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1.
Cytogenet Genome Res ; 159(1): 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31658463

RESUMO

The switch/sucrose non-fermenting (SWI/SNF) complex is an ATP-dependent chromatin remodeller that regulates the spacing of nucleosomes and thereby controls gene expression. Heterozygous mutations in genes encoding subunits of the SWI/SNF complex have been reported in individuals with Coffin-Siris syndrome (CSS), with the majority of the mutations in ARID1B. CSS is a rare congenital disorder characterized by facial dysmorphisms, digital anomalies, and variable intellectual disability. We hypothesized that mutations in genes encoding subunits of the ubiquitously expressed SWI/SNF complex may lead to alterations of the nucleosome profiles in different cell types. We performed the first study on CSS-patient samples and investigated the nucleosome landscapes of cell-free DNA (cfDNA) isolated from blood plasma by whole-genome sequencing. In addition, we studied the nucleosome landscapes of CD14+ monocytes from CSS-affected individuals by nucleosome occupancy and methylome-sequencing (NOMe-seq) as well as their expression profiles. In cfDNA of CSS-affected individuals with heterozygous ARID1B mutations, we did not observe major changes in the nucleosome profile around transcription start sites. In CD14+ monocytes, we found few genomic regions with different nucleosome occupancy when compared to controls. RNA-seq analysis of CD14+ monocytes of these individuals detected only few differentially expressed genes, which were not in proximity to any of the identified differential nucleosome-depleted regions. In conclusion, we show that heterozygous mutations in the human SWI/SNF subunit ARID1B do not have a major impact on the nucleosome landscape or gene expression in blood cells. This might be due to functional redundancy, cell-type specificity, or alternative functions of ARID1B.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteínas Nucleares/genética , Nucleossomos/genética , Fatores de Transcrição/genética , Adolescente , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Criança , Pré-Escolar , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Monócitos/citologia , Adulto Jovem
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 890-892, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515783

RESUMO

OBJECTIVE: To detect potential mutation in a Chinese pedigree affected with congenital limb malformations. METHODS: Clinical data was collected. Genomic DNA was extracted from peripheral blood samples of family members. The zone of polarizing activity regulatory sequence (ZRS) were amplified by PCR and subjected to direct sequencing. RESULTS: Among the 13 individuals in this pedigree, there were 4 PPD patients, who were characterized by varying degrees of deformity. The female patients suffered triphalangeal thumb and preaxial polydactyly, while the male patients only had preaxial polydactyly. Only one patient had foot involvement. TA heterogeneous mutations was discovered in the ZRS (105C>G) in all patients, the same mutation was not detected in 2 healthy family members. CONCLUSION: The inheritance pattern of PPD was autosomal dominant inheritance. There was a significant variability of symptoms among family patients. The heterozygous mutation of the ZRS (105C>G) probably underlie the disease.


Assuntos
Deformidades Congênitas da Mão/genética , Deformidades Congênitas dos Membros/genética , Proteínas de Membrana/genética , Polidactilia/genética , Feminino , Testes Genéticos , Humanos , Masculino , Linhagem , Polegar/patologia
3.
Yi Chuan ; 41(8): 716-724, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31447422

RESUMO

In order to investigate the genetic variations and the clinical manifestations of a range of congenital ectrodactyly family and to summarize the split hand/foot malformation (SHFM) types and their related pathogenic genes, we conducted phenotypic analyses of patient's limbs by physical and X-ray examination. The haplotypes were analyzed by using the extracted genes from peripheral blood on D10S1709, D10S192, D10S597, D10S1693 and D10S587 loci, and the mutation duplication loci were confirmed by Array-CGH detection. The pathogenic factors and inheritance pattern of SHFM were analyzed based on family investigation and gene analysis. Results demonstrate the proband's phenotype is typically of a congenital SHFM which is manifested by missing bilateral index and middle fingers, short bilateral thumbs, deformed left ring finger with webbing of the skin missing at the middle finger; bilateral big toe with the second and the third toe missing, fourth and fifth toe fusion leading to a deformed toe separated from the first toe by the middle of the foot. The haplotype analyses show that there is a repeat of at least 610 kb in chromosome 10q24.31-10q24.32 region. Array-CGH analysis shows 10q24.31 (102 832 650-103 511 083) ×3. Our results demonstrate that the pathogenic gene variation of ectrodactyly in this family is due to duplication of 10q24.31 (102 832 650~103 511 083). The haplotype 165-251-289-219-102 can be used as a disease marker for detecting 10q24.31~10q24.32 allele for SHFM.


