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1.
Zhonghua Er Ke Za Zhi ; 58(3): 218-222, 2020 Mar 02.
Artículo en Chino | MEDLINE | ID: mdl-32135594

RESUMEN

Objective: To explore the clinical phenotype, immunological features, pathogenesis and gene variation of a case with A20 haploinsufficiency (HA20). Methods: A patient diagnosed with tumor necrosis factor α-induced protein 3 (TNFAIP3) mutated HA20 was admitted into Shenzhen Children's Hospital in May,2019.The clinical data was analyzed. Flow cytometry was used to detect the patient's peripheral blood lymphocyte subsets, and also, the percentage of follicular helper T cell (TFH) cells in the patient and thirteen healthy controls. After the construction of empty vector, wild-type and mutant plasmid vectors, a wild-type or mutant overexpression system of the TNFAIP3 gene was established in 293T cells and Hela cells. Then, the expression level of A20 in 293T cells and the expression of inhibitor K binding α (IKBα) in green fluorescent protein (GFP)+Hela cells before and after tumor necrosis factor α (TNF-α) stimulation were measured, to verify the pathogenicity of this variation. Results: A 5 years and 11 months old boy, presented with recurrent oral ulcer, abdominal pain, joint swelling and arthralgia. Oral ulcer, chronic skin rashes, knee joint swelling were observed. The levels of inflammatory markers were increased. Colonoscopy showed congestion of mucosa and multiple ulcers in terminal ileum and ileocecus. The absolute number of naive B cells was 124×10(6) cells/L (reference range 147×10(6)-431×10(6) cells/L), accounting for 0.430 of the total B cells (reference range 0.484-0.758). Compared to healthy controls (0.016-0.071), the percentage of TFH cells in CD4(+)T cells was much lower (0.008).A heterozygous mutation of TNFAIP3 gene (c.909_913 del, p.L303fs) was identified by genetic analysis. In vitro study showed that truncated A20 protein was expressed in TNFAIP3 mutant overexpressed 293T cells, which verified the pathogenicity of this variation. Besides, after TNF-α stimulation, the degradation rate of IkBα protein in mutant overexpressed Hela cells (35%) was between the other two groups (15% in the wild-type group and 57% in the non-loaded group). Conclusions: This case with HA20 due to a de novo TNFAIP3 gene mutation presents with early onset Behcet-like autoinflammatory syndrome. This variation leads to expression of truncated A20 protein, enhanced degradation of IkBα, and further activation of nuclear factor κB signaling pathway.


Asunto(s)
Enfermedades Autoinmunes , Haploinsuficiencia , FN-kappa B , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/genética , Preescolar , Haploinsuficiencia/genética , Células HeLa , Heterocigoto , Humanos , Masculino , Fenotipo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética
2.
Zhonghua Er Ke Za Zhi ; 58(3): 223-227, 2020 Mar 02.
Artículo en Chino | MEDLINE | ID: mdl-32135595

RESUMEN

Objective: To analyze the clinical , immunological and genetic features of a child with BCL11B mutation induced neurodevelopmental disorder. Methods: The clinical data and genetic test of a child with BCL11B mutation hospitalized in the Department of Rheumatology and Immunology in Children's Hospital of Chongqing Medical University in December 2018 were extracted and analyzed. The literature was searched with "BCL11B mutation" and "immunodeficiency 49" as key words in Chinese databases and Pubmed until January 2019 was reviewed. Results: A male patient aged 3 years and 11 months with facial dysmorphisms and delayed language and motor development was admitted due to neurodevelopmental retardation over two years. Laboratory tests showed normal human immunoglobulin (IgG 12.90 g/L, IgA 1.02 g/L, IgM 1.15 g/L, IgE 532 000 U/L), Trec (228) and proliferation of T and B cells. The lymphocyte subsets revealeda reduced percentage of B cells (0.108) but normal absolute numbers (0.574×10(-3)/L), and an increased percentage (0.828) as well as absolute numbers (4.415×10(-3)/L) of T cells. A heterozygous BCL11B mutation was detected by sanger sequencing, showing a de novo frameshift mutation c.1887_c.1893delCGGCGGG in exon 4. Two papers were found which were all in English, with total of 14 patients(13 patients with complete information). Thirteen mutations were reposed, including 7 frameshift, 2 nonsense, 2 missense, and 2 chromosomal rearrangements; Thirteen patients had heterozygous mutations. All patients had delayed language and motor development and facial dysplasia which were mainly hypertelorism, thin eyebrows and small palpebral fissures. Some patients had dental anomalies, ametropia and allergy, and a few were combined with immune impairment, but without overt signs of immunodeficiency. Only one patient had multisystem anomalies and profound immune deficiency. Conclusions: BCL11B is essential for development of the nervous and the immune system. In this study, the de novo mutation of BCL11B gene resulted in neurodevelopmental and immunological disorders.


