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1.
Zhonghua Yi Xue Za Zhi ; 101(2): 115-121, 2021 Jan 12.
Artículo en Chino | MEDLINE | ID: mdl-33455126

RESUMEN

Objective: To perform the phenotype and genetic analysis on two families with moderate sensorineural hearing impairment and determine the cause of deafness. Methods: The phenotype and genetic analysis was performed on the two hearing impairment pedigrees coming to Chinese PLA General Hospital from January 2014 to August 2020. DNA samples of the proband from family 1 and the parents from family 2 were collected and tested through next generation sequencing on all deafness genes, and Sanger sequencing was performed to verify the mutation sites. The reported pathogenic variants of the otogelin-like (OTOGL) gene, the autosomal recessive inherited deafness genes that cause moderate sensorineural hearing loss and the clinical manifestations of the deafness genes that have the similar expression location as the OTOGL gene were summarized and analyzed. Results: The pathogenic variants in the families were compound heterozygous variants in the OTOGL gene c.2773C>T/c.2826C>G (p.Arg925*/p.Tyr942*) and c.4455G>A/c.875C>G (Trp1485*/p.Ser292*), respectively. c.2773C>T was an already reported pathogenic variant causing hearing impairment in the literature, while c.2826C>G, c.4455G>A and c.875C>G were novel reported variant sites. The above four variants were classified as pathogenic variants according to the variant interpretation standards and guideline of the Amercian College of Medical Genetics and Genomics. Conclusions: Pathogenic variants in OTOGL gene is an important genetic factor leading to moderate sensorineural hearing loss. The newly discovered variant sites c.2826C>G, c.4455G>A and c.875C>G enrich the variant spectrum of OTOGL gene. The results of the current study provide a basis for genetic counseling of the related families and a new target for the treatment of hereditary hearing loss in the future.


Asunto(s)
Sordera , Pérdida Auditiva Sensorineural , Genotipo , Pérdida Auditiva Sensorineural/genética , Humanos , Proteínas de la Membrana/genética , Mutación , Linaje , Fenotipo
2.
Zhonghua Yi Xue Za Zhi ; 101(2): 122-126, 2021 Jan 12.
Artículo en Chino | MEDLINE | ID: mdl-33455127

RESUMEN

Objective: To analyze the clinical characteristics and identify the causative gene of a case with congenital deafness. Methods: Detailed medical history and clinical examination of a 4-year-old male child with congenital deafness were conducted in the First Affiliated Hospital of Army Military Medical University in June 2016. He was diagnosed with sensorineural deafness. The venous blood of the child and his parents was drawn, and genomic DNA was extracted. Proband's DNA was performed with targeted capture of high-throughput sequencing, then Sanger sequencing was used to verify the suspected mutation and segregation in this pedigree. According to the genetic diagnosis of the proband's deafness, ophthalmic examinations were performed. Genetic prenatal diagnosis was performed when the proband's mother was pregnant again. Results: The patient was detected with p.Trp1466Ter/p.Tyr2042Ter compound heterozygous mutations of MYO7A gene with targeted high-throughput sequencing. The mutation of p.Trp1466Ter was a reported mutation, while p.Tyr2042Ter has not been reported. In addition to congenital deafness, retinitis pigmentosa was also found by ophthalmologic examination, and the patient was clinically diagnosed with Usher syndrome type 1. Amniocentesis and fetal DNA sequencing were performed on the repregnancy fetus of this family at 18 weeks of gestation. The heterozygous mutation of MYO7A gene p.Tyr2042Ter was found, and the other allele was the wild type, indicating that the child will not exhibit clinical manifestations of Usher syndrome type 1. Indeed, the second child passed neonatal hearing screening. Conclusions: The clinical features and genetic variants were delineated in this family with Usher syndrome type 1. The results of the current study have enriched the phenotype and genotype data of the disease and provided a basis for genetic counseling.


