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1.
Br J Haematol ; 194(1): 53-60, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34114218

RESUMO

Measurement of BCR activator of RhoGEF and GTPase -ABL proto-oncogene 1, non-receptor tyrosine kinase (BCR-ABL1) mRNA levels by reverse transcription quantitative polymerase chain reaction (RTqPCR) has been critical to treatment protocols and clinical trials in chronic myeloid leukaemia; however, interlaboratory variation remains a significant issue. Reverse transcriptase droplet digital PCR (RTddPCR) has shown potential to improve testing but a large-scale interlaboratory study is required to definitively establish this. In the present study, 10 BCR-ABL1-positive samples with levels ranging from molecular response (MR)1·0 -MR5·0 were tested by 23 laboratories using RTddPCR with the QXDX BCR-ABL %IS kit. A subset of participants tested the samples using RTqPCR. All 23 participants using RTddPCR detected BCR-ABL1 in all samples to MR4·0 . Detection rates for deep-response samples were 95·7% at MR4·5 , 78·3% at MR4·7 and 87·0% at MR5·0 . Interlaboratory coefficient of variation was indirectly proportional to BCR-ABL1 level ranging from 29·3% to 69·0%. Linearity ranged from 0·9330 to 1·000 (average 0·9936). When results were compared for the 11 participants who performed both RTddPCR and RTqPCR, RTddPCR showed a similar limit of detection to RTqPCR with reduced interlaboratory variation and better assay linearity. The ability to detect deep responses with RTddPCR, matched with an improved linearity and reduced interlaboratory variation will allow improved patient management, and is of particular importance for future clinical trials focussed on achieving and maintaining treatment-free remission.


Assuntos
Proteínas de Fusão bcr-abl/sangue , Ensaio de Proficiência Laboratorial , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Ásia , Biomarcadores Tumorais/sangue , Europa (Continente) , Células HL-60/química , Humanos , Células K562/química , Laboratórios Clínicos , Modelos Lineares , América do Norte , Kit de Reagentes para Diagnóstico , Reprodutibilidade dos Testes
2.
Clin Genet ; 95(4): 496-506, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30666632

RESUMO

Whole-exome sequencing has established IQSEC2 as a neurodevelopmental disability gene. The IQSEC2 variant phenotype includes developmental delay, intellectual disability, epilepsy, hypotonia, autism, developmental regression, microcephaly and stereotypies but is yet to be fully described. Presented here are 14 new patients with IQSEC2 variants. In addition to the established features, we observed: gait ataxia in 7 of 9 (77.8%), drooling in 9 of 14 (64.2%), early feeding difficulties in 7 of 14 (50%), structural brain abnormalities in 6 of 13 (46.2%), brachycephaly in 5 of 14 (35.7%), and scoliosis and paroxysms of laughter each in 4 of 14 (28.6%). We suggest that these are features of the IQSEC2-related disorder. Gastrostomy requirement, plagiocephaly, strabismus and cortical blindness, each seen in 2 of 14 (14.3%), may also be associated. Shared facial features were noted in 8 of 14 patients, and shared hair patterning was identified in 5 of 14 patients. This study further delineates the IQSEC2 phenotypic spectrum and supports the notion of an emerging IQSEC2 syndrome. We draw parallels between the IQSEC2-related disorder and the Angelman-/Rett-/Pitt-Hopkins syndrome group of conditions and recommend the addition of IQSEC2 to epilepsy and developmental delay gene panels. We observed discordant phenotypes in monozygotic twins and apparent gonadal mosaicism, which has implications for recurrence risk counselling in the IQSEC2-related disorder.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Fatores de Troca do Nucleotídeo Guanina/genética , Fenótipo , Gêmeos Monozigóticos/genética , Alelos , Substituição de Aminoácidos , Criança , Pré-Escolar , Fácies , Feminino , Estudos de Associação Genética/métodos , Humanos , Lactente , Masculino , Sequenciamento do Exoma
3.
Am J Med Genet A ; 179(1): 43-49, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30556256

RESUMO

Biallelic loss of function variants in the TMCO1 gene have been previously demonstrated to result in cerebrofaciothoracic dysplasia (CFTD; MIM #213980). The phenotype of this condition includes severe intellectual disability, as well as distinctive craniofacial features, including brachycephaly, synophrys, arched eyebrows, "cupid's bow" upper lip, and microdontia. In addition, nonspecific skeletal anomalies are common, including bifid ribs, scoliosis, and spinal fusion. Only 19 molecularly confirmed patients have been previously described. Here, we present four patients with CFTD, including three brothers from a Pakistani background and an additional unrelated white Scottish patient. All share the characteristic craniofacial appearance, with severe intellectual disability and skeletal abnormalities. We further define the phenotype with comparison to the published literature, and present images to define the dysmorphic features in a previously unreported ethnic group. All of our patient series are homozygous for the same c.292_293del (p.Ser98*) TMCO1 pathogenic variant, which has been previously reported only in an isolated Amish population. Thus we provide evidence that CFTD may be more common than previously thought. The patients presented here further delineate the phenotypic spectrum of CFTD and provide evidence for a recurrent pathogenic variant in TMCO1.