Asunto(s)
Trastornos del Neurodesarrollo , Factores de Transcripción , Proteínas Supresoras de Tumor , Preescolar , Heterocigoto , Humanos , Masculino , Mutación , Trastornos del Neurodesarrollo/genética , Proteínas Represoras , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(3): 263-268, 2020 Mar 10.
Artículo en Chino | MEDLINE | ID: mdl-32128742

RESUMEN

Spinal muscular atrophy (SMA) is one of the most common fatal autosomal recessive genetic disorders among infants. It is caused by mutations of motor neuron survival gene 1 (SMN1). The incidence of SMA among newborns is approximately 1/10 000 - 1/6000, and the carrier rate is 1/72 - 1/47 with an ethnic variance. Based on the time of onset and clinical phenotype, SMA can be divided into types I - IV. Approximately 95% of SMA patients have carried homozygous deletions of exon 7 of the (SMN1)] gene. For its significant phenotypic difference, abundant changes of (SMN1)] gene copy number, presence of pseudogene interference and high carrier rate, early diagnosis, genetic consultation, treatment and prevention of SMA can be difficult. This guideline summarizes the relevant research, guideline and consensus issued at home and abroad, clinical manifestations and pathogenesis of SMA patients, and experience in its diagnosis and genetic counseling, with an aim to promote a standardized diagnosis and treatment and reduce the births of children affected with the disease.


Asunto(s)
Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/terapia , Guías de Práctica Clínica como Asunto , Exones , Dosificación de Gen , Asesoramiento Genético , Heterocigoto , Humanos , Recién Nacido , Fenotipo , Eliminación de Secuencia , Proteína 1 para la Supervivencia de la Neurona Motora/genética
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 131-134, 2020 Feb 10.
Artículo en Chino | MEDLINE | ID: mdl-32034737

RESUMEN

OBJECTIVE: To explore the genetic basis for a child featuring severe mental retardation. METHODS: The child was subjected to target region capture and next generation sequencing. Suspected variants were verified by Sanger sequencing. RESULTS: The child was found to harbor a hemizygous c.1A>G (pMet1?) variation of the ARX gene, for which his mother was a heterozygous carrier. The mutation was unreported previously and was predicted to be "probably pathogenic" by bioinformatic analysis. CONCLUSION: The c.1A>G (pMet1?) variant of the ARX gene may underlie the occurrence of severe mental retardation in this child.


Asunto(s)
Discapacidad Intelectual , Niño , Codón , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de Homeodominio , Humanos , Discapacidad Intelectual/genética , Mutación , Factores de Transcripción
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 142-146, 2020 Feb 10.
Artículo en Chino | MEDLINE | ID: mdl-32034740

RESUMEN

OBJECTIVE: To explore the genetic basis for a newborn infant suspected with Donohue syndrome. METHODS: Whole exome sequencing (WES) was used to screen potential variants in the child. Suspected variants were validated through Sanger sequencing and real-time PCR. RESULTS: The child was found to carry two heterozygous variants in the INSR gene, including c.3258+4(IVS17)A>G and deletion of exon 2, which were respectively inherited from her mother and father. CONCLUSION: The compound heterozygous variants of the INSR gene probably underlie the disease in this patient.


Asunto(s)
Síndrome de Donohue , Síndrome de Donohue/genética , Exones , Femenino , Heterocigoto , Humanos , Recién Nacido , Mutación , Secuenciación del Exoma Completo
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 153-155, 2020 Feb 10.
Artículo en Chino | MEDLINE | ID: mdl-32034743

RESUMEN

OBJECTIVE: To detect variants of ARSA gene in a child featuring late infantile metachromatic leukodystrophy (MLD). METHODS: PCR and Sanger sequencing was carried out for the patient and her parents. RESULTS: The patient had typical features of MLD including ARSA deficiency, regression of walking ability, and demyelination. Compound heterozygous variants of the ARSA gene, namely c.960G>A and c.244C>T, were detected in the patient, for which her mother and father were respectively heterozygous carriers. ARSA c.960G>A was known to be pathogenic, while ARSA c.244C>T was a novel variant. The same variants were not detected among 50 healthy controls. CONCLUSION: The compound heterozygous variants c.960G>A and c.244C>T of the ARSA gene probably underlie the MLD in this patient.


