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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 586-590, 2021 Apr.
Artículo en Chino | MEDLINE | ID: mdl-33812435

RESUMEN

OBJECTIVE: To detect and analyze coagulation related indexes and genotypes of a patient with congenital fibrinogen deficiency and his family members, and to investigate the possible molecular pathogenesis. METHODS: Four peripheral blood samples (proband and 3 family members) were collected and the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg), D-Dimer and eight coagulation factor indicators were detected. All exons and flanking sequences of the FGA, FGB, and FGG genes encoding the three peptide chains of fibrinogen were sequenced and analyzed by bioinformatics. RESULTS: Among the eight coagulation factors of the proband and the elder sister, F Ⅴ and F Ⅷ were slightly higher, TT was significantly prolonged, and Fg was significantly reduced. Sequencing results showed that c.901C>T heterozygous mutation existed in the FGG gene. Bioinformatics analysis showed that the mutation changed the original protein structure and reduced the number of hydrogen bonds. CONCLUSION: The fibrinogen gamma chain c.901C>T heterozygous mutation is the main cause of congenital fibrinogen deficiency in this family. This mutation is reported for the first time at home and abroad.


Asunto(s)
Afibrinogenemia , Afibrinogenemia/genética , Anciano , Fibrinógeno/genética , Heterocigoto , Humanos , Mutación , Linaje
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 591-595, 2021 Apr.
Artículo en Chino | MEDLINE | ID: mdl-33812436

RESUMEN

OBJECTIVE: To test the anticoagulation functions, perform the genetic diagnosis and analyze the clinical characteristics in a family with combined heterozygous genetic variants of PROC and PROS1. METHODS: Peripheral blood was collected from all the family members. Hematological phenotypes and activity of anticoagulant factors were analyzed. Target genes were amplified by PCR from DNA isolated from peripheral blood, and then were analyzed by Sanger DNA sequencing. RESULTS: Many members in the family displayed the combined genetic variants in protein C and protein S, and six family members accompanied by deep venous thrombosis (DVT). The influences of genetic and secondary factors on the incidence of venous thrombosis in the family members were analyzed. The results showed that in this family, carriers of combined protein C and protein S gene defects had a higher incidence of VTE, but acquired factors still played a key role in the eventual thrombotic symptoms. CONCLUSION: Venous thromboembolism (VTE) is a multifactorial disease, the combined genetic heterozygous mutations of protein C and S is an important genetic factor, and the clinical phenotype show a high heterogenicity, the secondary factors contribute to the VTE incidence.


Asunto(s)
Tromboembolia Venosa , Trombosis de la Vena , Heterocigoto , Humanos , Mutación , Proteína C/genética , Proteína S/genética , Factores de Riesgo , Trombosis de la Vena/genética
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 596-620, 2021 Apr.
Artículo en Chino | MEDLINE | ID: mdl-33812437

RESUMEN

OBJECTIVE: To detecte the carrying rate, the type and distribution of α-Thalassemia gene mutation in Honghe Prefecture, Yunnan Province, and analyze the differences in average erythrocyte volume (MCV), mean erythrocyte hemoglobin content (MCH) and hemoglobin among different types of α-Thalassemia. METHODS: The DNA samples from small cell hypochromic carriers or anemia patients and women of childbearing age who underwent hematological screening in The First People's Hospital of Honghe State was from 2015 to 2019 were enrolled and analyzed, and the mutation types and frequency of alpha-thalassemia positive rate were diagnosed by PCR reverse dot blot or PCR fluorescence dissolution curve. RESULTS: Among the 1 016 samples, 141(13.88%) of the patients were diagnosed as α-thalassemia. The α-thalassemia was subdivided into 3 types, silent (36.17%), minor (51.77%), and HbH disease (12.06%), and the MCV, MCH and HB levels were detected and showed a obvious decrease trend with significant difference (P < 0.05). The gene mutation types were 9 kinds, the deletion type gene was mainly --SEA (51.06%), followed by -α3.7/αα deletion (29.79%), the α- mutation type gene was mainly αcsα(3.55%). The absence of complex heterozygote was most common, which was 17 cases, accounting for 12.77%, mainly --SEA/-α3.7 (10.64%). The areas were mainly distributed in Mengzi (47.52%), followed by Jinping (17.02%). Ethnic groups were mainly distributed in Han nationality (49.65%), followed by Zhuang (15.60%), Yi (3.48%) and Dai (7.09%). The patients with double heterozygous mutation was slightly higher in Mengzi than that in Jinping County (4.26% vs 3.55%), the Dai (2.13%) showed Zhuang ethnic group (2.13%) had the relatively high incidence except the Hans, and showed the most serious anemia. CONCLUSION: Alpha-thalassemia in Honghe prefecture of Yunnan Province shows complex genetic diversity and significant genetic heterogeneity, and the mainly type of gene mutation is --SEA and --SEA/-α3.7, which is mainly distributed in Han, Zhuang and Dai ethnic groups in Mengzi, Jinping. The anemia index of HbH group is the most obvious, and it is significantly different from other groups.