Assuntos
Duplicação Cromossômica , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Deformidades Congênitas dos Membros/genética , Cromossomos Humanos Par 10/genética , Humanos , Linhagem
4.
Nat Commun ; 10(1): 2966, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273213

RESUMO

Mutations in genes encoding components of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes cause neurodevelopmental disorders and tumors. The mechanisms leading to the development of these two disease entities alone or in combination remain unclear. We generated mice with a heterozygous nervous system-specific partial loss-of-function mutation in a BAF core component gene, Smarcb1. These Smarcb1 mutant mice show various brain midline abnormalities that are also found in individuals with Coffin-Siris syndrome (CSS) caused by SMARCB1, SMARCE1, and ARID1B mutations and in SMARCB1-related intellectual disability (ID) with choroid plexus hyperplasia (CPH). Analyses of the Smarcb1 mutant animals indicate that one prominent midline abnormality, corpus callosum agenesis, is due to midline glia aberrations. Our results establish a novel role of Smarcb1 in the development of the brain midline and have important clinical implications for BAF complex-related ID/neurodevelopmental disorders.


Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/genética , Corpo Caloso/crescimento & desenvolvimento , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteína SMARCB1/genética , Anormalidades Múltiplas/diagnóstico por imagem , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/patologia , Alelos , Animais , Criança , Pré-Escolar , Corpo Caloso/citologia , Corpo Caloso/diagnóstico por imagem , Modelos Animais de Doenças , Embrião de Mamíferos , Face/diagnóstico por imagem , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Micrognatismo/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Neuroglia/patologia , Cultura Primária de Células
5.
BMC Med Genet ; 20(1): 108, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200655

RESUMO

BACKGROUND: Split hand/foot malformation (SHFM) is a group of congenital skeletal disorders which may occur either as an isolated abnormality or in syndromic forms with extra-limb manifestations. Chromosomal micro-duplication or micro-triplication involving 17p13.3 region has been described as the most common cause of split hand/foot malformation with long bone deficiency (SHFLD) in several different Caucasian and Asian populations. Gene dosage effect of the extra copies of BHLHA9 gene at this locus has been implicated in the pathogenesis of SHFLD. CASE PRESENTATION: The proband was a female child born to non-consanguineous parents. She was referred for genetic evaluation of bilateral asymmetric ectrodactyly involving both hands and right foot along with right tibial hemimelia. The right foot had fixed clubfoot deformity with only 2 toes. The mother had bilateral ectrodactyly involving both hands, but the rest of the upper limbs and both lower limbs were normal. Neither of them had any other congenital malformations or neurodevelopmental abnormalities. Genetic testing for rearrangement of BHLHA9 gene by quantitative polymerase chain reaction confirmed the duplication of the BHLHA9 gene in both the proband and the mother. CONCLUSIONS: We report the first Sri Lankan family with genetic diagnosis of BHLHA9 duplication causing SHFLD. This report along with the previously reported cases corroborate the possible etiopathogenic role of BHLHA9 gene dosage imbalances in SHFM and SHFLD across different populations.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Duplicação Gênica , Deformidades Congênitas dos Membros/genética , Tíbia/anormalidades , Duplicação Cromossômica , Cromossomos Humanos Par 17/genética , Hibridização Genômica Comparativa , Ectromelia , Feminino , Deformidades Congênitas do Pé/genética , Dosagem de Genes , Rearranjo Gênico/genética , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Deformidades Congênitas da Mão/genética , Humanos , Recém-Nascido , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/fisiopatologia , Tíbia/diagnóstico por imagem , Tíbia/fisiopatologia
6.
J Hum Genet ; 64(6): 561-572, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30858506