Asunto(s)
Leucodistrofia Metacromática , Cerebrósido Sulfatasa , Niño , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Leucodistrofia Metacromática/genética , Mutación
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 156-158, 2020 Feb 10.
Artículo en Chino | MEDLINE | ID: mdl-32034744

RESUMEN

OBJECTIVE: To explore the genetic basis for a Chinese neonate with lipoprotein lipase deficiency. METHODS: Targeted capture and next-generation sequencing (NGS) were carried out to detect variants of genes associated with inborn errors of metabolism. Suspected variants were validated by Sanger sequencing. RESULTS: Genetic testing revealed novel complex heterozygous variants, namely c.347G>C (p.Arg116Pro) and c.472T>G (p.Tyr158Asp), of the LPL gene, which were respectively inherited from his father and mother. CONCLUSION: Compound heterozygous variants c.347G>C and c.472T>G of the LPL gene probably underlie the lipoprotein lipase deficiency in this child.


Asunto(s)
Hiperlipoproteinemia Tipo I , Lipoproteína Lipasa/genética , Grupo de Ascendencia Continental Asiática , Pruebas Genéticas , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hiperlipoproteinemia Tipo I/genética , Recién Nacido , Mutación
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 159-161, 2020 Feb 10.
Artículo en Chino | MEDLINE | ID: mdl-32034745

RESUMEN

OBJECTIVE: To analyze INS gene variant in a patient with maturity-onset diabetes of the young type 10. METHODS: High-throughput sequencing was used to screen for the variants. Suspected variant was verified by Sanger sequencing. RESULTS: Genetic testing indicated that the patient and his mother have both carried a heterozygous c.130G>A (p.Gly44Arg) variant in exon 1 of the INS gene. Prediction of protein structure suggested the variant to be pathogenic. CONCLUSION: The c.130G>A (p.Gly44Arg) variant of the INS gene probably underlies the disease in this patient.


Asunto(s)
Diabetes Mellitus Tipo 2 , Insulina/genética , Adolescente , Femenino , Pruebas Genéticas , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación
10.
BMC Med Genet ; 21(1): 20, 2020 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-32005174

RESUMEN

BACKGROUND: X-linked ichthyosis (XLI; OMIM# 308100) is a recessive keratinization disorder characterized by the presence of dark brown, polygonal, adherent scales on different parts of the body surface. It almost exclusively affects males and the estimated prevalence ranges from 1:2000-6000 in males worldwide. Extracutaneous manifestations are frequent including corneal opacities, cryptorchidism, neuropsychiatric symptoms or others. Up to 90% of XLI cases are caused by recurrent hemizygous microdeletion encompassing entire STS gene on chromosome Xp22.3, while only a minority of patients shows partial deletions or loss of function point mutations in STS. Larger deletions also involving contiguous genes are identified in syndromic patients. METHODS: Here, we report clinical and genetic findings of a large Pakistani family having 16 affected individuals including 2 females with XLI. Molecular karyotyping and direct DNA sequencing of coding region of the STS gene was performed. RESULTS: The clinical manifestations in affected individuals involved generalized dryness and scaling of the skin with polygonal, dark scales of the skin on scalp, trunk, limbs, and neck while sparing face, palms and soles. There were no associated extra-cutaneous features such as short stature, cryptorchidism, photophobia, corneal opacities, male baldness, and behavioral, cognitive, or neurological phenotypes including intellectual disability, autism or attention deficit hyperactivity disorder. Molecular karyotyping was normal and no copy number variation was found. Sanger sequencing identified a novel hemizygous nonsense mutation (c.287G > A; p.W96*), in exon 4 of STS gene in all affected male individuals. In addition, two XLI affected females in the family were found to be homozygous for the identified variant. CONCLUSIONS: This study is useful for understanding the genetic basis of XLI in the patients studied, for extending the known mutational spectrum of STS, diagnosis of female carriers and for further application of mutation screening in the genetic counseling of this family.


