RESUMEN
Typical Xq25 duplications are large and associated with heterogeneous phenotypes. Recently, small duplications involving this genomic region and encompassing the GRIA3 and STAG2 genes have been reported. These Xq25 microduplications are associated with a recognizable syndrome including intellectual disability and distinctive facial appearance. We report on Xq25 microduplications in two unrelated families identified by array comparative genomic hybridization. In both families, the genomic imbalances segregated with the disease in male individuals, while the phenotypes of the heterozygous females appeared to be modulated by their X-inactivation pattern. These rearrangements of about 600 kb involved only three genes: THOC2, XIAP, and STAG2. Further characterization by FISH analyses showed tandem duplication in the Xq25 locus of these genes. These data refine the Xq25 candidate region, identifying a minimal duplicated region of about 270 kb encompassing the XIAP and STAG2 genes. We discuss the function of the genes in the rearrangements and their involvement in the pathogenesis of this disorder.
Asunto(s)
Antígenos Nucleares/genética , Duplicación Cromosómica , Trisomía/diagnóstico , Trisomía/genética , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Adolescente , Adulto , Anciano , Encéfalo/patología , Proteínas de Ciclo Celular , Niño , Preescolar , Puntos de Rotura del Cromosoma , Mapeo Cromosómico , Cromosomas Humanos X/genética , Hibridación Genómica Comparativa , Exones , Facies , Femenino , Estudios de Asociación Genética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Aberraciones Cromosómicas Sexuales , Síndrome , Adulto JovenRESUMEN
Molecular defects affecting the ATRX gene lead to the ATRX syndrome (alpha thalassemia/mental retardation syndrome, X-linked), characterized by severe mental retardation, microcephaly, distinct facial dysmorphism, and genital abnormalities, as well as a wide spectrum of other pathological features. Alpha thalassemia is frequent but does not represent a constant characteristic of the syndrome. An expanding phenotype of the ATRX gene (a RAD54 homologue encoding a putative zinc-finger helicase) has been demonstrated as a result of the association of single mutations with specific X-linked mental retardation syndromes. To date, mutational analysis of the gene has been based on direct DNA sequencing or using methods with a lower detection rate. In this paper, we present a broad-range DGGE method for single-step mutation scanning of the entire open reading frame (ORF) and canonical splice sites of the gene. Using this method, we successfully identified five novel sequence changes in the ATRX gene, including four missense mutations (K1733E, R2085C, D2136N, T2169A) and one polymorphism (IVS5+35G>A).
Asunto(s)
ADN Helicasas/genética , Análisis Mutacional de ADN/métodos , Electroforesis en Gel de Poliacrilamida/métodos , Proteínas Nucleares/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Cromosomas Humanos X/genética , ADN/química , ADN/genética , Ligamiento Genético , Humanos , Discapacidad Intelectual/complicaciones , Mutación , Sensibilidad y Especificidad , Síndrome , Proteína Nuclear Ligada al Cromosoma X , Talasemia alfa/complicacionesRESUMEN
Interstitial duplications involving chromosome 11q have rarely been reported in the literature and mainly represent large, cytogenetically detectable rearrangements associated with a wide and variable spectrum of neurodevelopmental disorders. We report on a patient affected by intellectual disability, craniosynostosis, and microcephaly. Array-CGH analysis identified a de novo 290 kb interstitial duplication of chromosome 11q13.3 including the FGF3 and FGF4 genes. Clinical comparison of our patient with those previously reported with overlapping 11q duplications allows us to define the minimal duplicated region associated with craniosynostosis and strongly supports the hypothesis that the constitutional increased dosage of the FGF3 and FGF4 genes is a risk factor for craniosynostosis in humans.
Asunto(s)
Craneosinostosis/genética , Factor 3 de Crecimiento de Fibroblastos/genética , Factor 4 de Crecimiento de Fibroblastos/genética , Dosificación de Gen , Niño , Cromosomas Humanos Par 11 , Humanos , Discapacidad Intelectual/genética , Masculino , Microcefalia/genética , Factores de RiesgoRESUMEN
BACKGROUND: Despite the extensive use of chromosomal microarray technologies in patients with neurodevelopmental disorders has permitted the identification of an increasing number of causative submicroscopic rearrangements throughout the genome, constitutional duplications involving chromosome 1q22 have seldom been described in those patients. RESULTS: We report on a pedigree with seven affected members showing varying degrees of behavioural and emotional disturbances including general anxiety disorder, mood disorders, and intellectual disability. Two adult female patients also showed late onset autoimmune inflammatory responses characterized by alopecia, skin ulcers secondary to inflammatory vasculitis, interstitial lung disease, and Raynaud's phenomenon. Array-CGH analysis identified in the affected individuals a 290 Kb microduplication in the chromosome 1q22. The rearrangement involves eleven known genes and is not present in the databases of polymorphic copy number variants. CONCLUSIONS: The rearrangement segregates with the neurological clinical features observed in our patients, suggesting that dosage imbalance of one or more genes in this genomic region may lead to the observed phenotype. The association between the microduplication and the inflammatory disease is much less evident. Additional reported patients carrying similar microduplications are needed to clarify this aspect.