Asunto(s)
Síndromes de Usher , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación , Miosina VIIa , Miosinas/genética , Linaje , Embarazo , Diagnóstico Prenatal , Síndromes de Usher/genética
3.
Blood Coagul Fibrinolysis ; 32(1): 57-63, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33196512

RESUMEN

THE AIM OF THE REPORT WAS T: o explore the phenotype and genotype of a hereditary antithrombin deficient Chinese family. Functional and molecular analysis of the proband and his family members was performed. Online bioinformatics software was used to predict the pathogenicity of the novel mutation. ClustalX-2.1-win and PyMol software were applied to conservative analysis and generate molecular graphic images, respectively. Functional analysis had shown that the antithrombin (AT):A of the proband was reduced to 32% whereas AT:Ag was normal. Molecular analysis revealed a heterozygous missense mutation p. Leu417Gln in exon 7 of SERPINC1 gene. Bioinformatics and model analysis indicated that this mutation could affect the integrity of local intermolecular structures, resulting in a mild type of antithrombin deficiency but when combined with other genetic or acquired thrombophilic factors, patients may develop venous thrombosis. The p.Leu417Gln mutation was responsible for the decrease of AT:A in this family and caused type II antithrombin deficiency.


Asunto(s)
Mutación Missense/genética , Trombofilia/genética , Adolescente , Adulto , Anciano , Grupo de Ascendencia Continental Asiática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Adulto Joven
4.
Gene ; 765: 145129, 2021 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-32905827

RESUMEN

Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic disorders characterized by lower-limb spastic paralysis. We report on a family with three generations of autosomal dominant inheritance of HSP caused by a novel heterozygous splice-site mutation (c.303 + 2 T > C) in REEP1 that was confirmed by RFLP analysis. Carriers of the mutation, including one asymptomatic individual, showed a mild HSP phenotype with a wide range of intrafamilial variation. All symptomatic carriers had ankle contractures in addition to other classical clinical symptoms of HSP. Clinicians should suspect REEP1-related HSP in patients who show ankle contractures with other symptoms of HSP and should consider that these patients have asymptomatic carriers within their family.


Asunto(s)
Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Paraplejía Espástica Hereditaria/genética , Adulto , Familia , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Fenotipo , Empalme del ARN/genética , Paraplejía Espástica Hereditaria/fisiopatología
5.
PLoS One ; 15(12): e0241848, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33264312

RESUMEN

It was hypothesized that single-nucleotide polymorphisms (SNPs) extracted from text-mined genes could be more tightly related to causal variant for each trait and that differentially weighting of this SNP panel in the GBLUP model could improve the performance of genomic prediction in cattle. Fitting two GRMs constructed by text-mined SNPs and SNPs except text-mined SNPs from 777k SNPs set (exp_777K) as different random effects showed better accuracy than fitting one GRM (Im_777K) for six traits (e.g. backfat thickness: + 0.002, eye muscle area: + 0.014, Warner-Bratzler Shear Force of semimembranosus and longissimus dorsi: + 0.024 and + 0.068, intramuscular fat content of semimembranosus and longissimus dorsi: + 0.008 and + 0.018). These results can suggest that attempts to incorporate text mining into genomic predictions seem valuable, and further study using text mining can be expected to present the significant results.


Asunto(s)
Estudio de Asociación del Genoma Completo , Genoma/genética , Sitios de Carácter Cuantitativo/genética , Animales , Cruzamiento , Bovinos , Minería de Datos , Genómica , Genotipo , Músculos Isquiosurales/crecimiento & desarrollo , Músculos Isquiosurales/metabolismo , Humanos , Modelos Genéticos , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple/genética , República de Corea
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(12): 1340-1343, 2020 Dec 10.
Artículo en Chino | MEDLINE | ID: mdl-33306817

RESUMEN

OBJECTIVE: The CYP4V2 gene of two pedigrees affected with Bietti crystalline corneoretinal dystrophy was analyzed to indentify the cause of the disease and provide a basis for clinical diagnosis. METHODS: The probands were subjected to next generation sequencing (NGS). Suspected variants were verified by Sanger sequencing. Pathogenicity of the variants were searched through relevant databases and PubMed by following the ACMG guidelines. RESULTS: A homozygous variant in the CYP4V2 gene c. (802-8) _810delTCATACAGGTCATCGCTinsGC was detected in proband from pedigree 1, parents did not detect; CYP4V2 genes c. (802-8)_810delTCATACAGGTCATCGCTinsGC and c. 958 C>T (p.Arg320X) compound heterozygous variants existed in the proband of pedigree 2,both parents were variant carriers. The results of Sanger sequencing showed that the variant of CYP4V2 gene in the two families was consistent with the NGS sequencing. The c. (802-8)_810delTCATACAGGTCATCGCTinsGC of CYP4V2 gene was splicing variant, and both splicing variant and nonsense variant could produce truncated nonfunctional protein products. Based on standards and guidelines by American College of Medical Genetics and Genomics, the CYP4V2 genes c. (802-8)_810del TCATACAGGTCATCGCTinsGC and c. 958 C>T (p.Arg320X) were predicted to be pathogenic variants (PVS1+PS1+PM2+PM3). CONCLUSION: The homozygous variant c. (802-8) _810delTCATACAGGTCATCGCTinsGC and the complex heterozygous variants c. (802-8) _810delTCATACAGGTCATCGCTinsGC and c.958C>T (p.Arg320X) in CYP4V2 gene are the cause of the disease in the probands of two pedigrees , respectively.