Asunto(s)
Tamización de Portadores Genéticos , Ictiosis Ligada al Cromosoma X/genética , Piel/metabolismo , Esteril-Sulfatasa/genética , Adolescente , Adulto , Codón sin Sentido/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Heterocigoto , Homocigoto , Humanos , Ictiosis Ligada al Cromosoma X/fisiopatología , Masculino , Persona de Mediana Edad , Pakistán/epidemiología , Fenotipo , Eliminación de Secuencia/genética , Piel/patología , Adulto Joven
12.
Zhonghua Er Ke Za Zhi ; 58(2): 101-106, 2020 Feb 02.
Artículo en Chino | MEDLINE | ID: mdl-32102145

RESUMEN

Objective: To analyze the genetic characteristics of a five generations pedigree with homozygous familial hypercholesterolemia (HoFH). Methods: Prospective study. Twenty family members included a proband diagnosed as familial hyperlipidemia at the cardiology Department of Xi'an Children's Hospital in October 2018 were research object. Clinical data were collected. Genome DNAs were extracted. Whole exons sequencing was performed on the proband using target capture next generation sequencing. Candidate gene mutation sites identified by bioinformatics were verified by Sanger sequencing in the family members. The genotype-phenotype correlation of the pedigree was analyzed between heterozygous mutation carriers and non-carriers. Results: The proband was a 7-years and 10-month-old boy. He was born with a roundgreen bean size yellow skin protuberance in the skin of the coccyx. Since the age of 3-4 years old, xanthoma-like lesions with a diameter of 0.5-1.5 cm gradually appeared in the skin of bilateral elbow joints, knee joints and Achilles tendon. The height, weight and intellectual development of the child were the same as those of normal children at the same age. No similar xanthoma-like lesion was found in the other family members. The proband's total cholesterol (TC) reached 18.16-21.24 mmol/L, and his low density lipoproteincholesterol (LDL-C) was 14.08-15.51 mmol/L. Carotid ultrasonography showed diffuse sclerotic plaques in bilateral carotid and vertebral arteries, and color Doppler echocardiography revealed aortic valve thickening and calcification. Gene testing identified that the proband carried a homozygous mutation C. 418G>A (p. E140K) in LDLR gene inherited from his parents who had a consanguineous marriage and carried a heterozygous mutation of LDLR-E140K, respectively.The TC, LDL-C and apolipoproteinB (ApoB) of LDLR-E140K gene heterozygous carriers ((8.40±0.13), (6.79±0.01) and (1.95±0.05) mmol/L, respectively) were significantly higher than those of non-carriers ((4.59±0.28), (3.35±0.39) and (0.86±0.10) mmol/L, t=7.269, 4.595, 6.311, respectively, P<0.05). Conclusions: LDLR-E140K gene homozygous mutation is first reported to be associated with most severe phenotype HoFH. The genotype-phenotype analysis of the pedigree shows that the clinical phenotype of the proband with homozygous mutation is the most serious, and all the heterozygous mutation carriers present with hypercholesterolemia phenotype. The investigation confirms that LDLR-E140K is the pathogenic variation of familial hyperlipidemia.


Asunto(s)
LDL-Colesterol/sangre , ADN/genética , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo I/genética , Receptores de LDL/genética , Válvula Aórtica/diagnóstico por imagen , Secuencia de Bases , Niño , Preescolar , Análisis Mutacional de ADN , Ecocardiografía Doppler , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/diagnóstico , Lactante , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Masculino , Proteínas de la Membrana , Mutación , Linaje , Fenotipo , Estudios Prospectivos
13.
Medicine (Baltimore) ; 99(5): e18947, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32000417

RESUMEN

INTRODUCTION: Congenital factor V deficiency (FVD) is a rare bleeding disorder characterized by low or undetectable plasma factor V (FV) levels leading to mild to severe bleeding symptoms. Currently, more than 100 mutations have been reported in F5. We herein report a patient with FVD from mutations in the F5 gene. PATIENT CONCERNS: A 52-year-old man with prolonged prothrombin time and activated partial thromboplastin time corrected by mixing test on preoperative screening. His past medical or family history was not remarkable. DIAGNOSIS: Factor assays revealed a markedly reduced FV activity at 7%. Other factors were not decreased. DNA sequencing analysis to detect F5 gene mutations showed the patient was compound heterozygous for c.286G>C (p.Asp96His) and c.2426del (p.Pro809Hisfs*2). Asp96His was previously described missense mutation and Pro809Hisfs*2 was a novel deleterious mutation. INTERVENTIONS: Fresh-frozen plasma was administered to supplement FV before surgery. OUTCOMES: Subsequent factor assays revealed temporarily increased FV activity at 33%. CONCLUSION: As was the case in our patient, genotype-phenotype correlations are poor in FVD, and molecular genetic test is necessary to confirm the diagnosis.