Asunto(s)
Talasemia alfa , Talasemia beta , China , Femenino , Genotipo , Heterocigoto , Humanos , Mutación , Talasemia alfa/genética
4.
Artículo en Ruso | MEDLINE | ID: mdl-33728854

RESUMEN

OBJECTIVE: In the course of studies of spastic paraplegias in Russian patients to detect AP4-associated forms, estimate their proportion in the total SPG group and analyze clinical and molecular characteristics. MATERIAL AND METHODS: Five families of Russian ethnicity: four with SPG47, one with SPG51 (4 girls and a boy aged 2.5-9 years) were studied. Clinical and genealogical methods, whole-exome sequencing (WES) and verification by familial Sanger sequencing were used. RESULTS: In our total group, including 118 families with 21 different forms, SPG AP4-associated forms accounted for 4.2% owing mainly to SPG47 (3.4%, 5th place in SPG structure; 20% and 2nd place in AE subgroup.) In non-consanguineous, unrelated SPG47 families three patients had identical genotypes: homozygosity for an earlier reported mutation c.1160_1161 delCA (p.Thr387ArgfsTer30) in AP4B1 exon 6; the 4th patient was compound-heterozygous for the same mutation and novel c.1240C>T (p.Gln414Ter) in exon 7. Frequency of c.1160_1161 delCA may be caused by founder effect in Slavic populations though the idea needs additional studies. The SPG51 patient was compound heterozygous for novel AP4E1 mutations c.2604delA (p.Ser868fs) and c.3346A>G (p.Arg1116Gly). Parent's heterozygosity in all cases was confirmed by Sanger sequencing. Phenotypes were typical: early development delay, muscle hypotony transforming into sever spasticity, mental deficiency, microceplaly (in all SPG47 cases), epilepsy (in 3 SPG47 and SPG51 cases), MRI changes, mainly hydrocephalus and/or hypoplasia of corpus callosum (in 3 SPG47 cases) and few extraneural signs. CONCLUSION: AP4-associated SPG should be taken into consideration in patients with early-onset severe nervous diseases mimicking non-genetic organic CNS disorders and massive exome sequencing (WES or other variants) should be performed.


Asunto(s)
Paraplejía Espástica Hereditaria , Niño , Preescolar , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Mutación , Linaje , Fenotipo , Federación de Rusia , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética
5.
Medicine (Baltimore) ; 100(9): e24620, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33655926

RESUMEN

RATIONALE: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital skeletal deformities and soft tissue masses that progress into heterotopic ossification. Deformities of the great toes are distinctive and heterotrophic ossification usually begins in the first decade of the patient's life. Any invasive procedure could potentially trigger a flare and heterotopic calcification. The diagnosis is difficult and there is no effective treatment for FOP and the approximate life expectancy is 4 decades. PATIENT CONCERNS: A 22-year-old male patient who had suffered from pain and movement limitations for 14 years. At the early stage of disease, the child underwent an operation on both thighs with a diagnosis of myophagism. He had serious stiffness and multiple bony masses with the characteristic bilateral hallux valgus deformity and microdactyly. DIAGNOSES: The patient was diagnosed with FOP by the help of characteristic great toe malformations and widespread heterotopic ossification throughout the body. Deoxyribonucleic acid sequencing demonstrated that the patient had a de novo heterozygous mutation (c.617G>A; p.R206H) in activin A receptor/activin-like kinase 2. INTERVENTIONS: We administered a co-therapy of glucocorticoids, NSAIDs to relieve pain, and montelukast for 2 months. Bisphosphonate (5 mg, intravenous) was used once. OUTCOMES: At the follow-up 12 months later, the patient still felt low back pain sometimes and need take NSAIDs three times a week. LESSONS: Clinicians and radiologists should realize the characteristic features of FOP and early diagnosis can prevent additional invasive harm to the patient.