Asunto(s)
Distrofias Hereditarias de la Córnea/genética , Distrofias Hereditarias de la Córnea/patología , Familia 4 del Citocromo P450/genética , Variación Genética , Enfermedades de la Retina/genética , Enfermedades de la Retina/patología , Humanos , Mutación , Linaje , Fenotipo
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(12): 1352-1355, 2020 Dec 10.
Artículo en Chino | MEDLINE | ID: mdl-33306820

RESUMEN

OBJECTIVE: To explore the genetic basis for a pedigree affected with X-linked recessive mental retardation Claes-Jensen type. METHODS: Genomic DNA was extracted from peripheral blood samples of the patient, his parents (phenotypically normal) and two elder brothers with similar clinical manifestations. Whole exome sequencing was carried out for the proband, and the result was verified by Sanger sequencing. RESULTS: The proband was found to harbor a hemizygous c.1565C>T missense variant in exon 11 of the KDM5C gene. The transition has resulted in replacement of serine by phenylalanine at position 522 (p.Ser522Phe). Sanger sequencing showed that the patient's two elder brothers and mother carried the same variant, which was predicted to be probably damaging by SIFT, PolyPhen2 and Mutation_Taster. The three affected brothers presented with similar clinical phenotypes characterized by mental retardation, speech delay, behavioral problem, self-limited epilepsy responsible to medication, short stature and microcephaly. The mother only had mild cognitive impairment and learning disability. The same variant was not found in their father and was unreported previously. CONCLUSION: The c.1565C>T (p.Ser522Phe) of the KDM5C gene probably underlay the X-linked recessive mental retardation Claes-Jensen type in this pedigree.


Asunto(s)
Histona Demetilasas , Retraso Mental Ligado al Cromosoma X , Anciano , Femenino , Histona Demetilasas/genética , Humanos , Masculino , Retraso Mental Ligado al Cromosoma X/genética , Retraso Mental Ligado al Cromosoma X/patología , Mutación Missense/genética , Linaje , Fenotipo , Secuenciación del Exoma Completo
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(12): 1360-1363, 2020 Dec 10.
Artículo en Chino | MEDLINE | ID: mdl-33306822

RESUMEN

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with N-acetylglutamate synthase deficiency. METHODS: Trio whole exome sequencing (WES) was carried out for the pedigree. Pathogenicity of the identified variant was predicted based on the latest recommendation of the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was provided for subsequent pregnancy through Sanger sequencing. RESULTS: Trio WES showed that the proband has carried compound heterozygous c.68delG and c.796G>C variants of NAGS gene, for which the mother and father were respectively heterozygous carriers. Neither variant was reported previously. Based on the ACMG guidelines, the c.68delG variant was classified as "likely pathogenic" (PVS1+PM2), while the c.796G>C variant was classified as with "uncertain significance" (PM2+BP4). Sanger sequencing validated the above findings, and only detected the heterozygous c.796G>C variant in the amniotic fluid sample. The fetus was followed up till 6 month after birth with no obvious abnormality. CONCLUSION: The compound heterozygous c.68delG and c.796G>C variants of the NAGS gene probably underlay the disorder in this pedigree, and the resulth asenabled genetic counseling and prenatal diagnosis for this pedigree.