Asunto(s)
Deficiencia del Factor V/genética , Factor V/genética , Mutación , Diagnóstico Diferencial , Deficiencia del Factor V/cirugía , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Fenotipo
14.
Medicine (Baltimore) ; 99(5): e18975, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32000428

RESUMEN

INTRODUCTION: Spinal muscular atrophy (SMA) was the second most fatal autosomal recessive hereditary disease in clinic. There had been no detailed study to characterize the prevalence of SMA carrier among people in China. So, we conducted a systematic review and meta-analysis to obtain a reliable estimation of the prevalence of SMA carrier to characterize its epidemiology for the first time. METHODS: We systematically searched for articles in kinds of important electronic databases, including PubMed, Embase, Wanfang Database and China National Knowledge Infrastructure (CNKI) to identify all relevant literatures about carrier rates of SMA in China. The prevalence was performed by forest plot choosing random effect models. The publication bias was evaluated by means of funnel plots and Egger test. The sensitivity analysis was carried out by the method of omitting any literature at a time. Combined with the results of subgroup analysis, the source of heterogeneity was also discussed absolutely. RESULTS: A total of 10 studies published between 2005 and 2016 were included in our analysis at last. The sample size ranged from 264 to 107,611 in included studies. The random effect models of meta-analysis showed that the overall carrier rate of SMA was 2.0% (95% confidence interval [CI], 1.7%-2.3%) in a heterogeneous set of studies (I = 64%). There was a gradual rise trend observed in the SMA carrier rate during the study period. The funnel plots and Egger test (Coef = 0.02, t = -0.45, P = .667 > .05) showed no obvious potential risk of publication bias. CONCLUSION: The overall carrying rate of SMA was high as 2.0% and may be on a slow upward trend. So it was recommended that the countries should take active and effective measures to roll out routine prenatal screening and health genetic counseling for SMA as early as possible. What is more, further studies also need to be conducted to explore the etiology and epidemic factors of SMA to better control the risk of this common birth defect.


Asunto(s)
Heterocigoto , Atrofia Muscular Espinal/epidemiología , Atrofia Muscular Espinal/genética , China/epidemiología , Humanos , Prevalencia
15.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 97-101, 2020 Jan.
Artículo en Chino | MEDLINE | ID: mdl-31950797

RESUMEN

Objective: To analyse potential genetic cause of a family affected with hereditary elliptocytosis (HE). Methods: Peripheral blood samples from this HE family were collected. Targeted capture and high-throughput sequencing of 4 813 genetic disease-associated genes was performed in four members of the family. Possible causative genetic variation was obtained and further confirmed by Sanger sequencing. Fifty healthy control subjects were recruited for detection of the candidate variation. Results: High-throughput sequencing detected a nonsense mutation c.1215G>A(p.Trp405Ter)in exon 13 of the EPB41 gene in the proband and his mother presenting with moderate anemia. The pathogenicity of this loss-of-function mutation is very strong, because the G→A transition leads to introduce the premature stop codon instead of tryptophan codon at position 405, which producing a truncating protein with loss of important functional domains. This causative mutation is extremely rare in the population, and it has not yet been reported. The grandmother of the proband was heterozygous for the same mutation. Genotype-phenotype cosegregation was observed in this family. This mutation was not found in the 50 unrelated healthy controls. Conclusion: The c.1215G>A mutation of the EPB41 gene probably accounts for the disease in this HE family. This study reports a pathogenic EPB41 mutation in a Chinese HE family for the first time.