Asunto(s)
Receptores de Activinas Tipo I/genética , Mutación/genética , Miositis Osificante/genética , Hallux/anomalías , Heterocigoto , Humanos , Masculino , Osificación Heterotópica/genética , Adulto Joven
6.
Medicine (Baltimore) ; 100(10): e24161, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33725819

RESUMEN

ABSTRACT: Propionic acidemia is associated with pathogenic variants in PCCA or PCCB gene. We investigated the potential pathogenic variants in PCCA or PCCB genes in Fujian Han population.Two probands and their families of Han ethnicity containing two generations were subject to newborn screening using tandem mass spectrometry, followed by diagnosis using urine gas chromatography mass spectrometry. Sanger sequencing was used to identify potential mutations in PCCA and PCCB genes.Compound heterozygous variants were identified in PCCB gene in two siblings of the first family, the youngest girl showed a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 and a heterozygous missense variant c.1301C>T (p.Ala434Val) in exon 13, which were inherited respectively from their parents. The oldest boy is a carrier with a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 which were inherited from his father. In the second family, c.1535G>A homozygous mutations were identified in the baby girl, which were inherited respectively from their parents. In silico analysis, several different types of bioinformatic software were utilized, which predicted that the novel variant c.1381G>C in PCCB gene was damaged. According to ACMG principle, the missense variant c.1381G>C (p.Ala461Pro) in exon 13 was a Variant of Undetermined Significance (VUS).One novel missense variant and two missense variants in PCCB gene were identified in the study. The novel variant of PCCB gene identified VUS was identified for the first time in the Chinese population, which enriched the mutational spectrum of PCCB gene.


Asunto(s)
Metilmalonil-CoA Descarboxilasa/genética , Acidemia Propiónica/genética , Grupo de Ascendencia Continental Asiática/genética , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Lactante , Recién Nacido , Mutación Missense , Tamizaje Neonatal , Linaje , Acidemia Propiónica/sangre , Acidemia Propiónica/diagnóstico , Espectrometría de Masas en Tándem
7.
Medicine (Baltimore) ; 100(10): e24991, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33725872

RESUMEN

RATIONALE: Crouzon syndrome is an autosomal dominant genetic disorder caused by mutations in fibroblast growth factor receptor 2 (FGFR2) and one of the most common types of craniosynostosis. Here we report the detection of FGFR2 mutation and its related clinical findings in 2 patients with Crouzon syndrome from a Chinese family. PATIENT CONCERNS: We report a case of a 28-year-old male patient presented with the chief complaint of gradually blurring of his eyes over the last 6 months before visiting our clinics. History revealed low visual acuity in his right eye since childhood. Physical examination showed that both the patient and his mother have the appearance of craniofacial dysostosis, mandibular prognathism, ocular proptosis, short superior lip, scoliosis, and thoracic deformity. DIAGNOSIS: Auxiliary examinations lead to the diagnosis of Crouzon syndrome with binocular optic atrophy, myelinated retina nerve fibers, and ametropia in both eyes, and amblyopia in the right eye of the male patient. The molecular genetic analysis confirmed the diagnosis by detecting a heterozygous pathogenic mutation c.1026C > G (C342W) in exon 10 of FGFR2 in both the patient and his mother, but not in any of the unaffected family members. INTERVENTIONS AND OUTCOMES: None. LESSONS: Our study confirms the presence of optic nerve atrophy in patients with Crouzon syndrome carrying FGFR2 C342W mutations and indicates that MRI and funduscopy should be performed to examine the optic nerve changes for patients with Crouzon syndrome.