Asunto(s)
Pruebas Genéticas , Diagnóstico Prenatal , Trastornos Innatos del Ciclo de la Urea , N-Acetiltransferasa de Aminoácidos/genética , China , Femenino , Humanos , Masculino , Mutación/genética , Linaje , Embarazo , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/genética , Secuenciación del Exoma Completo
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(12): 1364-1367, 2020 Dec 10.
Artículo en Chino | MEDLINE | ID: mdl-33306823

RESUMEN

OBJECTIVE: To analyze the dynamic variant and clinical subtype of a pedigree affected with spinocerebellar ataxia (SCA) by using fluorescent-labeled primer combined with capillary electrophoresis. METHODS: Genomic DNA was extracted from 8 members including 6 patients and 2 healthy individuals from the pedigree. Six pairs of fluorescent-labeled primers were designed to screen pathological variants in association with common subtypes of SCA including SCA1, SCA2, SCA3, SCA6, SCA12 and SCA17.The PCR products were detected by capillary electrophoresis. RESULTS: The number of CAG repeats in the SCA3 gene of the proband were determined as 8 and 70, exceeded the normal range(12 to 40), which suggested a diagnosis of SCA3. The other five patients were all detected with abnormal CAG repeats in the SCA3 gene, while the two healthy individuals were determined to be within the normal range. CONCLUSION: The abnormal expansion of CAG repeats in the SCA3 gene probably underlay the pathogenesis of the disease in this pedigree. Combined fluorescent-labeled primers PCR and capillary electrophoresis can detect dynamic variants among SCA patients with efficiency and accuracy.


Asunto(s)
Ataxina-3 , Enfermedad de Machado-Joseph , Proteínas Represoras , Repeticiones de Trinucleótidos , Ataxina-3/genética , Variación Genética , Humanos , Enfermedad de Machado-Joseph/genética , Linaje , Proteínas Represoras/genética , Repeticiones de Trinucleótidos/genética
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(12): 1368-1370, 2020 Dec 10.
Artículo en Chino | MEDLINE | ID: mdl-33306824

RESUMEN

OBJECTIVE: To detect pathological variants of the SLC12A3 gene in a Chinese pedigree affected with Gitelman syndrome (GS). METHODS: Clinical data and peripheral blood samples of the proband and his family members were collected. All exons of the SLC12A3 gene were amplified by PCR and subjected to Sanger sequencing. RESULTS: Sanger sequencing has revealed that the proband has carried a c.486_489 delTACG (p.Ile162Met fs*8) deletion and a heterozygous c.2890C>T (p.Arg964Trp) missense variant in the SLC12A3 gene. Neither variant was reported previously and was not found among healthy controls. CONCLUSION: The c.486_489delTACG (p.Ile162Met fs*8) and c.2890C>T (p.Arg964Trp) variants of the SLC12A3 gene probably underlay the GS in the proband. Above discovery has enriched the variant spectrum of GS.


Asunto(s)
Síndrome de Gitelman , China , Síndrome de Gitelman/genética , Heterocigoto , Humanos , Mutación/genética , Linaje , Miembro 3 de la Familia de Transportadores de Soluto 12/genética
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(12): 1376-1379, 2020 Dec 10.
Artículo en Chino | MEDLINE | ID: mdl-33306826

RESUMEN

OBJECTIVE: To detect potential variant in a male neonate affected with congenital nephrogenic diabetes insipidus (CNDI). METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples from the child and his parents. The whole coding regions of the arginine vasopressin V2 receptor (AVPR2) gene were amplified by PCR and subjected to Sanger sequencing. RESULTS: The patient presented recurrent fever and polyuria after birth. Multiple blood gas analyses indicated hypernatremia. Ultrasound showed bilateral hydronephrosis and hydroureter. The patient was partially responsive to hydrochlorothiazide. DNA analysis identified a hemizygous frameshift variant c.890-899delACCCGGAGGC in exon 2 of the AVPR2 gene in the proband. His mother was heterozygous for the same variant. CONCLUSION: The c.890-899delACCCGGAGGC variant of the AVPR2 gene probably underlies the CNDI in the child. Above discovery has enriched to spectrum of CNDI associated variants.


Asunto(s)
Diabetes Insípida Nefrogénica , Receptores de Vasopresinas , Adulto , Diabetes Insípida Nefrogénica/tratamiento farmacológico , Diabetes Insípida Nefrogénica/genética , Exones , Femenino , Mutación del Sistema de Lectura , Humanos , Hidroclorotiazida/uso terapéutico , Recién Nacido , Masculino , Linaje , Receptores de Vasopresinas/genética
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(12): 1391-1394, 2020 Dec 10.
Artículo en Chino | MEDLINE | ID: mdl-33306830