Asunto(s)
Proteínas del Citoesqueleto , Eliptocitosis Hereditaria , Proteínas de la Membrana , Mutación , Proteínas del Citoesqueleto/genética , Eliptocitosis Hereditaria/genética , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteínas de la Membrana/genética , Linaje
16.
BMC Infect Dis ; 20(1): 5, 2020 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-31900106

RESUMEN

BACKGROUND: Cysteine-cysteine chemokine receptor 5 is the main HIV co-receptor involved in the virus and cell-to-cell spread. A variant of the CCR5 gene known as CCR5-Δ32 which is a product of 32 base pair deletion in the gene plays critical role in the infection and progression to AIDS. The study was carried out to determine the CCR5 genotype of HIV-infected subjects attending University of Calabar Teaching Hospital, Calabar. METHODS: A total of 100 subjects attending HIV clinic, University of Calabar Teaching Hospital were purposively recruited for this study. DNA was extracted from each sample using the Quick gDNA miniprep DNA extraction kit, Zymo Research. Polymerase chain reaction (PCR) was used in the amplification of CCR5 gene in each DNA in a 9700 ABI Thermo cycler and then resolved on 4% agarose gel electrophoresis. RESULT: Out of the 100 samples assessed, 100 (100%) were homozygous for the CCR5 wild type gene (CCR5-wt), while none (0%) was homozygous for the CCR5-Δ32 (mutant type), and heterozygosity was not observed. CONCLUSION: This study observed absence of CCR5-Δ32 deletion gene among the studied subjects in Calabar, implying lack of genetic advantage in HIV infection and possible rapid progression towards AIDS if other precautions are not checked.


Asunto(s)
Infecciones por VIH/genética , Receptores CCR5/genética , Estudios Transversales , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Genotipo , Infecciones por VIH/patología , Infecciones por VIH/virología , VIH-1/genética , VIH-1/aislamiento & purificación , Heterocigoto , Hospitales de Enseñanza , Humanos , Masculino , Nigeria/epidemiología , Filogenia , Reacción en Cadena de la Polimerasa , Eliminación de Secuencia
17.
Cancer Sci ; 111(3): 840-848, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31925975

RESUMEN

Ionizing radiation can damage DNA and, therefore, is a risk factor for cancer. Eker rats, which carry a heterozygous germline mutation in the tumor-suppressor gene tuberous sclerosis complex 2 (Tsc2), are susceptible to radiation-induced renal carcinogenesis. However, the molecular mechanisms involved in Tsc2 inactivation are unclear. We subjected Fischer 344 × Eker (Long Evans Tsc2+/- ) F1 hybrid rats to gamma-irradiation (2 Gy) at gestational day 19 (GD19) or postnatal day 5 (PND5) and investigated the patterns of genomic alterations in the Tsc2 allele of renal tumors that developed at 1 year after irradiation (N = 24 tumors for GD19, N = 10 for PND5), in comparison with spontaneously developed tumors (N = 8 tumors). Gamma-irradiation significantly increased the multiplicity of renal tumors. The frequency of LOH at the chromosome 10q12 region, including the Tsc2 locus, was 38%, 29% and 60% in renal carcinomas developed from the nonirradiated, GD19 and PND5 groups, respectively. Array comparative genomic hybridization analysis revealed that the LOH patterns on chromosome 10 in renal carcinomas were classified into chromosomal missegregation, mitotic recombination and chromosomal deletion types. LOH of the interstitial chromosomal deletion type was observed only in radiation-associated carcinomas. Sequence analysis for the wild-type Tsc2 allele in the LOH-negative carcinomas identified deletions (nonirradiated: 26%; GD19: 21%) and base-substitution mutations (GD19: 4%). Reduced expression of Tsc2 was also observed in the majority of the LOH-negative carcinomas. Our results suggest that interstitial chromosomal deletion is a characteristic mutagenic event caused by ionizing radiation, and it may contribute to the assessment of radiation-induced cancer risk.


Asunto(s)
Neoplasias Renales/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Esclerosis Tuberosa/genética , Alelos , Animales , Deleción Cromosómica , Cromosomas Humanos Par 10/genética , Hibridación Genómica Comparativa/métodos , Rayos gamma/efectos adversos , Heterocigoto , Humanos , Masculino , Mutación/genética , Ratas , Ratas Endogámicas F344 , Ratas Long-Evans , Riesgo , Proteínas Supresoras de Tumor/genética
18.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 37-40, 2020 Jan 10.
Artículo en Chino | MEDLINE | ID: mdl-31922593

