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1.
Am J Med Genet A ; 161A(2): 244-53, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23303641

RESUMO

In a screening project of patients with (complex) craniosynostosis using genomic arrays, we identified two patients with craniosynostosis and microcephaly with a deletion in the 2p15p16.1 chromosomal region. This region has been associated with a new microdeletion syndrome, for which patients have various features in common, including microcephaly and intellectual disability. Deletions were identified using Affymetrix 250K SNP array and further characterized by fluorescence in situ hybridization (FISH) analysis and qPCR. The deletions in our two patients overlapped within the 2p15p16.1 microdeletion syndrome area and were 6.8 and 6.9 Mb in size, respectively. FISH and qPCR confirmed the presence of only one copy in this region. Finemapping of the breakpoints indicated precise borders in our patients and were further finemapped in two other previously reported patients. Clinical features of patients with deletions in the 2p15p16.1 region vary. Including data from our patients, now eight out of nine reported patients have microcephaly, one of the major features, and all had intellectual disability. The current reported two patients add different forms of craniosynostosis to the clinical spectrum of this recently recognized microdeletion syndrome.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 2 , Craniossinostoses/genética , Microcefalia/genética , Cariótipo Anormal , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Pré-Escolar , Deleção Cromossômica , Craniossinostoses/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Dedos/anormalidades , Estudos de Associação Genética , Humanos , Lactente , Masculino , Microcefalia/diagnóstico , Técnicas de Diagnóstico Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único , Síndrome
2.
Am J Hum Genet ; 85(1): 40-52, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19559397

RESUMO

Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography. Homozygosity mapping with SNPs was performed for identification of the chromosomal locus for the disease. In the 14 Mb candidate region on chromosome 7q22, RNA expression profiling was used for selecting among the 203 genes in the area. In postmortem brain tissue available from one patient, histology and immunohistochemistry were performed. Disease course and imaging were mostly reminiscent of hypoxic-ischemic tetraplegic cerebral palsy, with neuroaxonal degeneration and white matter loss. In all five patients, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G-->T), was identified. AP4M1, encoding for the mu subunit of the adaptor protein complex-4, is involved in intracellular trafficking of glutamate receptors. Aberrant GluRdelta2 glutamate receptor localization and dendritic spine morphology were observed in the postmortem brain specimen. This disease entity, which we refer to as congenital spastic tetraplegia (CST), is therefore a genetic model for congenital cerebral palsy with evidence for neuroaxonal damage and glutamate receptor abnormality, mimicking perinatally acquired hypoxic-ischemic white matter injury.


Assuntos
Complexo 4 de Proteínas Adaptadoras/genética , Subunidades mu do Complexo de Proteínas Adaptadoras/genética , Paralisia Cerebral/genética , Encéfalo/patologia , Linhagem Celular , Células Cultivadas , Paralisia Cerebral/patologia , Paralisia Cerebral/fisiopatologia , Feminino , Fibroblastos/patologia , Genes Recessivos , Humanos , Masculino , Linhagem , Quadriplegia/genética , Quadriplegia/fisiopatologia , Adulto Jovem
3.
J Mol Diagn ; 23(1): 120-129, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152501

RESUMO

Multiple myeloma (MM) is an incurable plasma cell cancer with a large variability in survival. Patients with MM classified as high risk by the SKY92 gene expression classifier are at high risk of relapse and short survival. Analytical validation of the SKY92 assay was performed with primary bone marrow specimens from 12 patients with MM and 7 reference cell line specimens. The SKY92 results were 100% concordant with the reference and/or their expected result for sensitivity, specificity, microarray stability, and RLT buffer stability. The SKY92 results were 90% concordant for primary specimen stability, 96.4% concordant for intermediate precision, and 80% to 100% concordant for RNA stability. For the cell-line reproducibility, the concordance was at least 92.9%, except for one near-cut point specimen. For the clinical specimen reproducibility, the concordance was 100%, except for two near-cut point specimens. Three independent laboratories were concordant in ≥77.8% and ≥92.9% of experiments for patient specimens and cell lines, respectively. Statistical acceptance thresholds were developed as Δ ≤1.48 (change in SKY92 score) and SD ≤0.45 (SD across SKY92 scores). Using the Clinical and Laboratory Standards Institute method of choice (EP05-A2/A3), restricted maximum likelihood, the observed Δ values (0 to 1.14) and SDs (0.22 to 0.31) passed acceptance criteria. Thus, we successfully present analytical validation for the SKY92 assay as a prognostic molecular test for individual patients with MM.