Asunto(s)
Disostosis Craneofacial/complicaciones , Atrofias Ópticas Hereditarias/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Adulto , China , Disostosis Craneofacial/genética , Análisis Mutacional de ADN , Exones/genética , Femenino , Angiografía con Fluoresceína , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Mutación Missense , Atrofias Ópticas Hereditarias/diagnóstico , Nervio Óptico/diagnóstico por imagen , Linaje , Tomografía Computarizada por Rayos X
8.
Adv Clin Exp Med ; 30(3): 289-299, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33757164

RESUMEN

BACKGROUND: 3ß-HSD deficiency is a rare type of congenital adrenal hyperplasia (CAH), which is caused by HSD3B2 gene mutations. OBJECTIVES: In order to improve the understanding and diagnosis of the disease, we analyzed and summarized the clinical characteristics, genetic variants and treatment for 3 children with 3ß-HSD deficiency in this study. MATERIAL AND METHODS: A summary of the clinical data, hormone levels (17-hydroxyprogesterone, adrenocorticotropic hormone, cortisol, testosterone, dehydroepiandrosterone, androstenedione, renin, and aldosterone), therapeutic drugs, and gene sequencing results from 3 3ß-HSD deficiency patients was created. RESULTS: The 3 patients developed external genital abnormalities and adrenal insufficiency in infancy. Steroid hormone levels were consistent with 3ß-hydroxysteroid dehydrogenase deficiency. Gene sequencing for the 3 patients detected complex heterozygous mutations in the HSD3B2 gene, which confirmed the diagnosis of 3ß-HSD deficiency type II. Among the mutation types, c.154_162delinsTCCTGTT and c.674T>A have not been reported in the literature. The 3 children were treated with glucocorticoid and mineralocorticoid replacement, which controlled the adrenal insufficiency satisfactorily. In 2 male patients, external genital dysplasia manifested as hypospadias and small penis. After long-acting testosterone intramuscular injection to increase the penis size, the hypospadias were repaired. Mild masculinization in the female patient resulted in skin pigmentation and clitoral hypertrophy; however, no surgical intervention was required. CONCLUSIONS: The main clinical manifestations of 3ß-HSD deficiency were adrenal insufficiency and sex hormone synthesis dysfunction. There was a strong phenotype correlation between the observed clinical manifestations in conjunction with steroid hormone levels and HSD3B2 mutations. The novel mutations c.154_162delinsTCCTGTT and c.674T>A were classified as pathogenic variants. Adrenal cortical function control was satisfactory after hormone replacement therapy, and hypospadias and small penis were attenuated using testosterone replacement therapy during mini-puberty for optimal surgical outcome.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/genética , Niño , Femenino , Heterocigoto , Humanos , Hidrocortisona , Masculino , Mineralocorticoides
9.
Methods Mol Biol ; 2212: 105-120, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33733353

RESUMEN

Reliable methods of phenotype prediction from genomic data play an increasingly important role in many areas of plant and animal breeding. Thus, developing methods that enhance prediction accuracy is of major interest. Here, we provide three methods for this purpose: (1) Genomic Best Linear Unbiased Prediction (GBLUP) as a model just accounting for additive SNP effects; (2) Epistatic Random Regression BLUP (ERRBLUP) as a full epistatic model which incorporates all pairwise SNP interactions, and (3) selective Epistatic Random Regression BLUP (sERRBLUP) as an epistatic model which incorporates a subset of pairwise SNP interactions selected based on their absolute effect sizes or the effect variances, which is computed based on solutions from the ERRBLUP model. We compared the predictive ability obtained from GBLUP, ERRBLUP, and sERRBLUP with genotypes from a publicly available wheat dataset and respective simulated phenotypes. Results showed that sERRBLUP provides a substantial increase in prediction accuracy compared to the other methods when the optimal proportion of SNP interactions is kept in the model, especially when an optimal proportion of SNP interactions is selected based on the SNP interaction effect sizes. All methods described here are implemented in the R-package EpiGP, which is able to process large-scale genomic data in a computationally efficient way.


