RESUMO
BACKGROUND: Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. METHODS: To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). RESULTS: The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. CONCLUSIONS: Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.
Assuntos
Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Canal de Potássio KCNQ2/genética , Proteínas de Membrana/genética , Paralisia Cerebral/genética , Paralisia Cerebral/patologia , Criança , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/patologia , Distonia/genética , Distonia/patologia , Epilepsia/genética , Epilepsia/patologia , Éxons/genética , Duplicação Gênica/genética , Humanos , Masculino , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Mutação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Convulsões/genética , Convulsões/patologia , Transmissão Sináptica/genéticaRESUMO
OBJECTIVE: To investigate the frequency of numerical aberrations of chromosomes 7, X and Y in patients with osteoarthritis (OA) by performing fluorescent in situ hybridization (FISH) studies on articular cartilage, and to correlate the chromosomal changes with the degree and location of articular involvement. PATIENTS: Thirty-four women and 10 men with OA were included in the study. As a control group, 6 women and 5 men operated for orthopedic disorders other than OA were analyzed. METHODS: FISH studies were performed on hip or knee cartilage, using two-color centromere-specific probes for chromosomes 7 & X for women and 7 & Y for men. RESULTS: FISH analysis revealed that 46% of OA patients had numerical abnormalities of chromosomes 7, X or Y. An extra chromosome 7 (trisomy 7) was present in 35% of patients with chromosomal aberrations. All males with OA lost the Y chromosome while 15% of the women had loss of one chromosome X (monosomy X). Trisomy 7 was associated with hip OA (p=0.019) and advanced OA according to the Kellgren and Lawrence classification (p=0.05). None of the 11 controls showed abnormalities in the chromosomes analyzed. CONCLUSIONS: FISH analysis showed the presence of numerical chromosomal abnormalities in the articular cartilage of patients with OA.