RESUMO
The clinical significance of chromosomal microdeletions and microduplications was predicted based on their gene content, de novo or familial inheritance and accumulated knowledge recorded on public databases. A patient group comprised of 247 cases with epilepsy and its common co-morbidities of developmental delay, intellectual disability, autism spectrum disorders, and congenital abnormalities was reviewed prospectively in a diagnostic setting using a standardized oligo-array CGH platform. Seventy-three (29.6%) had copy number variations (CNVs) and of these 73 cases, 27 (37.0%) had CNVs that were likely causative. These 27 cases comprised 10.9% of the 247 cases reviewed. The range of pathogenic CNVs associated with seizures was consistent with the existence of many genetic determinants for epilepsy.
Assuntos
Transtornos Globais do Desenvolvimento Infantil/complicações , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Cognitivos/complicações , Transtornos Cognitivos/diagnóstico , Hibridização Genômica Comparativa , Epilepsia/complicações , Epilepsia/diagnóstico , Adolescente , Adulto , Idoso , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica/genética , Transtornos Cognitivos/genética , Variações do Número de Cópias de DNA/genética , Epilepsia/genética , Feminino , Aconselhamento Genético , Predisposição Genética para Doença , Humanos , Achados Incidentais , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
We report two rare genetic aberrations in a schizophrenia patient that may act together to confer disease susceptibility. A previously unreported balanced t(9;17)(q33.2;q25.3) translocation was observed in two schizophrenia-affected members of a small family with diverse psychiatric disorders. The proband also carried a 1.5 Mbp microduplication at 16p13.1 that could not be investigated in other family members. The duplication has been reported to predispose to schizophrenia, autism and mental retardation, with incomplete penetrance and variable expressivity. The t(9;17) (q33.2;q25.3) translocation breakpoint occurs within the open reading frames of KIAA1618 on 17q25.3, and TTLL11 (tyrosine tubulin ligase like 11) on 9q33.2, causing no change in the expression level of KIAA1618 but leading to loss of expression of one TTLL11 allele. TTLL11 belongs to a family of enzymes catalyzing polyglutamylation, an unusual neuron-specific post-translational modification of microtubule proteins, which modulates microtubule development and dynamics. The 16p13.1 duplication resulted in increased expression of NDE1, encoding a DISC1 protein partner mediating DISC1 functions in microtubule dynamics. We hypothesize that concomitant TTLL11-NDE1 deregulation may increase mutation load, among others, also on the DISC1 pathway, which could contribute to disease pathogenesis through multiple effects on neuronal development, synaptic plasticity, and neurotransmission. Our data illustrate the difficulties in interpreting the contribution of multiple potentially pathogenic changes likely to emerge in future next-generation sequencing studies, where access to extended families will be increasingly important.
Assuntos
Cromossomos Humanos Par 16 , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 9/genética , Esquizofrenia/genética , Duplicações Segmentares Genômicas , Translocação Genética , Adulto , Alelos , Família , Humanos , Masculino , Mutação/genética , Proteínas do Tecido Nervoso/genética , Linhagem , Processamento de Proteína Pós-Traducional , Esquizofrenia/metabolismo , Esquizofrenia/patologiaRESUMO
A family with dominantly inherited neonatal seizures and intellectual disability was atypical for neonatal and infantile seizure syndromes associated with potassium (KCNQ2 and KCNQ3) and sodium (SCN2A) channel mutations. Microsatellite markers linked to KCNQ2, KCNQ3, and SCN2A were examined to exclude candidate locations, but instead revealed a duplication detected by observation of three alleles for two markers flanking SCN2A. Characterization revealed a 1.57 Mb duplication at 2q24.3 containing eight genes including SCN2A, SCN3A, and the 3¢ end of SCN1A. The duplication was partially inverted and inserted within or near SCN1A, probably affecting the expression levels of associated genes, including sodium channels. Rare or unique microchromosomal copy number mutations might underlie familial epilepsies that do not fit within the clinical criteria for the established syndromes.
