with conditional loss of Fgfr2. We find that decreased auditory function in Fgfr2 mutant mice correlates with hypoplasia of the auditory bulla and ectopic bone growth at sites of tendon/ligament attachment. We show that ectopic bone associated with the intra-articular ligaments of the incudomalleal joint is derived from Scx-expressing cells and preceded by decreased expression of the joint progenitor marker Gdf5. Together, these results identify a role for Fgfr2 in development of the middle ear skeletal tissues and suggest potential causes for conductive hearing loss in LADD syndrome.


Assuntos
Anormalidades Múltiplas/genética , Orelha Média/metabolismo , Perda Auditiva/genética , Doenças do Aparelho Lacrimal/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Sindactilia/genética , Anormalidades Dentárias/genética , Animais , Desenvolvimento Ósseo , Orelha Média/anormalidades , Orelha Média/embriologia , Fator 5 de Diferenciação de Crescimento/metabolismo , Mutação com Perda de Função , Camundongos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética
19.
Eur J Med Genet ; 62(2): 85-89, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29852250

RESUMO

Runt-related transcription factor 2 (RUNX2) is well-known for its role in bone development and tooth morphogenesis. Most RUNX2 mutations described in the literature result in loss-of-function mutations of RUNX2 responsible for cleidocranial dysplasia, an autosomal dominant disorder. We describe here the oro-dental phenotype of four patients of a unique family with a 285 kb duplication including the entire sequence of RUNX2, likely responsible for three functional copies of the gene, leading to an increased RUNX2 dosage. Several dental anomalies of number (hypodontia or oligodontia), morphology (microdontia, radiculomegaly, taurodontism or dens invaginatus) and tooth position (rotation) were found in these patients.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/genética , Duplicação Gênica , Fenótipo , Anormalidades Dentárias/genética , Adolescente , Adulto , Criança , Feminino , Dosagem de Genes , Humanos , Masculino , Linhagem , Anormalidades Dentárias/patologia
20.
Congenit Anom (Kyoto) ; 59(5): 162-168, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30315601

RESUMO

Williams syndrome (WS) is a rare congenital anomaly that is characterized by distinctive facial features, congenital heart disease, and behavioral characteristics that include mental retardation. However, only a few reports have documented the dentocraniofacial morphological characteristics of WS in Japanese individuals. The aim of this study was to analyze the dentocraniofacial morphology and growth patterns in a group of nine Japanese subjects (two males and seven females; mean age at admission, 10.1 years) with WS. The analytical methods included an initial medical questionnaire, lateral cephalography, panoramic radiography, dental casts, and oral examinations. The dental findings showed congenitally missing teeth, microdontia, and peg-shaped teeth. Regarding cranial morphology, microcephaly occurred at high frequencies, and a short posterior cranial base and thick calvarial bones, including frontal, parietal, and occipital bones, were seen in patients with WS. An analysis of maxillofacial morphology showed the large gonial angles and lingual inclination of the lower incisors in patients with WS. In addition, the chin button was deficient and in three of four growing subjects the maxillofacial growth pattern demonstrated a downward and backward tendency. The results of this study provide important information that will improve our understanding of the characteristics of patients with WS.


Assuntos
Anormalidades Craniofaciais/diagnóstico , Fenótipo , Anormalidades Dentárias/diagnóstico , Síndrome de Williams/diagnóstico , Adolescente , Cefalometria , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , Deformidades Dentofaciais/diagnóstico , Deformidades Dentofaciais/genética , Feminino , Humanos , Japão , Masculino , Anormalidades Dentárias/genética , Síndrome de Williams/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA