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1.
Genet Med ; 21(7): 1667-1671, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30783266

RESUMO

The article has been corrected to account for one patient being investigated through genome sequencing rather than exome sequencing as originally published; thus amendments to the Abstract and Methods have been made as well as addition of the relevant authors and acknowledgment.

2.
Genet Med ; 21(6): 1308-1318, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30356099

RESUMO

PURPOSE: Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations. METHODS: We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing), genome sequencing. RESULTS: Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes. CONCLUSION: Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.

3.
Am J Med Genet A ; 170A(5): 1115-26, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26971886

RESUMO

Cerebro-Costo-Mandibular syndrome (CCMS) is a rare autosomal dominant condition comprising branchial arch-derivative malformations with striking rib-gaps. Affected patients often have respiratory difficulties, associated with upper airway obstruction, reduced thoracic capacity, and scoliosis. We describe a series of 12 sporadic and 4 familial patients including 13 infants/children and 3 adults. Severe micrognathia and reduced numbers of ribs with gaps are consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis are common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defect may occur. Microcephaly and significant developmental delay are present in a small minority of patients. Key radiological findings are of a narrow thorax, multiple posterior rib gaps and abnormal costo-transverse articulation. A novel finding in 2 patients is bilateral accessory ossicles arising from the hyoid bone. Recently, specific mutations in SNRPB, which encodes components of the major spliceosome, have been found to cause CCMS. These mutations cluster in an alternatively spliced regulatory exon and result in altered SNRPB expression. DNA was available from 14 patients and SNRPB mutations were identified in 12 (4 previously reported). Eleven had recurrent mutations previously described in patients with CCMS and one had a novel mutation in the alternative exon. These results confirm the specificity of SNRPB mutations in CCMS and provide further evidence for the role of spliceosomal proteins in craniofacial and thoracic development.


Assuntos
Anormalidades Múltiplas/genética , Fissura Palatina/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Costelas/anormalidades , Proteínas Centrais de snRNP/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Pré-Escolar , Fissura Palatina/complicações , Fissura Palatina/fisiopatologia , Éxons , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Micrognatismo/complicações , Micrognatismo/fisiopatologia , Mutação , Costelas/crescimento & desenvolvimento , Costelas/fisiopatologia , Escoliose/complicações , Escoliose/genética , Escoliose/fisiopatologia , Spliceossomos/genética
4.
J Clin Endocrinol Metab ; 99(6): E1067-71, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24606082

RESUMO

BACKGROUND: Maturity-onset diabetes of the young (MODY) is uncommon; however, accurate diagnosis facilitates personalized management and informs prognosis in probands and relatives. OBJECTIVE: The objective of the study was to highlight that the appropriate use of genetic and nongenetic investigations leads to the correct classification of diabetes etiology. CASE DISCUSSION: A 30-year-old European female was diagnosed with insulin-treated gestational diabetes. She discontinued insulin after delivery; however, her fasting hyperglycemia persisted. ß-Cell antibodies were negative and C-peptide was 0.79 nmol/L. Glucokinase (GCK)-MODY was suspected and confirmed by the identification of a GCK mutation (p.T206M). METHODS: Systematic clinical and biochemical characterization and GCK mutational analysis were implemented to determine the diabetes etiology in five relatives. Functional characterization of GCK mutations was performed. RESULTS: Identification of the p.T206M mutation in the proband's sister confirmed a diagnosis of GCK-MODY. Her daughter was diagnosed at 16 weeks with permanent neonatal diabetes (PNDM). Mutation analysis identified two GCK mutations that were inherited in trans-p. [(R43P);(T206M)], confirming a diagnosis of GCK-PNDM. Both mutations were shown to be kinetically inactivating. The proband's mother, other sister, and daughter all had a clinical diagnosis of type 1 diabetes, confirmed by undetectable C-peptide levels and ß-cell antibody positivity. GCK mutations were not detected. CONCLUSIONS: Two previously misclassified family members were shown to have GCK-MODY, whereas another was shown to have GCK-PNDM. A diagnosis of type 1 diabetes was confirmed in three relatives. This family exemplifies the importance of careful phenotyping and systematic evaluation of relatives after discovering monogenic diabetes in an individual.


Assuntos
Diabetes Mellitus Tipo 2/classificação , Diabetes Mellitus Tipo 2/etiologia , Diabetes Gestacional/diagnóstico , Transtornos Puerperais/diagnóstico , Adulto , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Linhagem , Gravidez
5.
Am J Med Genet A ; 164A(5): 1289-92, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24664873

RESUMO

Kabuki syndrome is a rare malformation syndrome characterized by a typical facial appearance, skeletal anomalies, cardiac malformation, and mild to moderate intellectual disability. In 55-80% of patients with Kabuki syndrome, a mutation in MLL2 is identified. Recently, eight patients with Kabuki syndrome and a mutation in KDM6A were described. In this report, we describe two brothers with a mutation in KDM6A inherited from their mother and maternal grandmother. The two boys have Kabuki-like phenotypes whereas the mother and grandmother present with attenuated phenotypes. This family represents the first instance of hereditary X-linked Kabuki syndrome. We present a short literature review of the patients described with a mutation in KDM6A.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Face/anormalidades , Mutação da Fase de Leitura , Genes Ligados ao Cromossomo X , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Histona Desmetilases/genética , Proteínas Nucleares/genética , Fenótipo , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/genética , Adulto , Facies , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Linhagem , Gravidez , Diagnóstico Pré-Natal
6.
Am J Med Genet A ; 161A(12): 2972-80, 2013 12.
Artigo em Inglês | MEDLINE | ID: mdl-24214728