RESUMEN

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with inherited afibrinogenemia. METHODS: For the proband and his family members, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), Fibrin(ogen) degradation products (FDPs), D-dimer (D-D), plasminogen activity (PLG:A) and the TT mixed experiment with protamine sulfate were determined with a STAGO-R automatic coagulation analyzer. The activity and antigen of fibrinogen (Fg) in plasma were measured with the Clauss method and immunonephelometry method, respectively. All exons and flanking regions of the fibrinogen genes (FGA, FGB and FGG) were amplified by PCR and directly sequenced. Human Splicing Finder software was used to predict and score the change of splicing site caused by the mutation. RESULTS: The proband showed normal FDPs and D-D but significantly prolonged TT, PT and APTT. The activity and antigen of fibrinogen in plasma were significantly decreased (<0.1 g/L). His young sister and parents showed slightly prolonged TT (18.20-18.50 s) and decreased fibrinogen activity (1.27-1.54 g/L) and fibrinogen antigenic content (1.34-1.56 g/L). Genetic testing revealed that the proband has carried homozygous IVS7-12A>G (g.4147A>G) mutations of the FGG gene, for which his parents and young sister were heterozygous. As predicted by Human Splicing Finder and Mutation Taster software, the variant may generate a new splicing site which can extend the sequence of exon 7 by 11 bp, with alteration of the coding sequence. PROVEAN suggested the variant to be deleterious. CONCLUSION: The afibrinogenemia of the proband may be attributed to the FGG IVS7-12A>G variant, which was unreported previously.


Asunto(s)
Afibrinogenemia , Fibrinógeno , Adulto , Afibrinogenemia/genética , Femenino , Fibrinógeno/genética , Heterocigoto , Humanos , Masculino , Mutación , Linaje
13.
BMC Med Genet ; 21(1): 240, 2020 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-33308164

RESUMEN

BACKGROUND: In Morocco, consanguinity rate is very high; which lead to an increase in the birth prevalence of infants with autosomal recessive disorders. Previously, it was difficult to diagnose rare autosomal recessive diseases. Next Generation Sequencing (NGS) techniques have considerably improved clinical diagnostics. A genetic diagnosis showing biallelic causative mutations is the requirement for targeted carrier testing in parents, prenatal and preimplantation genetic diagnosis in further pregnancies, and also for targeted premarital testing in future couples at risk of producing affected children by a known autosomal recessive disease. METHODS: In this report, we present our strategy to advise a future couple of first cousins, whose descendants would risk cystinosis; an autosomal recessive lysosomal disease caused by mutations in the CTNS gene. Indeed, our future husband's sister is clinically and biochemically diagnosed with cystinosis in early childhood. First, we opted to identify the patient's CTNS gene abnormality by using (NGS), then we searched for heterozygosity in the couple's DNA, which allows us to predict the exact risk of this familial disease in the future couple's offspring. RESULTS: We have shown that the future husband, brother of the patient is heterozygous for the familial mutation. On the other hand, his future wife did not inherit the familial mutation. Therefore, genetic counseling was reassuring for the risk of familial cystinosis in this couple's offspring. CONCLUSIONS: We report in this study, one of the major applications of (NGS), an effective tool to improve clinical diagnosis and to provide the possibility of targeted premarital carrier testing in couples at risk.


Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/genética , Consanguinidad , Cistinosis/genética , Asesoramiento Genético , Mutación , Adulto , Sistemas de Transporte de Aminoácidos Neutros/deficiencia , Cistinosis/diagnóstico , Cistinosis/patología , Femenino , Expresión Génica , Pruebas Genéticas , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Marruecos , Linaje , Riesgo
14.
BMC Ophthalmol ; 20(1): 487, 2020 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-33308182