Asunto(s)
Epistasis Genética , Modelos Genéticos , Modelos Estadísticos , Fenotipo , Carácter Cuantitativo Heredable , Triticum/genética , Conjuntos de Datos como Asunto , Estudios de Asociación Genética , Genotipo , Heterocigoto , Fitomejoramiento/métodos , Tumores de Planta/genética , Tumores de Planta/microbiología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Triticum/anatomía & histología , Triticum/metabolismo
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(3): 214-218, 2021 Mar 10.
Artículo en Chino | MEDLINE | ID: mdl-33751527

RESUMEN

OBJECTIVE: To carry out prenatal diagnosis for families with high risk for spinal muscular atrophy (SMA) by using multiplex ligation-dependent probe amplification (MLPA). METHODS: Twenty-one families were enrolled. MLPA was used to detect copy numbers of SMN1 and SMN2 genes. Maternal contamination was excluded by using a short tandem repeat method. RESULTS: For 23 fetuses from the 21 families, 14 were identified as carriers, 1 as SMA patient, and 8 as normal. By linkage analysis of parental samples, three individuals were determined as silent (2+0) carriers. CONCLUSION: MLPA can determine the carrier status of SMA. The identification of three silent (2+0) carriers among the 44 parental samples indicated a risk for such families, for which genetic counseling and reproduction guidance should be provided.


Asunto(s)
Asesoramiento Genético , Atrofia Muscular Espinal , Diagnóstico Prenatal , Femenino , Heterocigoto , Humanos , Reacción en Cadena de la Polimerasa Multiplex , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Embarazo , Proteína 1 para la Supervivencia de la Neurona Motora/genética
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(3): 242-246, 2021 Mar 10.
Artículo en Chino | MEDLINE | ID: mdl-33751533

RESUMEN

OBJECTIVE: To analyze the clinical phenotype and genetic basis for a Chinese pedigree affected with coagulation factor XI (FXI) deficiency. METHODS: Activated partial thromboplastin time (APTT) and other blood coagulation factors, and activities of FXI:C and other relevant coagulation factors for a large Chinese pedigree including 6 patients from 3 generations were determined on a Stago automatic coagulometer. The FXI:Ag was determined with an ELISA method. All exons and flanking regions of the F11 gene were subjected to Sanger sequencing. ClustalX-2.1-win software was used to analyze the conservation of amino acids. Pathogenicity of the variants was predicted with online bioinformatics software including Mutation Taster and Swiss-Pdb Viewer. RESULTS: The APTT of the proband was prolonged to 94.2 s. The FXI:C and FXI:Ag were decreased to 1% and 1.3%, respectively. The APTT of her father, mother, son and daughter was 42.1 s, 43.0 s, 42.5 s and 41.0 s, respectively. The FXI:C and FXI:Ag of them were almost halved compared with the normal values. The APTT, FXI:C and FXI:Ag of her husband were all normal. Genetic testing revealed that the proband has carried a heterozygous missense c.1103G>A (p.Gly350Glu) variant in exon 10 and a heterozygous missense c.1556G>A (p.Trp501stop) variant in exon 13 of the F11 gene. The father and daughter were heterozygous for the c.1103G>A variant, whilst the mother and son were heterozygous for the c.1556G>A variant. Both Gly350 and Trp501 are highly conserved among homologous species, and both variants were predicted to be "disease causing" by Mutation Taster. Protein modeling indicated there are two hydrogen bonds between Gly350 and Phe312 in the wild-type, while the p.Gly350Glu variant may add a hydrogen bond to Glu and Tyr351 and create steric resistance between the two, both may affect the structure and stability of protein. CONCLUSION: The c.1103G>A and c.1556G>A compound heterozygous variants probably underlay the pathogenesis of congenital FXI deficiency in this pedigree.


Asunto(s)
Deficiencia del Factor XI , Factor XI , Exones/genética , Factor XI/genética , Deficiencia del Factor XI/genética , Femenino , Heterocigoto , Humanos , Masculino , Mutación , Linaje
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(3): 275-277, 2021 Mar 10.
Artículo en Chino | MEDLINE | ID: mdl-33751541

RESUMEN

OBJECTIVE: To explore the genetic basis for a child affected with Bainbridge-Ropers syndrome. METHODS: Genomic DNA was extracted from peripheral venous blood samples from the patient and his parents. Whole exome sequencing (WES) was carried out to detect genetic variant of the proband. Candidate variant was verified by Sanger sequencing. RESULTS: The 3-year-old boy presented with psychomotor retardation, linguistic difficulties, mental retardation and peculiar craniofacial phenotype. A de novo heterozygous nonsense variant of the ASXL3 gene, c.3106C>T, was identified by WES in the proband, and the same mutation was not found among his parents. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.3106C>T variant was predicted to be pathogenic (PVS1+PS2+PP4). CONCLUSION: The heterozygous variant c.3106C>T of the ASXL3 gene probably underlies the Bainbridge-Ropers syndrome in the patient. Above result has enabled the clinical diagnosis and genetic counseling for the family.


