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1.
BMC Med Genet ; 16: 41, 2015 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-26104215

RESUMO

BACKGROUND: Cohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits. METHODS: Clinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations. RESULTS: We identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population. CONCLUSION: We suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.


Assuntos
Anormalidades Múltiplas/genética , Transtorno Autístico/patologia , Dedos/anormalidades , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Microcefalia/genética , Microcefalia/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Miopia/genética , Miopia/patologia , Obesidade/genética , Obesidade/patologia , Fenótipo , Deleção de Sequência/genética , Proteínas de Transporte Vesicular/genética , Transtorno Autístico/genética , Sequência de Bases , Deficiências do Desenvolvimento/classificação , Deficiências do Desenvolvimento/etnologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Feminino , Dedos/patologia , Genes Recessivos , Genótipo , Haplótipos/genética , Homozigoto , Humanos , Deficiência Intelectual/classificação , Deficiência Intelectual/etnologia , Masculino , Microcefalia/classificação , Microcefalia/etnologia , Dados de Sequência Molecular , Hipotonia Muscular/classificação , Hipotonia Muscular/etnologia , Miopia/classificação , Miopia/etnologia , Obesidade/classificação , Obesidade/etnologia , Paquistão , Linhagem , Degeneração Retiniana , Análise de Sequência de DNA
2.
Am J Med Genet B Neuropsychiatr Genet ; 165B(4): 303-13, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24700553

RESUMO

Genome-wide single nucleotide polymorphism (SNP) data from 936 bipolar disorder (BD) individuals and 940 psychiatrically healthy comparison individuals of North European descent were analyzed for copy number variation (CNV). Using multiple CNV calling algorithms, and validating using in vitro molecular analyses, we identified CNVs implicating several candidate genes that encode synaptic proteins, such as DLG1, DLG2, DPP6, NRXN1, NRXN2, NRXN3, SHANK2, and EPHA5, as well as the neuronal splicing regulator RBFOX1 (A2BP1), and neuronal cell adhesion molecule CHL1. We have also identified recurrent CNVs on 15q13.3 and 16p11.2-regions previously reported as risk loci for neuropsychiatric disorders. In addition, we performed CNV analysis of individuals from 215 BD trios and identified de novo CNVs involving the NRXN1 and DRD5 genes. Our study provides further evidence of the occasional involvement of genomic mutations in the etiology of BD, however, there is no evidence of an increased burden of CNVs in BD. Further, the identification of CNVs at multiple members of the neurexin gene family in BD individuals, supports the role of synaptic disruption in the etiology of BD.


Assuntos
Transtorno Bipolar/genética , Variações do Número de Cópias de DNA/genética , Sinapses/genética , Proteínas de Ligação ao Cálcio , Canadá , Estudos de Casos e Controles , Moléculas de Adesão Celular Neuronais/genética , Humanos , Proteínas do Tecido Nervoso/genética , Moléculas de Adesão de Célula Nervosa , Reprodutibilidade dos Testes , Reino Unido , Adulto Jovem
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