RESUMO
Array comparative genomic hybridization (aCGH) is now widely adopted as a first-tier clinical diagnostic test for patients with developmental delay (DD)/intellectual disability (ID), autism spectrum disorders, and multiple congenital anomalies. Nevertheless, classic karyotyping still has its impact in diagnosing genetic diseases, particularly mosaic cases. We report on a 30 year old patient with syndromic intellectual disability, a 22q13.2 microdeletion and mosaic trisomy 22. The patient had the following clinical features: intrauterine growth retardation at birth, hypotonia, cryptorchidism, facial asymmetry, enophthalmus, mild prognathism, bifid uvula, hypoplastic upper limb phalanges, DD including speech delay, and ID. Whole genome aCGH showed a de novo 1 Mb interstitial heterozygous deletion in 22q13.2, confirmed by fluorescence in situ hybridization in all cells examined. Moreover, 18% cells had an extra chromosome 22 suggesting a trisomy 22 mosaicism. Almost all 22q13 deletions published so far have been terminal deletions with variable sizes (100 kb to over 9 Mb). Very few cases of interstitial 22q13.2 deletions were reported. In its mosaic form, trisomy 22 is compatible with life, and there are about 20 reports in the literature. It has a variable clinical presentation: growth restriction, dysmorphic features, cardiovascular abnormalities, hemihyperplasia, genitourinary tract anomalies and ID. Neurodevelopmental outcome ranges from normal to severe DD. The patient presents clinical features that are common to both the interstitial 22q13 deletion and the mosaic trisomy 22; characteristics related to the interstitial deletion alone and others explained solely by the mosaic trisomy. Our case points out the role of conventional cytogenetic tools in mosaic cases that could be missed by microarray technology. We therefore suggest the combination of both conventional and molecular karyotyping in the investigation of certain genetic diseases.
Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22 , Deficiência Intelectual/genética , Trissomia/genética , Dissomia Uniparental/genética , Adulto , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Hibridização Genômica Comparativa/métodos , Deficiências do Desenvolvimento/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , MosaicismoRESUMO
We report on a 22-year-old woman with features of osteogenesis imperfecta (OI), tricho-dento-osseous (TDO) syndrome and intellectual disability. Whole genome oligonucleotide microarray analysis revealed a copy number gain of 3 Mb in 7q32.3-q33 and a loss of 3.4 Mb in 17q21.33-q22. FISH analysis showed that the third copy of 7q32 was inserted into the long arm of one chromosome 17, exactly in the region 17q21.33-q22 that was deleted. The maternal uncle presented with clinical features similar to the proposita and had the same chromosomal anomalies. The mother of the proposita and two other family members were balanced carriers of this rearrangement, interpreted as an interchromosomal reciprocal insertion. Reciprocal insertion/four-break rearrangement is a very rare chromosomal event. The deleted region on chromosome 17 contains 39 genes, including COL1A1 and DLX3 involved in OI and TDO syndrome respectively. The CACNA1G gene on the deleted segment of chromosome 17 may be a good candidate gene to explain the intellectual impairment. © 2013 Wiley Periodicals, Inc.
Assuntos
Anormalidades Craniofaciais/genética , Hipoplasia do Esmalte Dentário/genética , Doenças do Cabelo/genética , Deficiência Intelectual/genética , Osteogênese Imperfeita/genética , Duplicação Cromossômica , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 7 , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Hibridização Genômica Comparativa , Anormalidades Craniofaciais/diagnóstico , Hipoplasia do Esmalte Dentário/diagnóstico , Feminino , Doenças do Cabelo/diagnóstico , Proteínas de Homeodomínio/genética , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Osteogênese Imperfeita/diagnóstico , Linhagem , Fenótipo , Deleção de Sequência , Síndrome , Fatores de Transcrição/genética , Adulto JovemRESUMO
Ocular coloboma, heart malformation, choanal atresia, retardation of growth and/or development, genital hypoplasia, and ear anomalies associated with deafness (CHARGE) syndrome is a rare, usually sporadic, autosomal dominant disorder, caused by mutations within the CHD7 (chromodomain helicase DNA-binding protein 7) gene, in nearly 70% of cases. Because human CHD7 is relatively large (38 exons encoding a 300-kDa protein), genetic analysis requires cost-effective and time-consuming techniques. Herein, we propose an alternative screening method to quickly detect CHD7 mutations using mainly denaturing high-performance liquid chromatography. The entire coding region with exon-intron boundaries was amplified under the same experimental conditions. Each amplicon of the same CHD7 region was subjected to denaturing high-performance liquid chromatography analysis, and resulting chromatograms were compared within small series of patients. Because a CHD7 mutation differs generally from one patient to another, corresponding chromatograms exhibited a unique pattern that is significantly different from common polymorphisms. Only amplicons exhibiting a unique profile were subjected to DNA sequencing analysis. Intragenic rearrangements were investigated with only nine multiplex PCRs. In conclusion, using our protocol, we can quickly detect the right containing mutation amplicon and we provide a robust, rapid, and cheaper method to screen CHD7 microrearrangements or an entire deletion.
