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2.
BMC Med Genet ; 13: 84, 2012 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-22984989

RESUMO

BACKGROUND: Diagnostic analysis of patients with developmental disorders has improved over recent years largely due to the use of microarray technology. Array methods that facilitate copy number analysis have enabled the diagnosis of up to 20% more patients with previously normal karyotyping results. A substantial number of patients remain undiagnosed, however. METHODS AND RESULTS: Using the Genome-Wide Human SNP array 6.0, we analyzed 35 patients with a developmental disorder of unknown cause and normal array comparative genomic hybridization (array CGH) results, in order to characterize previously undefined genomic aberrations. We detected no seemingly pathogenic copy number aberrations. Most of the vast amount of data produced by the array was polymorphic and non-informative. Filtering of this data, based on copy number variant (CNV) population frequencies as well as phenotypically relevant genes, enabled pinpointing regions of allelic homozygosity that included candidate genes correlating to the phenotypic features in four patients, but results could not be confirmed. CONCLUSIONS: In this study, the use of an ultra high-resolution SNP array did not contribute to further diagnose patients with developmental disorders of unknown cause. The statistical power of these results is limited by the small size of the patient cohort, and interpretation of these negative results can only be applied to the patients studied here. We present the results of our study and the recurrence of clustered allelic homozygosity present in this material, as detected by the SNP 6.0 array.


Assuntos
Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Variações do Número de Cópias de DNA , Homozigoto , Humanos , Repetições de Microssatélites , Dissomia Uniparental
3.
Orphanet J Rare Dis ; 6: 45, 2011 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-21693067

RESUMO

BACKGROUND: Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400) due to haploinsufficiency of the PTCH1 gene (MIM *601309). METHODS AND RESULTS: We report two mentally retarded female siblings and their cognitively normal father, all carrying a similar 5.3 Mb microdeletion at 9q22.2q22.32, detected by array CGH (244 K). The deletion does not involve the PTCH1 gene, but instead 30 other gene,s including the ROR2 gene (MIM *602337) which causing both brachydactyly type 1 (MIM #113000) and Robinow syndrome (MIM #268310), and the immunologically active SYK gene (MIM *600085). The deletion in the father was de novo and FISH analysis of blood lymphocytes did not suggest mosaicism. All three patients share similar mild dysmorphic features with downslanting palpebral fissures, narrow, high bridged nose with small nares, long, deeply grooved philtrum, ears with broad helix and uplifted lobuli, and small toenails. All have significant dysarthria and suffer from continuous middle ear and upper respiratory infections. The father also has a funnel chest and unilateral hypoplastic kidney but the daughters have no malformations. CONCLUSIONS: This is the first report of a familial constitutional 9q22 deletion and the first deletion studied by array-CGH which does not involve the PTCH1 gene. The phenotype and penetrance are variable and the deletion found in the cognitively normal normal father poses a challenge in genetic counseling.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Deficiência Intelectual/genética , Adulto , Transtornos Dismórficos Corporais , Pré-Escolar , Hibridização Genômica Comparativa , Família , Feminino , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Tirosina Quinases/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Quinase Syk
4.
Am J Med Genet B Neuropsychiatr Genet ; 156B(4): 448-53, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21438145

RESUMO

We present a family with mild developmental delay and a duplication (6)(p22.2). Array CGH analyses revealed this 0.7 Mb duplication in all three patients, spanning candidate genes ALDH5A1, DCDC2, and KIAA0319. Results were confirmed by MLPA analysis of the dyslexia genes DCDC2 and KIAA0319. Of interest, ALDH5A1 encodes succinate semialdehyde dehydrogenase (SSADH), an enzyme responsible for γ-amino-butyric acid (GABA) degradation. Inherited deficiency of SSADH results in accumulation of the neuromodulator γ-hydroxybutyrate (GHB), which likely contributes to some aspects of the neurological phenotype of SSADH deficiency (MIM #271980). Based on autosomal-recessive inheritance, we sequenced ALDH5A1 in all patients, which revealed no pathogenic mutations. SSADH enzyme studies in cultured white cells confirmed elevated SSADH activity, consistent with the duplication, whereas concentrations of SSA were slightly elevated in urine, suggesting oxidant stress. We speculate that the duplication (6)(p22.2) and corresponding hyperactive level of SSADH activity may have negative consequences for GABA metabolism and the role of SSADH in other metabolic sequences.


Assuntos
Duplicação Cromossômica , Cromossomos Humanos Par 6/genética , Deficiências do Desenvolvimento/genética , Succinato-Semialdeído Desidrogenase/urina , Adolescente , Adulto , Células Cultivadas , Deficiências do Desenvolvimento/enzimologia , Família , Feminino , Humanos , Leucócitos , Masculino , Succinato-Semialdeído Desidrogenase/metabolismo , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
5.
Am J Med Genet A ; 152A(6): 1398-410, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20503314

RESUMO

We report on the results of an array comparative genomic hybridization (array CGH) study of 150 karyotypically normal Finnish patients with idiopathic mental retardation and/or dysmorphic features and/or malformations. Using high-resolution microarray analysis, we sought to identify clinically relevant microdeletions and microduplications in these patients. The results were confirmed using other methods and compared with findings reported in recent publications and internet databases. Small aberrations of potential clinical significance were found in 28 (18.6%) of the 150 patients. Eight of the identified aberrations are known to cause syndromes, 4 affected the X chromosome in males, 4 were familial, and 13 have yet to be associated with a phenotype. This study demonstrates the benefits of array CGH in clinical diagnostics of developmental disorders. Further, our findings give evidence of new syndromes.


Assuntos
Hibridização Genômica Comparativa/métodos , Deficiência Intelectual/diagnóstico , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos X/genética , Feminino , Finlândia , Duplicação Gênica , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Deleção de Sequência
6.
Am J Med Genet A ; 146A(19): 2490-4, 2008 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-18792983

RESUMO

The oculoauriculovertebral anomaly (OAV) or Goldenhar syndrome is a malformation complex that has been described in several chromosomal rearrangements. Among them a deletion of the terminal 5p has recurred in seven previous patients. We wish to report on an additional such patient in order to reinforce the significance of this genomic region in the cause of at least a subgroup of OAV cases. Future studies, particularly in the OAV patients with a lateral facial cleft, might define one genetic background of the disorder. Our patient had a complex translocation chromosome 45,XX, inv(2) (q32q37)mat, dic(5;21) (p15.3;q22.3)dn, resulting in a terminal 5p deletion, a terminal deletion of 21q demonstrated by FISH studies, and a duplication of 21q22.11-q22.12 documented by molecular karyotyping. In addition to OAV she developed myelodysplasia treated with bone marrow transplantation. We discuss her clinical findings with reference to her karyotype findings and review the patients with OAV and a terminal deletion of 5p.


Assuntos
Deleção Cromossômica , Inversão Cromossômica , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 5 , Síndrome de Goldenhar/genética , Translocação Genética , Transplante de Medula Óssea , Pré-Escolar , Quebra Cromossômica , Análise Citogenética , Feminino , Dosagem de Genes , Humanos , Cariotipagem , Técnicas de Diagnóstico Molecular , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Trombocitopenia/diagnóstico , Transplante Homólogo , Resultado do Tratamento
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