RESUMEN

OBJECTIVE: To determine the frequency, common chromosomal karyotypes and breakpoints, and involved regions among carriers of reciprocal translocations from Henan Province, and to explore the influence of common breakpoint regions on pregnancy and fetal development. METHODS: For 586 carriers of reciprocal translocations, the above features were retrospectively analyzed. RESULTS: The 586 reciprocal translocations were identified among 62 477 subjects, which yielded a frequency of 0.94%. Among these, 572 (0.92%) had abnormal fertility, and 14 (0.02%) had a history of abnormal fetal development. Statistical analysis showed that chromosomes 1, 4, 7 and 11 were most frequently involved, with t(11;22)(q25;q13) being the most common type of translocation. In total 437 breakpoint regions were identified, with 11q23, 22q13 and 1p36 being most frequently involved, which resulted in infertility, abortion, embryo death, congenital malformation, development delay, mental retardation or a normal phenotype. CONCLUSION: Above results indicated a 0.92% carrier rate for reciprocal chromosomal translocations in Henan. The location of breakpoint regions may affect the pregnancy and/or fetal development. Discovery of such regions may enable more accurate genetic, reproductive and developmental counseling for carriers, and provide reference for delineation of function and pathogenetic mechanism of the relevant genes.


Asunto(s)
Puntos de Rotura del Cromosoma , Translocación Genética , Femenino , Heterocigoto , Humanos , Cariotipo , Cariotipificación , Embarazo , Estudios Retrospectivos , Translocación Genética/genética
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 41-43, 2020 Jan 10.
Artículo en Chino | MEDLINE | ID: mdl-31922594

RESUMEN

OBJECTIVE: To explore the genetic basis of a patient featuring global developmental delay, intellectual disability, cleft palate, seizures and hypotonia. METHODS: Clinical examination and laboratory tests were carried out. Peripheral blood samples were obtained from the patient and his parents. Whole genomic DNA was extracted and subjected to next generation sequencing. Candidate variation was analyzed by using bioinformatic software and validated by Sanger sequencing. RESULTS: The proband was found to carry a heterozygous c.2117T>C (p.Leu706Pro) variant of the NEDD4L gene, which was a de novo variant validated by Sanger sequencing and predicted to be likely pathogenic according to the American College of Medical Genetics Guidelines. CONCLUSION: The heterozygous variant of c.2117T>C (p.Leu706Pro) of the NEDD4L gene probably underlies the disorders in the patient.


Asunto(s)
Ubiquitina-Proteína Ligasas Nedd4 , Heterotopia Nodular Periventricular , Pruebas Genéticas , Heterocigoto , Humanos , Discapacidad Intelectual/etiología , Discapacidad Intelectual/genética , Masculino , Mutación , Ubiquitina-Proteína Ligasas Nedd4/genética , Heterotopia Nodular Periventricular/complicaciones , Heterotopia Nodular Periventricular/genética
20.
BMC Med Genet ; 21(1): 1, 2020 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-31898538

RESUMEN

BACKGROUND: Hearing loss (HL) represents the most common congenital sensory impairment with an incidence of 1-5 per 1000 live births. Non-syndromic hearing loss (NSHL) is an isolated finding that is not part of any other disorder accounting for 70% of all genetic hearing loss cases. METHODS: In the current study, we reported a polygenic mode of inheritance in an NSHL consanguineous family using exome sequencing technology and we evaluated the possible effect of the detected single nucleotide variants (SNVs) using in silico methods. RESULTS: Two bi-allelic SNVs were detected in the affected patients; a MYO15A (. p.V485A) variant, and a novel MITF (p.P338L) variant. Along with these homozygous mutations, we detected two heterozygous variants in well described hearing loss genes (MYO7A and MYH14). The novel MITF p. Pro338Leu missense mutation was predicted to change the protein structure and function. CONCLUSION: A novel MITF mutation along with a previously described MYO15A mutation segregate with an autosomal recessive non-syndromic HL case with a post-lingual onset. The findings highlight the importance of carrying whole exome sequencing for a comprehensive assessment of HL genetic heterogeneity.


Asunto(s)
Heterogeneidad Genética , Pérdida Auditiva Sensorineural/genética , Factor de Transcripción Asociado a Microftalmía/genética , Miosinas/genética , Edad de Inicio , Alelos , Niño , Femenino , Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/fisiopatología , Heterocigoto , Homocigoto , Humanos , Masculino , Herencia Multifactorial/genética , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Secuenciación del Exoma Completo
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