RESUMEN
We report on a female patient with Dandy-Walker malformation possibly caused by heterozygous loss of ZIC1 and ZIC4. The patient presented with mental retardation, epilepsy, and multiple congenital malformations including spina bifida, mild dysmorphic facial features including, thick eyebrows, broad nose, full lips, macroglossia, and hypoplasia of the cerebellar vermis with enlargement of the fourth ventricle on brain magnetic resonance imaging, which is consistent with Dandy-Walker malformation. A chromosome analysis showed interstitial deletion of chromosome 3q23-q25.1. Fluorescence in situ hybridization (FISH) and microarray-based genomic analysis revealed the heterozygous deletion of ZIC1 and ZIC4 loci on 3q24. Her facial features were not consistent with those observed in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) involving FOXL2 abnormality. Other deleted genes at 3q23-25.1 might contribute to the dysmorphic facial appearance. A milder phenotype as the Dandy-Walker malformation in our patient supports the idea that modifying loci/genes can influence the development of cerebellar malformation.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 3/genética , Síndrome de Dandy-Walker/genética , Proteínas del Tejido Nervioso/genética , Fenotipo , Factores de Transcripción/genética , Síndrome de Dandy-Walker/patología , Femenino , Humanos , Hibridación Fluorescente in Situ , Análisis por MicromatricesRESUMEN
We report on complex rearrangements of the 7q21.3 region in a female patient with bilateral split-foot malformation and hearing loss. G-banding karyotype was 46,XX,t(7;15)(q21;q15),t(9;14)(q21;q11.2)dn. By fluorescence, in situ hybridization (FISH), Southern hybridization, and inverse PCR, the 7q21.3 translocation breakpoint was determined at the nucleotide level. The breakpoint did not disrupt any genes, but was mapped to 38-kb telomeric to the DSS1 gene, and 258- and 272-kb centromeric to the DLX6 and DLX5 genes, respectively. It remains possible that the translocation would disrupt the interaction between these genes and their regulatory elements. Interestingly, microarray analysis also revealed an interstitial deletion close to (but not continuous to) the 7q21.3 breakpoint, indicating complex rearrangements within the split-hand/foot malformation 1 (SHFM1) locus in this patient. Furthermore, a 4.6-Mb deletion at 15q21.1-q21.2 adjacent to the 15q15 breakpoint was also identified. Cloning of the deletion junction at 7q21.3 revealed that the 0.8-Mb deletion was located 750-kb telomeric to the translocation breakpoint, encompassing TAC1, ASNS, OCM, and a part of LMTK2. Because TAC1, ASNS, and OCM genes were located on the reported copy number variation regions, it was less likely that the three genes were related to the split-foot malformation. LMTK2 appeared to be a potential candidate gene for SHFM1, but no LMTK2 mutations were found in 29 individuals with SHFM. Further LMTK2 analysis of SHFM patients together with hearing loss is warranted.
Asunto(s)
Cromosomas Humanos Par 7 , Deformidades Congénitas del Pie/genética , Eliminación de Gen , Pérdida Auditiva/genética , Translocación Genética , Secuencia de Bases , Niño , Bandeo Cromosómico , Rotura Cromosómica , Análisis Mutacional de ADN , Femenino , Deformidades Congénitas del Pie/diagnóstico por imagen , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Análisis de Secuencia por Matrices de Oligonucleótidos , Mapeo Físico de Cromosoma , RadiografíaAsunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 21 , Síndrome de Down/genética , Adulto , Preescolar , Femenino , Humanos , Masculino , FenotipoAsunto(s)
Cromosomas Humanos Par 21 , Síndrome de Down/genética , Trisomía , Aneuploidia , Centrómero , Bandeo Cromosómico , Rotura Cromosómica , Pintura Cromosómica , Cromosomas Humanos Par 13/genética , Síndrome de Down/patología , Femenino , Colorantes Fluorescentes , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación , MetafaseRESUMEN
Array using 2,173 BAC clones covering the whole human genome has been constructed. All clones spotted were confirmed to show a unique signal at the predicted chromosomal location by FISH analysis in our laboratory. A total of 30 individuals with idiopathic mental retardation (MR) were analyzed by comparative genomic hybridization using this array. Three deletions, one duplication, and one unbalanced translocation could be detected in five patients, which are likely to contribute to MR. The constructed array was shown to be an efficient tool for the detection of pathogenic genomic rearrangements in MR patients as well as copy number polymorphisms (CPNs).
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Artificiales Bacterianos/genética , Genoma Humano , Discapacidad Intelectual/genética , Hibridación de Ácido Nucleico/métodos , Bandeo Cromosómico , Deleción Cromosómica , Femenino , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/etiología , Cariotipificación , Masculino , Translocación GenéticaRESUMEN
A 2-year-old boy with clinical manifestations of monosomy 9p syndrome and brown hair is described. G-banding and chromosome FISH studies demonstrated complex rearrangements involving seven breakpoints in chromosomes 2 and 9, which included a 6.6-Mb deletion at 9p22.2-p23. This, together with previous studies in the literature, narrowed the shortest region of overlap (SRO) for the syndrome to a 4.7-Mb interval. Candidate genes for trigonocephaly, mental retardation, and brown hair are discussed.