RESUMEN

BACKGROUND: Choroidal ganglioneuroma is an extremely rare tumor, and there is little knowledge regarding its pathogenesis. We aimed to investigate the phenotypic and genetic alterations in one sporadic patient with a rare case of bilateral choroidal ganglioneuroma. METHODS: A 6-year-old boy with histological diagnosis of bilateral ganglioneuroma was recruited for the study. Comprehensive ophthalmic examinations were performed. Genomic DNA was extracted from the peripheral blood samples collected from the patient, his unaffected family members, and 200 unrelated control subjects from the same population. Whole exome sequencing was performed and raw reads were aligned to the human genome reference (hg19) using Burrows-Wheeler Aligner. DNA from all available family members was Sanger sequenced for segregation analysis. RESULTS: Extensive bilateral retinal detachments were observed via optical coherence tomography. Diffuse thickening of choroid was identified with ultrasound B scan and magnetic resonance imaging. Genetic analysis revealed the presence of a novel heterozygous PTEN frameshift mutation, c.498delA (p.Thr167LeufsTer16), in exon 6. It was present in the affected individual, but not in any of the family members. Genetic analysis revealed that there was no mutation in neurofibromatosis-related genes in the family. Upon performing comprehensive systemic examinations, no obvious abnormalities in other organs were observed. CONCLUSIONS: A novel de novo PTEN mutation was identified in a patient with bilateral choroidal ganglioneuroma. Although PTEN mutations are known to induce multiple abnormalities, choroidal ganglioneuroma can be the first manifestation without abnormalities in other organs. Further studies are needed to confirm the association between choroidal ganglioneuroma and PTEN mutation.


Asunto(s)
Neoplasias de la Coroides/genética , Mutación del Sistema de Lectura/genética , Ganglioneuroma/genética , Fosfohidrolasa PTEN/genética , Adulto , Niño , Neoplasias de la Coroides/diagnóstico por imagen , Neoplasias de la Coroides/patología , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Femenino , Ganglioneuroma/diagnóstico por imagen , Ganglioneuroma/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Linaje , Desprendimiento de Retina/diagnóstico por imagen , Tomografía de Coherencia Óptica , Secuenciación Completa del Genoma
15.
J Stroke Cerebrovasc Dis ; 29(12): 105410, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33254371

RESUMEN

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vascular disease caused by the mutations of the NOTCH3 gene. The NOTCH3 gene consists of 33 exons. The pathogenic mutations of the NOTCH3 gene in CADASIL are located in 2-24 exons coding for the 34 EGFr (epidermal growth factor-like repeat) domains. The classical clinical manifestations are recurrent TIA or ischaemic stroke, migraine, cognitive disorder and affective disorder. The deposition of granular osmiophilic material (GOM) in the vascular wall is considered as a hallmark of the disease. METHODS: Here, we report a rare pathogenic mutation on exon 29 of the NOTCH3 gene in a Chinese family. Clinical data for the proband and available relatives is collected. Mutation analysis of the NOTCH3 gene was performed by screening the entire 33 exons in this family and 200 normal controls. A complete imaging evaluation and skin biopsy were performed on the proband. RESULTS: We identified a novel R1761H (c.5282G>A) mutation. The same mutation was not founded in 200 normal controls. The proband had recurrent stroke, depression, cognitive decline and cerebral lobe hemorrhage. Cranial MRI showed white matter lesions and multiple infarction. Susceptibility weighted imaging revealed numerous microbleeds.Most importantly, the deposition of GOM was found in the proband. CONCLUSION: 33 exons of NOTCH3 gene should be performed for individuals with a convincing CADASIL phenotype and positive family history.


Asunto(s)
CADASIL/genética , Exones , Mutación Missense , Receptor Notch3/genética , Adulto , CADASIL/diagnóstico , Predisposición Genética a la Enfermedad , Herencia , Heterocigoto , Humanos , Masculino , Linaje , Fenotipo , Dominios Proteicos , Receptor Notch3/química
16.
BMC Bioinformatics ; 21(1): 569, 2020 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-33297934

RESUMEN

BACKGROUND: Pedigree files are ubiquitously used within bioinformatics and genetics studies to convey critical information about relatedness, sex and affected status of study samples. While the text based format of ped files is efficient for computational methods, it is not immediately intuitive to a bioinformatician or geneticist trying to understand family structures, many of which encode the affected status of individuals across multiple generations. The visualization of pedigrees into connected nodes with descriptive shapes and shading provides a far more interpretable format to recognize visual patterns and intuit family structures. Despite these advantages of a visual pedigree, it remains difficult to quickly and accurately visualize a pedigree given a pedigree text file. RESULTS: Here we describe ped_draw a command line and web tool as a simple and easy solution to pedigree visualization. Ped_draw is capable of drawing complex multi-generational pedigrees and conforms to the accepted standards for depicting pedigrees visually. The command line tool can be used as a simple one liner command, utilizing graphviz to generate an image file. The web tool, https://peddraw.github.io , allows the user to either: paste a pedigree file, type to construct a pedigree file in the text box or upload a pedigree file. Users can save the generated image file in various formats. CONCLUSIONS: We believe ped_draw is a useful pedigree drawing tool that improves on current methods due to its ease of use and approachability. Ped_draw allows users with various levels of expertise to quickly and easily visualize pedigrees.