Assuntos
Cromossomos Humanos Par 2/genética , Duplicação Gênica , Deficiência Intelectual/genética , Mutação/genética , Epilepsia/genética , Epilepsia Neonatal Benigna/genética , Família , Feminino , Humanos , Lactente , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ2/metabolismo , Canal de Potássio KCNQ3/genética , Canal de Potássio KCNQ3/metabolismo , Masculino , Mutação de Sentido Incorreto/genética , Canal de Sódio Disparado por Voltagem NAV1.2 , Canal de Sódio Disparado por Voltagem NAV1.3 , Proteínas do Tecido Nervoso , Linhagem , Canais de Sódio/genética , Canais de Sódio/metabolismo , SíndromeRESUMO
PURPOSE: To identify genes involved in idiopathic absence epilepsies by analyzing gene expression using a monozygotic (MZ) twin design. METHODS: Genome-wide gene expression in lymphoblastoid cell lines (LCLs) was determined using microarrays derived from five discordant and four concordant MZ twin pairs with idiopathic absence epilepsies and five unaffected MZ twin pairs. Gene expression was analyzed using three strategies: discordant MZ twins were compared as matched pairs, MZ twins concordant for epilepsy were compared to control MZ twins, and a singleton design of affected versus unaffected MZ twin individuals was used irrespective of twin pairing. An overlapping gene list was generated from these analyses. Dysregulation of genes recognized from the microarray experiment was validated using quantitative real time PCR (qRT-PCR) in the twin sample and in an independent sample of 18 sporadic absence cases and 24 healthy controls. RESULTS: Sixty-five probe sets were identified from the three combined microarray analysis strategies. Sixteen genes were chosen for validation and nine of these genes confirmed by qRT-PCR in the twin sample. Differential expression for EGR1 (an immediate early gene) and RCN2 (coding for the calcium-binding protein Reticulocalbin 2) were reconfirmed by qRT-PCR in the independent sample. DISCUSSION: Using a unique sample of discordant MZ twins, our study identified genes with altered expression, which suggests novel mechanisms in idiopathic absence epilepsy. Dysregulation of EGR1 and RCN2 is implicated in idiopathic absence epilepsy.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tipo Ausência/genética , Expressão Gênica/genética , Gêmeos Monozigóticos/genética , Adulto , Anticonvulsivantes/uso terapêutico , Linhagem Celular Tumoral/patologia , Epilepsia Tipo Ausência/tratamento farmacológico , Feminino , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ácido Valproico/uso terapêuticoRESUMO
The t(8;14)(q11.2;q32) is emerging as an uncommon, though recurrent cytogenetic finding. As of yet, too few cases of acute lymphoblastic leukemia (ALL) characterized by this translocation have been studied to determine its prognostic significance with confidence. We therefore report three new patients (two male children and one adult female) and present their hematologic, immunophenotypic, and clinical data. The clinical and laboratory characteristics of 26 other patients with t(8;14)(q11.2;q32) are summarized. The total number of patients now reported in the literature is 29 with a mean age of 14 years. Early relapse, that is, relapse within 6 months, does not appear to be a common feature of this group. The gender distribution is 19 males: 9 females (gender not reported in one case). Twenty-three t(8;14) patients show a pre-B immunophenotype and 24 of 24, on whom information is available, achieved complete remission after induction chemotherapy for B-ALL. Approximately one third of patients with t(8;14) have Down syndrome, 19 of 27 have additional acquired cytogenetic abnormalities, 5 of these have the t(9;22), and 4 show duplication of the abnormal chromosome 14, which is derived from the t(8;14). Hemoglobin and platelet counts are low at presentation in 10 of 10 and 8 of 9 patients, respectively, and the average white blood count is 38.9 x 10(9)/L. Of the 7 patients for whom IgH status has been determined, all show rearrangement of the IgH locus. Two of the present three patients are included in this group; their IgH rearrangement was demonstrated by fluorescence in situ hybridization with IgH break-apart probes.