Asunto(s)
Discapacidad Intelectual , Factores de Transcripción , Niño , Preescolar , Heterocigoto , Humanos , Discapacidad Intelectual/genética , Masculino , Mutación , Fenotipo , Factores de Transcripción/genética , Secuenciación del Exoma Completo
13.
Phytochemistry ; 184: 112652, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33535085

RESUMEN

We used ESI-MS/MS to profile glycerolipids in a mutant of Arabidopsis thaliana that is null and heterozygous for the TOC132 and TOC120 genes, and is referred to as the toc132toc120± mutant. The goal was to assess the impact of a defective atToc132/120 receptor on the accumulation of chloroplast lipids. The mutant accumulated decreased amounts of monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG) and phosphatidylglycerol (PG). In the cold-acclimated mutant, PG accumulated at the control levels. However, 34:4-PG (18:3/16:1Δ3trans) was significantly decreased, which indicates that the mutant was impaired in synthesis of the chloroplast-derived PG. Major molecular species of MGDG and DGDG were significantly decreased, which was indicative of the decreased levels of triunsaturated fatty acids in galactolipids. The cold-acclimated mutant accumulated increased levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS), which indicate that defect in the atToc132/120 receptor did not impair the ER pathway of lipid synthesis. Both cold-acclimated wildtype and mutant plants accumulated increased levels of phosphatidic acid (PA). The increased levels of major molecular species of PA suggest that some pool of PA was derived from degradation of both the chloroplast and extra-chloroplast lipids. The cold-acclimated mutant had decreased double bond index (DBI) and increased acyl chain length (ACL), which was indicative of decreased membrane fluidity. However, a decrease in the ratio of MGDG to DGDG indicate that the mutant was capable of remodeling membrane lipids in response to low temperatures. We conclude that the defective Toc132/120 receptor resulted in decreased synthesis of chloroplast lipids and decreased membrane fluidity.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Cloroplastos , Galactolípidos , Heterocigoto , Receptores de Superficie Celular , Receptores Citoplasmáticos y Nucleares , Espectrometría de Masas en Tándem
14.
Nature ; 590(7845): 290-299, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33568819

RESUMEN

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.


Asunto(s)
Variación Genética/genética , Genoma Humano/genética , Genómica , National Heart, Lung, and Blood Institute (U.S.) , Medicina de Precisión , Citocromo P-450 CYP2D6/genética , Haplotipos/genética , Heterocigoto , Humanos , Mutación INDEL , Mutación con Pérdida de Función , Mutagénesis , Fenotipo , Polimorfismo de Nucleótido Simple , Densidad de Población , Medicina de Precisión/normas , Control de Calidad , Tamaño de la Muestra , Estados Unidos , Secuenciación Completa del Genoma/normas
15.
Nucleic Acids Res ; 49(5): 2642-2654, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33591308

RESUMEN

The CRISPR/Cas9 system is a technology for genome engineering, which has been applied to indel mutations in genes as well as targeted gene deletion and replacement. Here, we describe paired gRNA deletions along the PIGA locus on the human X chromosome ranging from 17 kb to 2 Mb. We found no compelling linear correlation between deletion size and the deletion efficiency, and there is no substantial impact of topologically associating domains on deletion frequency. Using this precise deletion technique, we have engineered a series of designer deletion cell lines, including one with deletions of two X-chromosomal counterselectable (negative selection) markers, PIGA and HPRT1, and additional cell lines bearing each individual deletion. PIGA encodes a component of the glycosylphosphatidylinositol (GPI) anchor biosynthetic apparatus. The PIGA gene counterselectable marker has unique features, including existing single cell level assays for both function and loss of function of PIGA and the existence of a potent counterselectable agent, proaerolysin, which we use routinely for selection against cells expressing PIGA. These designer cell lines may serve as a general platform with multiple selection markers and may be particularly useful for large scale genome engineering projects such as Genome Project-Write (GP-write).