Asunto(s)
Biología Computacional/métodos , Linaje , Programas Informáticos , Humanos
17.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(6): 2033-2038, 2020 Dec.
Artículo en Chino | MEDLINE | ID: mdl-33283738

RESUMEN

OBJECTIVE: To analyze the molecular pathogenesis by analysis of phenotype and gene mutation in families with hereditary coagulation factor V (FⅤ) defect caused by complex heterozygous mutation. METHODS: Plasma pro-thrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), FⅤ procoagulant activity (FⅤ∶C), FⅤ antigen (FⅤ∶Ag), and other related coagulation indexes were detected in the proband and his family members (3 generations 10 people). Using DNA direct sequencing to analyze all exons, flanks, 5' and 3' untranslated regions of F5 genes and the corresponding mutation site regions of family members, the mutation site was confirmed by reverse sequencing.The conservation of mutant amino acids was analyzed by ClustalX-2.1-win software. The PROVEAN and MutationTaster online bioinformatics software were used to predict the effect of mutation on protein function. Protein model and amino acid interaction at mutation sites was analyzed by Swiss-pdbviewer software. RESULTS: The PT and APTT of the proband were significantly prolonged compared with healthy controls (34.2 vs 13.2 s and 119.3 vs 36.0 s), while FⅤ∶C and FⅤ∶Ag extremely reduced (3% and 6%). The PT and APTT of the second-born, the third son, daughter, and grandson of the proband were slightly prolonged, and the FⅤ∶C and FⅤ∶Ag decreased to varying degrees. The related coagulant parameters of other family members were within normal range. Genetic analysis revealed that the proband had a c.911G>A heterozygous missense mutation on the exon 6 lead to p.Gly276Glu, and a c.5343C>G heterozygous missense mutation on the exon 16 lead to p.Ser1781Arg of the proband. The second-born, the third son, and grandson of the proband carry p.Gly276Glu heterozygotes, and the daughter carries p.Ser1781Arg heterozygotes, while the other family members were wild-type. The results of conservative analysis indicated that p.Gly276 and p.Ser1781 were highly conserved in homologous species. The two bioinformatics software predicted the same results, PROVEAN (score -6.214 and -12.79) indicated that the compound heterozygous mutation was a harmful mutation; MutationTaster (score 0.976 and 0.999) suggested that these mutations might cause corresponding disease. p.Gly276Glu protein model analysis showed that, the Glu side chain was prolonged and the molecular weight became larger, which would increase the steric hindrance between it and the surrounding amino acids, affect the normal local folding of the FⅤ protein, and eventually lead to the decrease of protein activity and content. This paper can not provide analysis of the spatial structure of p.Ser1781Arg mutant protein because of the lack of X ray 3 D structure file of FⅤ exon 16. CONCLUSION: The new compound heterozygous mutations (p.Gly276Glu and p.Ser1781Arg) identified in this study are the main reasons for the decrease in the FⅤ level of the family, among which p.Ser1781Arg is rarely reported at home and abroad.


Asunto(s)
Factor V , Familia , Factor V/genética , Genotipo , Heterocigoto , Humanos , Mutación , Linaje , Fenotipo
18.
Fa Yi Xue Za Zhi ; 36(5): 691-698, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33295173

RESUMEN

Abstract: Complex kinship analysis refers to a kind of special kinship analysis taken for the purpose of personal identification or other issues in civil or criminal cases because the father or (and) mother is dead, or cannot participate in the analysis for other reasons. Due to the absence of significant appraised persons in this kind of kinship analysis, grandparents, siblings or collateral relatives are required to participate in the analysis. Complex kinship analysis is widely used and the demand is increasing year by year. This paper analyzes the main types of complex kinships, the genetic markers of complex kinship analysis and their advantages and disadvantages and the calculation methods for complex kinship analysis by referring to the relevant literatures at home and abroad in recent years. At the same time, the shortcomings of the present research on complex kinship and its future development are prospected.