Assuntos
Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Técnicas de Diagnóstico Molecular/métodos , Mieloma Múltiplo/genética , Transcriptoma , Biomarcadores Tumorais/genética , Doadores de Sangue , Estudos de Casos e Controles , Linhagem Celular Tumoral , Humanos , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Recidiva , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e Especificidade
4.
Blood Adv ; 4(24): 6298-6309, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33351127

RESUMO

The standard prognostic marker for multiple myeloma (MM) patients is the revised International Staging System (R-ISS). However, there is room for improvement in guiding treatment. This applies particularly to older patients, in whom the benefit/risk ratio is reduced because of comorbidities and subsequent side effects. We hypothesized that adding gene-expression data to R-ISS would generate a stronger marker. This was tested by combining R-ISS with the SKY92 classifier (SKY-RISS). The HOVON-87/NMSG-18 trial (EudraCT: 2007-004007-34) compared melphalan-prednisone-thalidomide followed by thalidomide maintenance (MPT-T) with melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R). From this trial, 168 patients with available R-ISS status and gene-expression profiles were analyzed. R-ISS stages I, II, and III were assigned to 8%, 75%, and 7% of patients, respectively (3-year overall survival [OS] rates: 80%, 65%, 33%, P = 8 × 10-3). Using the SKY92 classifier, 13% of patients were high risk (HR) (3-year OS rates: standard risk [SR], 70%; HR, 28%; P < .001). Combining SKY92 with R-ISS resulted in 3 risk groups: SKY-RISS I (SKY-SR + R-ISS-I; 15%), SKY-RISS III (SKY-HR + R-ISS-II/III; 11%), and SKY-RISS II (all other patients; 74%). The 3-year OS rates for SKY-RISS I, II, and III are 88%, 66%, and 26%, respectively (P = 6 × 10-7). The SKY-RISS model was validated in older patients from the CoMMpass dataset. Moreover, SKY-RISS demonstrated predictive potential: HR patients appeared to benefit from MPR-R over MPT-T (median OS, 55 and 14 months, respectively). Combined, SKY92 and R-ISS classify patients more accurately. Additionally, benefit was observed for MPR-R over MPT-T in SKY92-RISS HR patients only.


Assuntos
Mieloma Múltiplo , Idoso , Humanos , Lenalidomida , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Prognóstico , Talidomida
5.
Genet Test Mol Biomarkers ; 17(4): 295-300, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23530539

RESUMO

Mutations in the gene encoding nucleophosmin (NPM1) carry a prognostic value for patients with acute myeloid leukemia (AML). Various techniques are currently being used to detect these mutations in routine molecular diagnostics. Incorporation of accurate NPM1 mutation detection on a gene expression platform would enable simultaneous detection with various other expression biomarkers. Here we present an array-based mutation detection using custom probes for NPM1 WT mRNA and NPM1 type A, B, and D mutant mRNA. This method was 100% accurate on a training cohort of 505 newly diagnosed unselected AML cases. Validation on an independent cohort of 143 normal-karyotype AML cases revealed no false-negative results, and one false positive (sensitivity 100.0% and specificity 98.7%). Based on this, we conclude that this method provides a reliable method for NPM1 mutation detection. The method can be applied to other genes/mutations as long as the mutant alleles are sufficiently highly expressed.


Assuntos
Algoritmos , Leucemia Mieloide Aguda/genética , Mutação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Alelos , Sondas de DNA , Feminino , Expressão Gênica , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Nucleofosmina , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sensibilidade e Especificidade
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