Assuntos
Anormalidades Múltiplas/genética , Canais de Cálcio/genética , Deficiência Intelectual/genética , Anormalidades Musculoesqueléticas/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Consanguinidade , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Anormalidades Musculoesqueléticas/diagnóstico por imagem , Anormalidades Musculoesqueléticas/fisiopatologia , Mutação/genética , Fenótipo , Esqueleto/anormalidades , Esqueleto/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/genética , Anormalidades Dentárias/fisiopatologia
4.
Am J Med Genet A ; 176(5): 1049-1054, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29681108

RESUMO

WDR45 gene-associated neurodegeneration with brain iron accumulation (NBIA), referred to as beta-propeller protein-associated neurodegeneration (BPAN), is a rare disorder that presents with a very nonspecific clinical phenotype in children constituting global developmental delay. This case report illustrates the power of a combination of trio exome sequencing, in silico splicing analysis, and mRNA analysis to provide sufficient evidence for pathogenicity of a relatively intronic variant in WDR45, and in so doing, find a genetic diagnosis for a 6-year-old patient with developmental delay and seizures, a diagnosis which may otherwise have only been found once the characteristic MRI patterns of the disease became more obvious in young adulthood.


Assuntos
Proteínas de Transporte/genética , Predisposição Genética para Doença , Íntrons , Mutação , Distrofias Neuroaxonais/genética , Splicing de RNA , RNA Mensageiro , Alelos , Encéfalo/patologia , Criança , Hibridização Genômica Comparativa , Éxons , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Imageamento por Ressonância Magnética/métodos , Distrofias Neuroaxonais/diagnóstico , Fenótipo , Análise de Sequência de DNA , Transcriptoma
5.
Am J Med Genet A ; 173(11): 3003-3012, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28944577

RESUMO

Exome sequencing in the context of developmental disorders is a useful technique, but variants found need to be interpreted in the context of detailed phenotypic information. Whole gene deletions and loss-of-function-mutations in the HNRNPU gene have been associated with intellectual disability and seizures in some patients. However, a unifying syndromic phenotype has not been previously elucidated. Here, we report a total of seven patients (six patients identified through the Wellcome Trust Deciphering Developmental Disorders study, with one additional patient), who have heterozygous de novo mutations in HNRNPU. These were found via trio-based exome sequencing. All but one of the mutations is predicted to cause loss-of-function. These patients have dysmorphic features in common, including prominent eyebrows, long palpebral fissures, overhanging columella, and thin upper lip. All patients have developmental delay and intellectual disability (ID), ranging from moderate to severe. Seizures are common from early childhood. These initially occur in the context of febrile episodes. This series demonstrates common phenotypic features, including emerging dysmorphism, associated with heterozygous HNRNPU mutations. This allows us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency.


Assuntos
Deficiências do Desenvolvimento/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Exoma , Feminino , Predisposição Genética para Doença , Haploinsuficiência/genética , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Convulsões/fisiopatologia , Adulto Jovem
7.
Gene ; 685: 50-54, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30393191

RESUMO

The SRPX2 gene (Sushi-repeat-containing protein, X-linked, 2, OMIM*300642), located on Xq22.1, encodes a secreted protein that is highly expressed in neurons of cerebral cortex. SRPX2 was first implicated in neurodevelopment, learning and rolandic seizure when two patients with potentially pathogenic variants, c.980A>G (p.Asn327Ser) and c.215A>C (p.Tyr72Ser), in SRPX2 gene were identified. Subsequent experimental studies demonstrated that SRPX2 is needed for vocalization and synapse formation in mice, and that both silencing SRPX2 and injecting (p.Asn327Ser) in mouse models results in alteration in neuronal migration in cerebral cortex and epilepsy. A number of studies demonstrated that SRPX2 interacts with FOXP2 (Foxhead box protein P2), a gene responsible for speech and language disorder, and that FoxP2 controls timing and level of expression of SRPX2. Despite the supportive evidence for the role of SRPX2 in speech and language development and disorders, there are questions over its definitive association with neurodevelopmental disorders and epilepsy. In this paper, the role of SRPX2 as one in a network of many genes involved in speech and language is discussed. The goal of this paper is to examine the role of SRPX2 variants through describing two patients with potentially pathogenic variants in SRPX2, c.751G>C (p.Ala251Pro) and c.762G>T (p.Lys254Asn) presenting with language and motor delay, intellectual disability as well as congenital anomalies. We explore the contribution of SRPX2 variants to clinical phenotype in our patients and conclude that these variants at least partially explain the phenotype. Further studies are necessary to establish and confirm the association between SRPX2 and neurodevelopment particularly speech and language development.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Proteínas do Tecido Nervoso/genética , Neurogênese/genética , Alelos , Exoma , Testes Genéticos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Proteínas de Membrana , Proteínas de Neoplasias , Proteínas do Tecido Nervoso/metabolismo , Polimorfismo de Nucleotídeo Único , Distúrbios da Fala/genética , Distúrbios da Fala/metabolismo , Distúrbios da Fala/fisiopatologia
8.
Arch Dis Child ; 103(9): 895-900, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29574410

RESUMO

In recent years, there have been significant advances in genetic technologies, evolving the field of genomics from genetics. This has huge diagnostic potential, as genomic testing increasingly becomes part of mainstream medicine. However, there are numerous potential pitfalls in the interpretation of genomic data. It is therefore essential that we educate clinicians more widely about the appropriate interpretation and utilisation of genomic testing.


Assuntos
Serviços de Saúde da Criança , Testes Genéticos/métodos , Genômica/métodos , Criança , Serviços de Saúde da Criança/tendências , Predisposição Genética para Doença , Testes Genéticos/tendências , Genômica/tendências , Humanos , Fenótipo
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