RESUMO

Variants have been identified in the embryonic ectoderm development (EED) gene in seven patients with syndromic overgrowth similar to that observed in Weaver syndrome. Here, we present three additional patients with missense variants in the EED gene. All the missense variants reported to date (including the three presented here) have localized to one of seven WD40 domains of the EED protein, which are necessary for interaction with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). In addition, among the seven patients reported in the literature and the three new patients presented here, all of the reported pathogenic variants except one occurred at one of four amino acid residues in the EED protein. The recurrence of pathogenic variation at these loci suggests that these residues are functionally important (mutation hotspots). In silico modeling and calculations of the free energy changes resulting from these variants suggested that they not only destabilize the EED protein structure but also adversely affect interactions between EED, EZH2, and/or H3K27me3. These cases help demonstrate the mechanism(s) by which apparently deleterious variants in the EED gene might cause overgrowth and lend further support that amino acid residues in the WD40 domain region may be mutation hotspots.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Histona-Lisina N-Metiltransferase/genética , Complexo Repressor Polycomb 2/genética , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Simulação por Computador , Hipotireoidismo Congênito/etiologia , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/etiologia , Anormalidades Craniofaciais/fisiopatologia , Proteína Potenciadora do Homólogo 2 de Zeste/química , Feminino , Deformidades Congênitas da Mão/etiologia , Deformidades Congênitas da Mão/fisiopatologia , Histona-Lisina N-Metiltransferase/química , Humanos , Masculino , Simulação de Dinâmica Molecular , Taxa de Mutação , Mutação de Sentido Incorreto/genética , Complexo Repressor Polycomb 2/química , Conformação Proteica , Repetições WD40/genética , Sequenciamento Completo do Exoma
7.
J Dermatol ; 46(2): 154-157, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30565282

RESUMO

Vohwinkel syndrome (VS) is a rare autosomal dominant condition, also known as mutilating palmoplantar keratoderma accompanied by sensorineural deafness. The LOR and GJB2 genes are reported to be responsible for VS. The GJB2 gene encodes connexin 26, a component of intercellular gap junctions expressed in various tissues. We report the case of a 31-year-old Chinese woman with classic VS characterized by sensorineural deafness and mutilating palmoplantar keratoderma. Further genetic studies demonstrated a nucleotide change (c.175G>A) in the GJB2 gene, leading to an amino acid alteration (G59S). This identical missense mutation (G59S) has also been reported in a patient with Bart-Pumphrey syndrome. Together with our findings and previous studies, we conclude that the identical mutation (G59S) in the GJB2 gene contributes to various manifestations.


Assuntos
Anormalidades Múltiplas/genética , Conexinas/genética , Deformidades Congênitas da Mão/genética , Perda Auditiva Neurossensorial/genética , Ceratodermia Palmar e Plantar/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Mutação de Sentido Incorreto
8.
Am J Hum Genet ; 104(1): 164-178, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30580808

RESUMO

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.


Assuntos
Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Mutação , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Face/anormalidades , Feminino , Deformidades Congênitas da Mão/genética , Humanos , Masculino , Micrognatismo/genética , Pescoço/anormalidades , Síndrome
9.
Int J Mol Sci ; 19(8)2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30071673

RESUMO

Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.


Assuntos
Artrogripose/genética , Fissura Palatina/genética , Pé Torto Equinovaro/genética , Mutação da Fase de Leitura , Deformidades Congênitas da Mão/genética , Processamento de RNA/genética , Fator C de Crescimento do Endotélio Vascular/genética , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Artrogripose/metabolismo , Artrogripose/patologia , Pré-Escolar , Fissura Palatina/metabolismo , Fissura Palatina/patologia , Pé Torto Equinovaro/metabolismo , Pé Torto Equinovaro/patologia , Feminino , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Domínios Proteicos , Fator C de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
10.
An Bras Dermatol ; 93(5): 723-725, 2018 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30156625

RESUMO

Vohwinkel syndrome belongs to the group of hereditary palmoplantar keratoderma, having an autosomal dominant inheritance. In this report, the authors present a case of a four-year-old boy with diffuse scaling over his entire body and transgredient palmoplantar hyperkeratosis with some fissured areas. Family evaluation revealed that his mother and other family members were affected. Based on his clinical findings and on family history, the diagnosis of the ichthyotic Vohwinkel syndrome subtype, characterized by generalized ichthyosis and palmoplantar hyperkeratosis, was established.


Assuntos
Anormalidades Múltiplas/genética , Deformidades Congênitas da Mão/genética , Perda Auditiva Neurossensorial/genética , Ictiose/genética , Ceratodermia Palmar e Plantar/genética , Pré-Escolar , Humanos , Masculino , Linhagem
11.
Int J Pediatr Otorhinolaryngol ; 108: 208-212, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29605356

