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2.
Hum Mutat ; 34(1): 237-47, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23033313

RESUMO

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.


Assuntos
Deleção de Genes , Mutação , Síndromes Orofaciodigitais/genética , Proteínas/genética , Adolescente , Processamento Alternativo/genética , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Análise Mutacional de DNA , Éxons/genética , Saúde da Família , Feminino , Estudos de Associação Genética/métodos , Humanos , Lactente , Íntrons/genética , Imageamento por Ressonância Magnética , Masculino , Síndromes Orofaciodigitais/patologia , Linhagem , Inativação do Cromossomo X
3.
Eur J Hum Genet ; 18(10): 1100-6, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20512159

RESUMO

Warburg Micro Syndrome is a rare, autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. We have found five new mutations in the RAB3GAP1 gene in seven patients with suspected Micro Syndrome from families with Turkish, Palestinian, Danish, and Guatemalan backgrounds. A thorough clinical investigation of the patients has allowed the delineation of symptoms that are consistently present in the patients and may aid the differential diagnosis of Micro Syndrome for patients in the future. All patients had postnatal microcephaly, micropthalmia, microcornia, bilateral congenital cataracts, short palpebral fissures, optic atrophy, severe mental retardation, and congenital hypotonia with subsequent spasticity. Only one patient had microcephaly at birth, highlighting the fact that congenital microcephaly is not a consistent feature of Micro syndrome. Analysis of the brain magnetic resonance imagings (MRIs) revealed a consistent pattern of polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, a thin hypoplastic corpus callosum, and increased subdural spaces. All patients were homozygous for the mutations detected and all mutations were predicted to result in a truncated RAB3GAP1 protein. The analysis of nine polymorphic markers flanking the RAB3GAP1 gene showed that the mutation c.1410C>A (p.Tyr470X), for which a Danish patient was homozygous, occurred on a haplotype that is shared by the unrelated heterozygous parents of the patient. This suggests a possible founder effect for this mutation in the Danish population.


Assuntos
Encéfalo/patologia , Mutação , Proteínas rab3 de Ligação ao GTP/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Árabes , Encéfalo/anormalidades , Encéfalo/fisiopatologia , Catarata/congênito , Catarata/genética , Catarata/patologia , Cromossomos Humanos Par 2/genética , Córnea/anormalidades , Córnea/patologia , Dinamarca , Efeito Fundador , Marcadores Genéticos , Predisposição Genética para Doença , Guatemala , Humanos , Hipogonadismo/genética , Hipogonadismo/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Imageamento por Ressonância Magnética , Microcefalia/genética , Microcefalia/patologia , Atrofia Óptica/genética , Atrofia Óptica/patologia , Turquia
4.
Am J Med Genet A ; 143A(16): 1876-9, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17632775

RESUMO

FG syndrome was originally described as a rare syndromic cause of X-linked mental retardation associated with congenital heart disease, anal atresia, inguinal hernia, cryptorchidism, and other anomalies. However, recent reports have highlighted the more common milder presentation which has for cardinal features developmental delay, particularly in speech, neonatal hypotonia, relative macrocephaly, dysmorphic facial features, severe constipation, and few if any congenital malformations. Thus far, five separate loci have been identified on the X chromosome but attempts at finding the responsible gene have not yet been successful. Given that one putative FG locus (FGS2) is situated at Xq28, which is the location of the Filamin A gene (FLNA), and that a Filamin A mutation was reported in a boy with facial dysmorphism and constipation, it was hypothesized that Filamin A mutations could be one cause of FG syndrome. Indeed, a previously unreported FLNA missense mutation (P1291L) was detected in our patient with FG syndrome, thus supporting this hypothesis and indicating that FG syndrome could now be added to the list of Filamin A-related disorders. Filamin A studies in other children with FG syndrome would help to confirm this association.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas Contráteis/genética , Proteínas dos Microfilamentos/genética , Mutação , Canal Anal/anormalidades , Encéfalo/anormalidades , Cromossomos Humanos X , Proteínas Contráteis/metabolismo , Fácies , Filaminas , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Proteínas dos Microfilamentos/metabolismo , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Síndrome
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