Assuntos
Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 8/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genes de Imunoglobulinas/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The aim of this study was to determine prospectively the frequency of pathogenic chromosomal microdeletions and microduplications in a large group of referred patients with developmental delay (DD), intellectual disability (ID) or autism spectrum disorders (ASD) within a genetic diagnostic service. First tier testing was applied using a standardised oligo-array comparative genomic hybridization (CGH) platform, replacing conventional cytogenetic testing that would have been used in the past. Copy number variants (CNVs) found to be responsible for the clinical condition on the request form could all be subdivided into three groups: well established pathogenic microdeletion/microduplication/aneuploidy syndromes, predicted pathogenic CNVs as interpreted by the laboratory, and recently established pathogenic disease susceptibility CNVs. Totalled from these three groups, with CNVs of uncertain significance excluded, detection rates were: DD (13.0%), ID (15.6%), ASD (2.3%), ASD with DD (8.2%), ASD with ID (12.7%) and unexplained epilepsy with DD, ID and ASD (10.9%). The greater diagnostic sensitivity arising from routine application of array CGH, compared with previously used conventional cytogenetics, outweighs the interpretative issues for the reporting laboratory and referring clinician arising from detection of CNVs of uncertain significance. Precise determination of any previously hidden molecular defect responsible for the patient's condition is translated to improved genetic counselling.
Assuntos
Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Hibridização Genômica Comparativa/métodos , Deficiências do Desenvolvimento/diagnóstico , Deficiência Intelectual/diagnóstico , Austrália , Transtornos Globais do Desenvolvimento Infantil/complicações , Transtornos Globais do Desenvolvimento Infantil/genética , Estudos de Coortes , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Epilepsia/complicações , Epilepsia/diagnóstico , Epilepsia/genética , Duplicação Gênica , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Estudos Prospectivos , Deleção de SequênciaRESUMO
Robertsonian translocations (RTs) are amongst the most common chromosome abnormalities, but being essentially balanced are not usually associated with phenotypic abnormality. Despite being dicentric, RTs are almost always transmitted stably through cell division without chromosome breakage. We have investigated spontaneous fission of der(13;15)(q10;q10) chromosomes in eight individuals from two unrelated kindreds with a view to assessing clinical significance and to seek an explanation for the peculiar heritable instability displayed by these chromosomes. In Family 1, fission products were observed in five members in three generations. The instability was observed in cells derived from chorionic villus and lymphocytes. In Family 2, the same phenomenon was observed in amniocytes from two separate pregnancies and maternal blood lymphocytes. Detailed FISH analysis of these RTs showed them to be dicentric with an unremarkable pericentromeric structure. Notably, combined immunofluoresence and FISH analysis showed the presence of the centromere-specific proteins CENP-A and CENP-E, consistent with functional dicentricity in >75% of cells analyzed. The fission products are, therefore, presumed to be the result of sporadic, bipolar kinetochore attachment, anaphase bridging with resultant inter-centromeric breakage in a small proportion of mitoses. None of the eight carriers shows phenotypic abnormality and therefore, for prenatal counseling purposes, there appears to be no increased specific risk associated with this phenomenon.
Assuntos
Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 15/genética , Translocação Genética , Autoantígenos/imunologia , Proteína Centromérica A , Proteínas Cromossômicas não Histona/imunologia , Bandeamento Cromossômico , Saúde da Família , Feminino , Imunofluorescência/métodos , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , LinhagemRESUMO
We present six cases of 47,+i(5p)/46 mosaicism diagnosed at chorionic villus sampling (CVS), this being the first prospective series to be reported. The clinical indication in each was advanced maternal age. Further prenatal studies in four (amniocentesis, plus fetal blood sampling in one) did not show the isochromosome. In one case, subsequent amniocentesis showed 1/48 in situ colonies with the isochromosome, but fetal blood was karyotypically normal. These five pregnancies resulted in phenotypically normal livebirths; further normal follow-up reports (from age 4 months through 4 years) are noted in four of these. Analysis of placental tissue in one case confirmed the presence of the i(5p) mosaicism. In the remaining case, in which 100% of CVS cultured cells had the i(5p), the pregnancy was terminated. Fetal skin fibroblasts did not show the i(5p). Thus, in none of these six cases was true fetal mosaicism detected, nor an abnormal phenotype noted. We suggest that a 47,+i(5p)/46 karyotype, detected at CVS, may frequently reflect confined placental mosaicism. In addition, we report a case of the primary diagnosis of 47,+i(5p)/46 mosaicism at amniocentesis. The infant appeared normal at birth, but a brain malformation was subsequently identified.