RESUMO

OBJECTIVE: Evaluation of clinical findings and audiological outcome after surgery in a Danish family with autosomal dominant facio-audio-symphalangism syndrome with stapes fixation, syndactyly and symphalangism. METHODS: Retrospective report on eight affected family members in a Danish family. Clinical investigation included X-ray, audiology and in one case video-recorded surgery. Main outcome measure was audiologic results after stapedectomy. Sanger DNA sequencing of NOG was performed on peripheral blood. RESULTS: Audiologic analysis showed that seven of eight affected family members had bilateral conductive hearing loss. Three patients were treated with stapedectomy, on one or both ears, due to fixation of stapes. All the affected members had syndactyly and symphalangism. A not previously reported mutation in the NOG gene (c.688_699del, p.Cys230_Cys232delins11) was found to segregate with the stapes fixation, syndactyly, and symphalangism. p.Cys230_Cysdelins11 was classified as likely pathogenic according to guidelines from the American College of Medical Genetics and Genomics. CONCLUSION: The clinical presentation of the reported mutation corresponds with previous case reports of families with NOG mutation. In this family, surgery with stapedectomy had lasting effect without renewed fixation of the stapes in a follow up period of 18 months-38 years.


Assuntos
Ossos do Carpo/anormalidades , Proteínas de Transporte/genética , Deformidades Congênitas do Pé/cirurgia , Deformidades Congênitas da Mão/cirurgia , Perda Auditiva Condutiva/cirurgia , Cirurgia do Estribo/métodos , Estribo/anormalidades , Sinostose/cirurgia , Ossos do Tarso/anormalidades , Adolescente , Adulto , Idoso , Ossos do Carpo/cirurgia , Dinamarca , Feminino , Seguimentos , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Perda Auditiva Condutiva/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prótese Ossicular/efeitos adversos , Linhagem , Fenótipo , Estudos Retrospectivos , Cirurgia do Estribo/efeitos adversos , Sindactilia/genética , Sinostose/genética , Ossos do Tarso/cirurgia , Resultado do Tratamento
12.
J Genet ; 97(1): 35-46, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29666323

RESUMO

Schinzel-Giedion syndrome (SGS) is a rare autosomal dominant inheritance disorder. Heterozygous de novo mutations in the SETBP1 gene have been identified as the genetic cause of SGS. Here, we report a novel case with the syndrome with a novel insertion mutation in SETBP1. We also present a review of SGS cases, and first revise diagnostic criteria of SGS based on clinicalfindings and/or SETBP1 mutation worldwide. A revised diagnostic criteria and typing of SGS can be determined. Type I (complex and classic type) SGS patients present a development delay and typical facial features (prominent forehead, midface retraction, and short and upturned nose) associated with hydronephrosis or two of the characteristic skeletal anomalies (a sclerotic skull base, wideoccipital synchondrosis, increased cortical density or thickness, and broad ribs). Type II (middle type) patients show development delay and the distinctive facial phenotype (midface retraction, short and upturned nose), lacking both hydronephrosis and typical skeletal abnormalities, with existence of SETBP1mutation. Type III (simple type) patients with SETBP1 alteration show their major symptom is development delay, in which expressive language delay is the most striking feature. Central nervous system involvement with development delay in which expressive language delay is much more obviously affected is the most prominent feature of SGS. There is another indication that severity of phenotype of SGS may be inversely correlated with degree of SETBP1 alteration, besides gain-of-function or dominant-negative effects in SETBP1 alteration causing SGS.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Deformidades Congênitas da Mão/diagnóstico , Deficiência Intelectual/diagnóstico , Unhas Malformadas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Sequência de Bases , Proteínas de Transporte/genética , Criança , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Análise Mutacional de DNA , Eletroencefalografia , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/genética , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Unhas Malformadas/diagnóstico por imagem , Unhas Malformadas/genética , Proteínas Nucleares/genética , Mutação Puntual/genética
15.
Mol Genet Genomic Med ; 6(2): 230-248, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29397575

RESUMO

BACKGROUND: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage. METHODS: In the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families. In 28 patients, whole exome sequencing was used to investigate genomic variations. RESULTS: We found that camptodactyly of hands was the first symptom presented by most patients. Swelling of wrists, knees, and elbows began before 4 years of age, while the age of joint involvement was variable. Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20 years old. All patients presented developmental coxa vara and seven patients (~22%) had pleural effusion, pericarditis, and/or ascites. We identified nine novel genomic alterations, including the first case of homozygous complete deletion of exon 1 in the PRG4 gene. CONCLUSION: With this study, we contribute to the catalog of CACP causing variants. We confirm that the skeletal component of this disease worsens with age, and presents the potential mechanisms for interfamily variability, by discussing the influence of a modifier gene and escape from nonsense-mediated mRNA decay. We believe that this report will increase awareness of this familial arthropathic condition and the characteristic clinical and radiological findings will facilitate the differentiation from the common childhood rheumatic diseases such as juvenile idiopathic arthritis.