Asunto(s)
Investigación , Hermanos , Marcadores Genéticos , Humanos , Linaje
19.
Zhonghua Yi Xue Za Zhi ; 100(45): 3622-3625, 2020 Dec 08.
Artículo en Chino | MEDLINE | ID: mdl-33333687

RESUMEN

Objective: To report a Chinese family with hypokalemic periodic paralysis (HOKPP) and investigate the clinical and pathogenic gene characteristics of the family. Methods: The clinical, electrophysiological and pathological data of the proband of the family were analyzed, and the information of the family was investigated in detail. The peripheral venous blood of the six members of the family was collected and their genomic DNA was extracted. The genes related to periodic paralysis analysis of the proband were performed by the second generation sequencing. The pathogenicity of the mutant protein was respectively analyzed by the bioinformatics software SIFT, Polyphen2 and Mutation Tasker. The cosegregation analysis of phenotype and genotype of the family was performed by the first generation sequencing. Results: There were 3 patients in the family with the onset age of 21 to 42 years old. All the patients manifested with vomiting as the first symptoms, then presented with muscle weakness accompanied by muscle soreness. The muscle weakness gradually relieved in 3 to 5 days. Creatine kinase (CK) of the proband significantly increased. Electromyographic exercise test was positive, however, electromyography and muscle pathological analysis were normal. The genes related to periodic paralysis analysis of the proband found a novel mutation (c.2458A>T (p.N.820Y)) of SCN4A gene which was located in the conservative region. The function analysis showed it was a pathogenic mutation. Moreover, the first generation sequencing confirmed that the mutation was cosegregated with patients in the family. Meanwhile, it was found that the proband's son carried the same mutation, but without any symptom, indicating that he was a pre-symptomatic patient. Conclusions: Vomiting can be one of the symptoms of the patients with HOKPP. The novel mutation of SCN4A gene c.2458 A>T is the pathogenic mutation of the family. Patients with periodic paralysis should be tested for blood potassium and genes as early as possible to facilitate early diagnosis and genetic counseling.


Asunto(s)
Parálisis Periódica Hipopotasémica , Adulto , Grupo de Ascendencia Continental Asiática/genética , Humanos , Parálisis Periódica Hipopotasémica/genética , Masculino , Mutación , Canal de Sodio Activado por Voltaje NAV1.4/genética , Linaje , Adulto Joven
20.
Am J Hum Genet ; 107(6): 1044-1061, 2020 12 03.
Artículo en Inglés | MEDLINE | ID: mdl-33159882

RESUMEN

Heparan sulfate belongs to the group of glycosaminoglycans (GAGs), highly sulfated linear polysaccharides. Heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) is one of several specialized enzymes required for heparan sulfate synthesis and catalyzes the transfer of the sulfate groups to the sugar moiety of heparan sulfate. We report bi-allelic pathogenic variants in HS2ST1 in four individuals from three unrelated families. Affected individuals showed facial dysmorphism with coarse face, upslanted palpebral fissures, broad nasal tip, and wide mouth, developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, flexion contractures, brachydactyly of hands and feet with broad fingertips and toes, and uni- or bilateral renal agenesis in three individuals. HS2ST1 variants cause a reduction in HS2ST1 mRNA and decreased or absent heparan sulfate 2-O-sulfotransferase 1 in two of three fibroblast cell lines derived from affected individuals. The heparan sulfate synthesized by the individual 1 cell line lacks 2-O-sulfated domains but had an increase in N- and 6-O-sulfated domains demonstrating functional impairment of the HS2ST1. As heparan sulfate modulates FGF-mediated signaling, we found a significantly decreased activation of the MAP kinases ERK1/2 in FGF-2-stimulated cell lines of affected individuals that could be restored by addition of heparin, a GAG similar to heparan sulfate. Focal adhesions in FGF-2-stimulated fibroblasts of affected individuals concentrated at the cell periphery. Our data demonstrate that a heparan sulfate synthesis deficit causes a recognizable syndrome and emphasize a role for 2-O-sulfated heparan sulfate in human neuronal, skeletal, and renal development.


Asunto(s)
Huesos/anomalías , Cuerpo Calloso/patología , Discapacidades del Desarrollo/genética , Riñón/anomalías , Sulfotransferasas/genética , Adolescente , Alelos , Biopsia , Niño , Preescolar , Matriz Extracelular/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Salud de la Familia , Femenino , Fibroblastos/metabolismo , Variación Genética , Heparitina Sulfato/metabolismo , Humanos , Ácido Idurónico/farmacología , Recién Nacido , Masculino , Linaje , Fenotipo , Síndrome , Anomalías Urogenitales/genética
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