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1.
Clin Case Rep ; 11(5): e7332, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37180334

RESUMO

Key Clinical Message: Multiple genetic disorders can coexist in one patient. When the phenotype is not fully explained with one diagnosis, it is recommended to perform further genetic investigations in search for coexisting second diagnosis. Abstract: Craniofrontonasal dysplasia (CFND) (MIM: 304110) is an X-linked dominant disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. It is caused by a pathogenic variant in EFNB1. Pontocerebellar hypoplasia type 1B (PCH1B) (MIM: 614678) is an extremely rare condition with over 100 individuals reported to date. It is caused by biallelic pathogenic variants in EXOSC3. This report presents the case of a girl who was diagnosed prenatally with CFND based on the findings on the prenatal imaging and the known diagnosis of CFND in her mother. She has severe global development delay that cannot be explained solely by the CFND diagnosis. Around the age of 2 years, she was diagnosed with PCH1B following whole exome sequencing (WES) testing. The objective of this study is to highlight the importance of pursuing genetic investigation if the available genetic diagnosis cannot fully explain the clinical picture. This is a case report of one patient and review of the literature. Informed consent was obtained from the parents. WES was performed by a private lab using next-generation sequencing (NGS), DNA was sequenced on the NovaSeq 6000 using 2 × 150 bp paired-end read. WES identified the following: homozygous pathogenic variant in EXOSC3: C.395A>C, p.ASp132Ala, maternally inherited, likely pathogenic duplication at Xq13.1 (includes EFNB1) and paternally inherited 16p11.2 duplication that is classified as a variant of uncertain significance. Perusing more extensive genetic testing like: WES is indicated if the current genetic diagnosis cannot fully explain the phenotype in a patient.

2.
Am J Med Genet A ; 173(5): 1287-1293, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28371330

RESUMO

We present an 18-year-old boy with cerebral palsy, intellectual disability, speech delay, and seizures. He carries a likely pathogenic 1.3 Mb de novo heterozygous deletion in the 4q21.22 microdeletion syndrome region. He also carries a 436 kb maternally-inherited duplication impacting the first three exons of CHRNA7. The majority of previously published cases with 4q21.22 syndrome shared common features including growth restriction, muscular hypotonia, and absent or severely delayed speech. Using copy number variation (CNV) data available for other subjects, we defined a minimal critical region of 170.8 kb within the syndromic region, encompassing HNRNPD. We also identified a larger 2 Mb critical region encompassing ten protein-coding genes, of which six (PRKG2, RASGEF1B, HNRNPDL, HNRNPD, LIN54, COPS4) have a significantly low number of truncating loss-of-function mutations. Long-range chromatin interaction data suggest that this deletion may alter chromatin interactions at the 4q21.22 microdeletion region. We suggest that the deletion or misregulation of these genes is likely to contribute to the neurodevelopmental and neuromuscular abnormalities in 4q21.22 syndrome.


Assuntos
Paralisia Cerebral/genética , Cromossomos Humanos Par 4/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Adolescente , Paralisia Cerebral/fisiopatologia , Deleção Cromossômica , Variações do Número de Cópias de DNA/genética , Éxons/genética , Humanos , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Receptor Nicotínico de Acetilcolina alfa7/genética
3.
Clin Cancer Res ; 20(1): 176-86, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24170548

RESUMO

PURPOSE: Combinations of tyrosine kinase inhibitors (TKI) with gemcitabine have been attempted with little added benefit to patients. We hypothesized that TKIs designed to bind to ATP-binding pockets of growth factor receptors also bind to transporter proteins that recognize nucleosides. EXPERIMENTAL DESIGN: TKI inhibition of uridine transport was studied with recombinant human (h) equilibrative (E) and concentrative (C) nucleoside transporters (hENT, hCNT) produced individually in yeast. TKIs effects on uridine transport, gemcitabine accumulation, regulation of hENT1 activity, and cell viability in the presence or absence of gemcitabine were evaluated in human pancreatic and lung cancer cell lines. RESULTS: Erlotinib, gefitinib and vandetanib inhibited [(3)H]uridine transport in yeast and [(3)H]uridine and [(3)H]gemcitabine uptake in the four cell lines. Treatment of cell lines with erlotinib, gefitinib, or vandetanib for 24 hours reduced hENT1 activity which was reversed by subsequent incubation in drug-free media for 24 hours. Greater cytotoxicity was observed when gemcitabine was administered before erlotinib, gefitinib, or vandetanib than when administered together and synergy, evaluated using the CalcuSyn Software, was observed in three cell lines resulting in combination indices under 0.6 at 50% reduction of cell growth. CONCLUSIONS: Vandetanib inhibited hENT1, hENT2, hCNT1, hCNT2, and hCNT3, whereas erlotinib inhibited hENT1 and hCNT3 and gefitinib inhibited hENT1 and hCNT1. The potential for reduced accumulation of nucleoside chemotherapy drugs in tumor tissues due to inhibition of hENTs and/or hCNTs by TKIs indicates that pharmacokinetic properties of these agents must be considered when scheduling TKIs and nucleoside chemotherapy in combination.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Proteínas de Transporte de Nucleosídeos/antagonistas & inibidores , Piperidinas/farmacologia , Quinazolinas/farmacologia , Antimetabólitos Antineoplásicos/metabolismo , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/metabolismo , Desoxicitidina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Cloridrato de Erlotinib , Gefitinibe , Humanos , Concentração Inibidora 50 , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Uridina/metabolismo , Gencitabina
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