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Nat Genet ; 49(2): 249-255, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28067911


Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

Atresia das Cóanas/genética , Proteínas Cromossômicas não Histona/genética , Microftalmia/genética , Mutação de Sentido Incorreto/genética , Nariz/anormalidades , Animais , Linhagem Celular , Pré-Escolar , Epigênese Genética/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distrofia Muscular Facioescapuloumeral/genética , Xenopus laevis/genética
J Med Genet ; 53(8): 523-32, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27075013


BACKGROUND: AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children. METHODS: We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist. RESULTS: All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo. CONCLUSIONS: The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.

Deficiência Intelectual/genética , Transtornos Mentais/genética , Proteínas/genética , Adulto , Criança , Pré-Escolar , Éxons/genética , Feminino , Estudos de Associação Genética/métodos , Haploinsuficiência/genética , Humanos , Lactente , Masculino , Microcefalia/genética , Pessoa de Meia-Idade , Mutação/genética , Fenótipo , Deleção de Sequência/genética , Síndrome , Adulto Jovem
Am J Med Genet A ; 167A(10): 2231-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26079862


De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase-activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi-gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss-of-function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate-to-severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide-based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 Wiley Periodicals, Inc.

Heterozigoto , Deficiência Intelectual/genética , Mutação , Proteínas Ativadoras de ras GTPase/genética , Adolescente , Criança , Pré-Escolar , Constipação Intestinal/diagnóstico , Constipação Intestinal/genética , Constipação Intestinal/patologia , Análise Mutacional de DNA , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/genética , Transtornos Neurológicos da Marcha/patologia , Expressão Gênica , Haploinsuficiência , Luxação do Quadril/diagnóstico , Luxação do Quadril/genética , Luxação do Quadril/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Fenótipo , Estrabismo/diagnóstico , Estrabismo/genética , Estrabismo/patologia , Gêmeos Monozigóticos
J Med Genet ; 51(12): 806-13, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25342064


BACKGROUND: De novo mutations are emerging as an important cause of neurocognitive impairment, and whole exome sequencing of case-parent trios is a powerful way of detecting them. Here, we report the findings in four such trios. METHODS: The Deciphering Developmental Disorders study is using whole exome sequencing in family trios to investigate children with severe, sporadic, undiagnosed developmental delay. Three of our patients were ascertained from the first 1133 children to have been investigated through this large-scale study. Case 4 was a phenotypically isolated case recruited into an undiagnosed rare disorders sequencing study. RESULTS: Protein-altering de novo mutations in PURA were identified in four subjects. They include two different frameshifts, one inframe deletion and one missense mutation. PURA encodes Pur-α, a highly conserved multifunctional protein that has an important role in normal postnatal brain development in animal models. The associated human phenotype of de novo heterozygous mutations in this gene is variable, but moderate to severe neurodevelopmental delay and learning disability are common to all. Neonatal hypotonia, early feeding difficulties and seizures, or 'seizure-like' movements, were also common. Additionally, it is suspected that anterior pituitary dysregulation may be within the spectrum of this disorder. Psychomotor developmental outcomes appear variable between patients, and we propose a possible genotype-phenotype correlation, with disruption of Pur repeat III resulting in a more severe phenotype. CONCLUSIONS: These findings provide definitive evidence for the role of PURA in causing a variable syndrome of neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements and epilepsy in humans, and help clarify the role of PURA in the previously described 5q31.3 microdeletion phenotype.

Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Transtornos de Aprendizagem/genética , Mutação , Fatores de Transcrição/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Encéfalo/patologia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/química , Deficiências do Desenvolvimento/diagnóstico , Exoma , Facies , Feminino , Ordem dos Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Transtornos de Aprendizagem/diagnóstico , Imagem por Ressonância Magnética , Modelos Moleculares , Fenótipo , Conformação Proteica , Fatores de Transcrição/química
J Med Genet ; 51(10): 659-68, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25125236


BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. CONCLUSIONS: Future diagnostic testing in 'mutation-negative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

Síndrome de Lange/genética , Heterogeneidade Genética , Mosaicismo , Face/patologia , Estudos de Associação Genética , Humanos , Mutação , Fenótipo