RESUMO

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Complexo Repressor Polycomb 2/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/fisiopatologia , Deficiências do Desenvolvimento , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Transtornos do Crescimento/complicações , Transtornos do Crescimento/fisiopatologia , Deformidades Congênitas da Mão/complicações , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Fenótipo , Síndrome de Sotos/genética , Síndrome de Sotos/fisiopatologia
7.
Nat Genet ; 44(7): 793-6, 2012 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-22610116

RESUMO

Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Cardiomegalia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hipertricose/genética , Mutação de Sentido Incorreto , Osteocondrodisplasias/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Adulto , Linhagem Celular Transformada , Criança , Pré-Escolar , Exoma , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Lactente , Recém-Nascido , Canais KATP/genética , Masculino , Estrutura Terciária de Proteína/genética , Receptores Sulfonilureia , Adulto Jovem
8.
Hum Mol Genet ; 20(8): 1547-59, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21262861

RESUMO

SHOX (short stature homeobox-containing gene) encodes a transcription factor implicated in skeletal development. SHOX haploinsufficiency has been demonstrated in Leri-Weill dyschondrosteosis (LWD), a skeletal dysplasia associated with disproportionate short stature, as well as in a variable proportion of cases with idiopathic short stature (ISS). In order to gain insight into the SHOX signalling pathways, we performed a yeast two-hybrid screen to identify SHOX-interacting proteins. Two transcription factors, SOX5 and SOX6, were identified. Co-immunoprecipitation assays confirmed the existence of the SHOX-SOX5 and SHOX-SOX6 interactions in human cells, whereas immunohistochemical studies demonstrated the coexpression of these proteins in 18- and 32-week human fetal growth plates. The SHOX homeodomain and the SOX6 HMG domain were shown to be implicated in the SHOX-SOX6 interaction. Moreover, different SHOX missense mutations, identified in LWD and ISS patients, disrupted this interaction. The physiological importance of these interactions was investigated by studying the effect of SHOX on a transcriptional target of the SOX trio, Agc1, which encodes one of the main components of cartilage, aggrecan. Our results show that SHOX cooperates with SOX5/SOX6 and SOX9 in the activation of the upstream Agc1 enhancer and that SHOX mutations affect this activation. In conclusion, we have identified SOX5 and SOX6 as the first two SHOX-interacting proteins and have shown that this interaction regulates aggrecan expression, an essential factor in chondrogenesis and skeletal development.


Assuntos
Elementos Facilitadores Genéticos , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição SOXD/metabolismo , Agrecanas/genética , Animais , Condrogênese/genética , Desenvolvimento Fetal/genética , Genes Reporter , Transtornos do Crescimento/genética , Lâmina de Crescimento/embriologia , Lâmina de Crescimento/metabolismo , Células HEK293 , Proteínas de Homeodomínio/genética , Humanos , Imunoprecipitação , Luciferases de Vaga-Lume/biossíntese , Luciferases de Vaga-Lume/genética , Camundongos , Complexos Multiproteicos/metabolismo , Mutação de Sentido Incorreto , Osteocondrodisplasias/genética , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes de Fusão/metabolismo , Proteína de Homoeobox de Baixa Estatura , Técnicas do Sistema de Duplo-Híbrido
9.
Am J Hum Genet ; 87(6): 905-14, 2010 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-21129721

RESUMO

CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development.


Assuntos
3-Hidroxiesteroide Desidrogenases/genética , Anormalidades Múltiplas/genética , Alelos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Temperatura Ambiente , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Éxons , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Homologia de Sequência de Aminoácidos , Adulto Jovem
10.
Am J Med Genet A ; 143A(3): 258-64, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17236192

RESUMO

A series of 44 unrelated patients in whom COL2A1 screening demonstrated normal results but whose phenotype was nevertheless highly suggestive of either Stickler syndrome (with ocular involvement) or Marshall syndrome were investigated for mutations in the COL11A1 gene. Heterozygous COL11A1 mutations were found in 10 individuals. A splice site alteration (involving introns 47-55) was present in seven cases, with one in intron 50 (c.3816 + 1G > A) occurring in three patients. Two patients had a different deletion, and a missense mutation (Gly1471Asp) was observed in one case. In 4/10 patients the phenotype was classified as Marshall syndrome because of early-onset severe hearing loss and characteristic facial features. These four patients were all heterozygous for a splice site mutation in intron 50. One of these cases had a type 1 vitreous anomaly despite the presence of a COL11A1 mutation. The remaining 6/10 patients had an overlapping Marshall-Stickler phenotype with less pronounced facial features. None of these had a mutation in the hot spot region of intron 50.


Assuntos
Colágeno Tipo XI/genética , Doenças Genéticas Inatas/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Testes Genéticos , Heterozigoto , Humanos , Lactente , Masculino , Mutação , Fenótipo
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