RESUMEN
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.
Asunto(s)
Anomalías Múltiples/genética , Dosificación de Gen/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas Reguladoras de la Apoptosis , Receptor de Asialoglicoproteína/genética , Secuencia de Bases , Línea Celular , Puntos de Rotura del Cromosoma , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Proteínas Dishevelled , Citometría de Flujo , Humanos , Inmunohistoquímica , Proteínas Asociadas a Microtúbulos/genética , Datos de Secuencia Molecular , Fosfoproteínas/genética , Estudios Retrospectivos , Análisis de Secuencia de ADN , Síndrome de Smith-Magenis , Síndrome , Pez CebraRESUMEN
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.
Asunto(s)
Cromosomas Humanos X/genética , Discapacidad Intelectual/genética , Trastornos de los Cromosomas Sexuales/genética , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Duplicación Cromosómica , Mapeo Cromosómico , Hibridación Genómica Comparativa , Biología Computacional , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Femenino , Genoma Humano , Hemofilia A/genética , Hemofilia A/patología , Recombinación Homóloga , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/patología , Masculino , Linaje , Fenotipo , Duplicaciones Segmentarias en el Genoma , Aberraciones Cromosómicas Sexuales , Trastornos de los Cromosomas Sexuales/patología , Inactivación del Cromosoma XRESUMEN
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.