Asunto(s)
Sistemas CRISPR-Cas , Ingeniería Celular , Proteínas de la Membrana/genética , Eliminación de Secuencia , Toxinas Bacterianas/toxicidad , Línea Celular , Cromosomas Humanos X , Marcadores Genéticos , Heterocigoto , Humanos , Mutación , N-Acetilglucosaminiltransferasas/genética , Proteínas Citotóxicas Formadoras de Poros/toxicidad , ARN/genética
16.
BMJ Case Rep ; 14(2)2021 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-33542026

RESUMEN

Osteogenesis imperfecta (OI) consists of a group of genetically and phenotypically heterogeneous diseases characterised by bone fragility. Recent improvement in gene sequencing methods has helped us identify rare forms of OI that are inherited in an autosomal recessive manner. Paediatric endocrinology was consulted on a newborn girl with multiple fractures and wavy thin ribs noted on X-rays. In addition to the bone phenotype, she also has short stature and recurrent acute liver failure (ALF) episodes triggered by intercurrent illness. Whole exome sequencing revealed two novel compound heterozygous variants in neuroblastoma amplified sequence (NBAS) gene. NBAS gene codes for a protein that is involved in nonsense-mediated decay pathway and retrograde transport of proteins from Golgi to endoplasmic reticulum. Recognition of pathogenic variants in this gene as a rare cause of autosomal recessive OI and recurrent ALF has important therapeutic implications.


Asunto(s)
Heterocigoto , Fallo Hepático Agudo/genética , Proteínas de Neoplasias/genética , Osteogénesis Imperfecta/genética , Conservadores de la Densidad Ósea/uso terapéutico , Enanismo/genética , Femenino , Humanos , Lactante , Recién Nacido , Osteogénesis Imperfecta/tratamiento farmacológico , Pamidronato/uso terapéutico , Fenotipo , Recurrencia , Secuenciación del Exoma Completo
17.
Medicine (Baltimore) ; 100(7): e24712, 2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33607811

RESUMEN

RATIONALE: The aim of this study was to analyze the genetic abnormalities and clinical manifestations of Shwachman-Diamond syndrome (SDS). PATIENT CONCERNS: A Chinese infant with elevated transaminase and a novel mutation at of sbdsc.258 +2T>C and c.184a>Tc.292G>A. DIAGNOSES: The female patient was 5 months' old at onset, with elevated transaminase as the first manifestation accompanied by restricted growth and development and oily stool. After sequencing the blood samples from patients and their parents, the heterozygous mutations of sbdsc.258 +2T>C and c.184a>T were detected. INTERVENTIONS: After admission, the patient was provided compound glycyrrhizin, Newtide formula milk supplemented with probiotics, fat-soluble vitamins, oral medication to adjust the spleen and stomach, and other symptomatic treatments. OUTCOMES: The stool traits improved, and the levels of liver function transaminases decreased compared with before. LESSONS: SDS is a rare disease with a variety of clinical manifestations. Pancreatic exocrine dysfunction, blood system manifestations, and bone abnormalities are common clinical manifestations, and genetic testing is helpful for diagnosis.


Asunto(s)
Huesos/anomalías , Trastornos del Crecimiento/etiología , Páncreas Exocrino/fisiopatología , Síndrome de Shwachman-Diamond/genética , Antiinflamatorios/uso terapéutico , Insuficiencia Pancreática Exocrina/diagnóstico , Insuficiencia Pancreática Exocrina/etiología , Insuficiencia Pancreática Exocrina/genética , Femenino , Ácido Glicirrínico/uso terapéutico , Trastornos del Crecimiento/genética , Heterocigoto , Humanos , Lactante , Mutación/genética , Síndrome de Shwachman-Diamond/diagnóstico , Síndrome de Shwachman-Diamond/terapia , Transaminasas/sangre , Transaminasas/genética , Resultado del Tratamiento
18.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(2): 127-130, 2021 Feb 10.
Artículo en Chino | MEDLINE | ID: mdl-33565063

