RESUMO
The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.
Assuntos
Anormalidades Múltiplas/genética , Dosagem de Genes/genética , Deficiência Intelectual/genética , Microcefalia/genética , Acil-CoA Desidrogenase de Cadeia Longa/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas Reguladoras de Apoptose , Receptor de Asialoglicoproteína/genética , Sequência de Bases , Linhagem Celular , Pontos de Quebra do Cromossomo , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Proteínas Desgrenhadas , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Proteínas Associadas aos Microtúbulos/genética , Dados de Sequência Molecular , Fosfoproteínas/genética , Estudos Retrospectivos , Análise de Sequência de DNA , Síndrome de Smith-Magenis , Síndrome , Peixe-ZebraRESUMO
BACKGROUND: X linked intellectual disability (XLID) is common, with an estimated prevalence of 1/1000. The expanded use of array comparative genomic hybridisation (CGH) has led to the identification of several XLID-associated copy-number variants. METHODS: Array CGH analysis was performed using chromosomal microarray with â¼105â000 oligonucleotides covering the entire genome. Confirmatory fluorescence in situ hybridisation analyses were subsequently performed. Chromosome X-inactivation (XCI) was assessed using methylation-sensitive restriction enzyme digestion followed by PCR amplification. RESULTS: A novel â¼0.5 Mb duplication in Xq28 was identified in four cognitively impaired males who share behavioural abnormalities (hyperactivity and aggressiveness) and characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip). These duplications were inherited from mothers with skewed XCI and are mediated by nonallelic homologous recombination between the low-copy repeat regions int22h-1 and int22h-2, which, in addition to int22h-3, are also responsible for inversions disrupting the factor VIII gene in haemophilia A. In addition, we have identified a reciprocal deletion in a girl and her mother, both of whom exhibit normal cognition and completely skewed XCI. The mother also had two spontaneous abortions. CONCLUSIONS: The phenotypic similarities among subjects with int22h-1/int22h-2-mediated Xq28 duplications suggest that such duplications are responsible for a novel XLID syndrome. The reciprocal deletion may not be associated with a clinical phenotype in carrier females due to skewed XCI, but may be lethal for males in utero. Advancements in array CGH technology have enabled the identification of such small, clinically relevant copy-number variants.
Assuntos
Cromossomos Humanos X/genética , Deficiência Intelectual/genética , Transtornos dos Cromossomos Sexuais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Biologia Computacional , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Feminino , Genoma Humano , Hemofilia A/genética , Hemofilia A/patologia , Recombinação Homóloga , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/patologia , Masculino , Linhagem , Fenótipo , Duplicações Segmentares Genômicas , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/patologia , Inativação do Cromossomo XRESUMO
Interstitial deletions of the short arm of chromosome 6 are rare and have been associated with developmental delay, hypotonia, congenital anomalies, and dysmorphic features. We used array comparative genomic hybridization in a South Carolina Autism Project (SCAP) cohort of 97 subjects with autism spectrum disorders (ASDs) and identified an ~ 5.4 Mb deletion on chromosome 6p22.3-p23 in a 15-year-old patient with intellectual disability and ASDs. Subsequent database queries revealed five additional individuals with overlapping submicroscopic deletions and presenting with developmental and speech delay, seizures, behavioral abnormalities, heart defects, and dysmorphic features. The deletion found in the SCAP patient harbors ATXN1, DTNBP1, JARID2, and NHLRC1 that we propose may be responsible for ASDs and developmental delay.