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-Zebra