RESUMEN

OBJECTIVE: To analyze the clinical phenotype and genetic characterization of a child with early infantile epileptic encephalopathy. METHODS: The proband was subjected to history taking and was diagnosed based on his clinical manifestation, magnetic resonance imaging (MRI) and whole exome sequencing (WES). Sanger sequencing was carried out to determine the origin of pathogenic variant. RESULTS: The proband unconsciously tilts his head to one side with squint, which revealed an abnormal discharge. MRI indicated suspicious abnormal signal shadow in the left posterior frontal cortex in addition with inflammation signs in the right maxillary sinus and ethmoid sinus. WES revealed that the proband has carried a heterozygous c.5789G>A variant in the CACNAIA gene. The result of Sanger sequencing was in keeping with that of WES. Neither of his parents has carried the same variant. CONCLUSION: The heterozygous c.5789G>A variant of the CACNAIA gene probably underlay the early infantile epileptic encephalopathy 42 in the proband, which has a de novo origin.


Asunto(s)
Canales de Calcio/genética , Pruebas Genéticas , Espasmos Infantiles/genética , Heterocigoto , Humanos , Lactante , Mutación , Espasmos Infantiles/diagnóstico , Secuenciación del Exoma Completo
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(2): 131-133, 2021 Feb 10.
Artículo en Chino | MEDLINE | ID: mdl-33565064

RESUMEN

OBJECTIVE: To explore the genetic basis for a patient with intellectual disability. METHODS: Whole exome sequencing and Sanger sequencing were carried out for the patient. The result was verified in her family. RESULTS: DNA sequencing revealed that the patient has carried a heterozygous nonsense c.40C>T (p.Arg14X) variant of the TRIP12 gene, which was de novo in origin. The variant was unrecorded in the Human Gene Mutation Database. Based on the American College of Medical Genetics and Genomics standards and guidelines, the variant was predicted to be pathogenic (PVS1+ PS2+ PP3). CONCLUSION: The patient was diagnosed with autosomal dominant intellectual disability due to heterozygous c.40C>T variant of the TRIP12 gene.


Asunto(s)
Proteínas Portadoras/genética , Discapacidad Intelectual , Ubiquitina-Proteína Ligasas/genética , Codón sin Sentido , Femenino , Heterocigoto , Humanos , Discapacidad Intelectual/genética , Secuenciación del Exoma Completo
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(2): 150-153, 2021 Feb 10.
Artículo en Chino | MEDLINE | ID: mdl-33565069

RESUMEN

OBJECTIVE: To analyze the clinical features, biochemical characteristics and molecular pathogenesis of a girl with isovaleric acidemia. METHODS: Clinical features, blood spot amino acid profiles and urinary organic acid profiles of the patient were analyzed. Targeted capture, next generation sequencing and Sanger sequencing were carried out to detect potential variant of the IVD gene. RESULTS: The patient presented with poor weight gain, poor feeding, lethargy, and a "sweaty feet" odor 10 days after birth. Biochemical test suggested hyperammonemia. Blood spot amino acid profiles displayed a dramatic increase in isovalerylcarnitine (C5: 3. 044, reference range 0.04 - 0.4 µmol/L). Organic acid analysis of her urine sample revealed a high level of isovaleric glycine (669. 53, reference range 0 - 0.5). The child was ultimately diagnosed with isovaleric acidemia, and was found to harbor a paternally derived heterozygous variant c.149G>A (p.R50H) and a maternally derived heterozygous variant c.1123G>A (p.G375S) of the IVD gene. Her elder brother was a heterozygous carrier of c.1123G>A (p.G375S) variant. The c.149G>A (p.R50H) was a known pathogenic variant, while the c.1123G>A (p.G375S) variant was previously unreported. CONCLUSION: The pathogenesis of the patient was delineated from the perspective of genetics, which has provided a basis for clinical diagnosis, treatment as well as genetic counseling.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Isovaleril-CoA Deshidrogenasa/deficiencia , Niño , Femenino , Heterocigoto , Humanos , Isovaleril-CoA Deshidrogenasa/genética , Masculino , Mutación
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