Assuntos
Artropatia Neurogênica/diagnóstico , Artropatia Neurogênica/genética , Coxa Vara/diagnóstico , Coxa Vara/genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Proteoglicanas/genética , Sinovite/diagnóstico , Sinovite/genética , Adolescente , Adulto , Criança , Pré-Escolar , Éxons/genética , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteoglicanas/metabolismo , Estudos Retrospectivos , Deleção de Sequência , Sequenciamento Completo do Exoma/métodos
17.
J Hum Genet ; 63(4): 517-520, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29410511

RESUMO

Overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features are the main symptoms of Weaver syndrome, a rare condition caused by mutations in EZH2 gene. Recently, in four patients with Weaver-like symptoms without mutations in EZH2 gene, pathogenic variants in EED were described. We present another patient clinically diagnosed with Weaver syndrome in whom WES revealed an EED de novo mutation affecting two neighboring aminoacids, NM_003797.3:c.917_919delinsCGG/p.(Arg306_Asn307delinsThrAsp) located in one allele (in cis). Our observation, together with previous reports suggests that EED gene testing is warranted in patients with the overgrowth syndrome features and suspicion of Weaver syndrome with normal results of EZH2 gene sequencing.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Substituição de Aminoácidos , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Mutação , Complexo Repressor Polycomb 2/genética , Alelos , Análise Mutacional de DNA , Facies , Humanos , Lactente , Masculino , Fenótipo , Sequenciamento Completo do Exoma
18.
J Clin Endocrinol Metab ; 103(4): 1470-1478, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29244146

RESUMO

Context: Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for histone H3 at lysine 27 (H3K27) trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome. Objective: To test alternative hypotheses that EZH2 variants found in Weaver syndrome cause either a gain of function or a partial loss of function. Design: Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos. Results: A de novo missense EZH2 mutation [c.1876G>A (p.Val626Met)] was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality, whereas heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation. Conclusion: We generated a mouse model with the same mutation as our patient, found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Histona-Lisina N-Metiltransferase/metabolismo , Mutação , Animais , Criança , Exoma , Histona Metiltransferases , Humanos , Masculino , Camundongos
19.
Am J Med Genet A ; 176(1): 219-224, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29159868

RESUMO

We report a family of Indian origin presenting with Tarsal-carpal coalition syndrome (TCC), which is a rare genetic disorder of skeletal abnormalities, inherited in autosomal dominant manner. In this family, three individuals (mother and two children) were found to be similarly affected with slight intrafamilial individual variability in the phenotype. Sanger sequencing revealed a novel heterozygous missense mutation in NOG gene (NM_005450.4:c.611G>A) in all the affected individuals of the family. Until now only six mutations have been reported in different families affected with TCC syndrome worldwide. This report further delineates the phenotypic spectrum of this rare disorder with the addition of a new variant to the mutation spectrum.


Assuntos
Ossos do Carpo/anormalidades , Proteínas de Transporte/genética , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Mutação de Sentido Incorreto , Fenótipo , Estribo/anormalidades , Sinostose/genética , Ossos do Tarso/anormalidades , Alelos , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Linhagem , Radiografia
20.
Congenit Anom (Kyoto) ; 58(3): 105-107, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28787104

RESUMO

Coffin-Siris syndrome (CSS) is characterized by growth deficiency, intellectual disability, microcephaly, dysmorphic features, and hypoplastic nails of the fifth fingers and/or toes. Variants in the genes encoding subunits of the BAF complex as well as in SOX11 encoding the transcriptional factor under the control of BAF complex are associated with CSS. We report a new patient with a novel SOX11 mutation. He showed the CSS phenotype and coarctation of the aorta. Sox11 is known to be associated with cardiac outflow development in mouse studies. Therefore, cardiac anomalies might be an important complication in patients with SOX11 mutations.


Assuntos
Anormalidades Múltiplas/genética , Coartação Aórtica/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Mutação , Pescoço/anormalidades , Fatores de Transcrição SOXC/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/patologia , Pré-Escolar , Angiografia por Tomografia Computadorizada , Ecocardiografia , Face/diagnóstico por imagem , Face/patologia , Expressão Gênica , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Masculino , Micrognatismo/diagnóstico por imagem , Micrognatismo/patologia , Pescoço/diagnóstico por imagem , Pescoço/patologia , Fenótipo
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