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1.
Hum Mutat ; 43(5): 582-594, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35170830

RESUMO

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.


Assuntos
Otopatias , Orelha/anormalidades , Otopatias/genética , Humanos , Linhagem , Fenótipo
3.
Genet Med ; 21(6): 1295-1307, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30349098

RESUMO

PURPOSE: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. METHODS: Clinicians entered clinical data in an extensive web-based survey. RESULTS: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. CONCLUSION: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Proteínas Cromossômicas não Histona/genética , Exoma , Face/anormalidades , Feminino , Estudos de Associação Genética/métodos , Variação Genética/genética , Deformidades Congênitas da Mão/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Micrognatismo/genética , Pessoa de Meia-Idade , Mutação , Pescoço/anormalidades , Penetrância
4.
J Med Genet ; 50(3): 174-86, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23315542

RESUMO

BACKGROUND: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, ß 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. RESULTS: We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. CONCLUSIONS: These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.


Assuntos
Otopatias/genética , Orelha/anormalidades , Mutação , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Orelha/patologia , Otopatias/patologia , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Linhagem , Fosfolipase C beta/genética , Reação em Cadeia da Polimerase
5.
Hum Genomics ; 6: 12, 2012 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-23244495

RESUMO

Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder with an increased susceptibility to develop both benign and malignant tumors but with a wide spectrum of inter and intrafamilial clinical variability. The establishment of genotype-phenotype associations in NF1 is potentially useful for targeted therapeutic intervention but has generally been unsuccessful, apart from small subsets of molecularly defined patients. The objective of this study was to evaluate the clinical phenotype associated with the specific types of NF1 mutation in a retrospectively recorded clinical dataset comprising 149 NF1 mutation-known individuals from unrelated families. Each patient was assessed for ten NF1-related clinical features, including the number of café-au-lait spots, cutaneous and subcutaneous neurofibromas and the presence/absence of intertriginous skin freckling, Lisch nodules, plexiform and spinal neurofibromas, optic gliomas, other neoplasms (in particular CNS gliomas, malignant peripheral nerve sheath tumors (MPNSTs), juvenile myelomonocytic leukemia, rhabdomyosarcoma, phaechromocytoma, gastrointestinal stromal tumors, juvenile xanthogranuloma, and lipoma) and evidence of learning difficulties. Gender and age at examination were also recorded. Patients were subcategorized according to their associated NF1 germ line mutations: frame shift deletions (52), splice-site mutations (23), nonsense mutations (36), missense mutations (32) and other types of mutation (6). A significant association was apparent between possession of a splice-site mutation and the presence of brain gliomas and MPNSTs (p = 0.006). If confirmed, these findings are likely to be clinically important since up to a third of NF1 patients harbor splice-site mutations. A significant influence of gender was also observed on the number of subcutaneous neurofibromas (females, p = 0.009) and preschool learning difficulties (females, p = 0.022).


Assuntos
Estudos de Associação Genética , Neurofibromatose 1/diagnóstico , Neurofibromina 1/genética , Sítios de Splice de RNA , Adolescente , Adulto , Idoso , Manchas Café com Leite/complicações , Manchas Café com Leite/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Neurofibroma/complicações , Neurofibroma/genética , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Glioma do Nervo Óptico/complicações , Glioma do Nervo Óptico/genética , Fatores de Risco , Fatores Sexuais , Adulto Jovem
6.
Nat Genet ; 42(7): 619-25, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20512146

RESUMO

Joubert syndrome (JBTS), related disorders (JSRDs) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.


Assuntos
Anormalidades Múltiplas/genética , Cílios/patologia , Proteínas de Membrana/genética , Mutação , Anormalidades Múltiplas/patologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Consanguinidade , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Gastrulação/genética , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Hibridização In Situ , Judeus/genética , Microscopia Confocal , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Interferência de RNA , Síndrome , Peixe-Zebra/embriologia , Peixe-Zebra/genética
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