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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 833-837, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487524

RESUMO

OBJECTIVE: To analyze gene variants in a Chinese pedigree with oculocutaneous albinism (OCA). METHODS: Gene sequencing of the proband and his parents was performed using chip capture high-throughput sequencing and Sanger sequencing techniques, and PolyPhen-2, SIFT, MutationTaster, and FATHMM software were used to predict the function of new variants. At the same time,the pedigree and variant genes of 4 albinism patients from this pedigree were analyzed. RESULTS: Sequencing results showed that the proband's TYR gene (NM_000372) has c.230G>A (p.Arg77Gln) and c.120_121insG (p.Asp42GlyfsTer35) compound heterozygous variants. The proband's father carries c.230G>A heterozygous variant, and the mother carries c.120_121insG heterozygous variant, indicating that the proband's two variants are from his father and mother. The former is a known missense variant, which can cause abnormal or loss of the original function of the protein polypeptide chain. The latter c.120_121insG(p.Asp42GlyfsTer35) is an unreported frameshift variant of the TYR gene subregion (EX1; CDS1). PolyPhen-2, SIFT, MutationTaster and FATHMM predictions are all prompted as "harmful variants". This variant caused the amino acid encoded protein to terminate prematurely, producing a truncated protein, which eventually formed a 76-amino acid short-type TYR protein instead of the 529-amino acid wild-type TYR protein. Through the pedigree analysis, the four patients in the pedigree are all of the same type of compound heterozygous variants, and the disease-causing genes are all from the patient's parents. They belong to a special form of consanguineous marriage within 5 generations. CONCLUSION: The compound heterozygous variants of c.230G>A (p.Arg77Gln) and c.120_121insG (p.Asp42GlyfsTer35) of the TYR gene may underlie the disease in this pedigree. The gene sequencing results enrich the variant spectrum of the TYR gene, and has facilitated molecular diagnosis for the patient.


Assuntos
Albinismo Oculocutâneo , Albinismo Oculocutâneo/genética , Consanguinidade , Heterozigoto , Humanos , Mutação , Linhagem
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 838-840, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487525

RESUMO

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with resistance to thyroid hormone syndrome (RTH). METHODS: Exons 7 to 10 of the THRbeta gene were sequenced for the proband and members of his pedigree. RESULTS: Three patients from the pedigree were identified. All have presented with palpitation, fatigue, goiter, elevated free thyroid hormone and free triiodothyronine, and normal or elevated thyrotropin. Genetic testing revealed that the proband, his mother, second sister and one of her daughters had carried a heterozygous c.1336T>A variant of the THRbeta gene, which resulted in substitution of Cysteine by Serine at position 446. The variant was unreported previously. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.1336T>A(p.Cys446Ser) variant of THRbeta gene was predicted to be lilely pathogenic(PM1+PM2+PM5+PP3). CONCLUSION: The c.1336T>A variant, identified in the exon 10 of the THRbeta gene, probably underlay the RTH in this pedigree. Genetic testing has validated the clinical diagnosis for this pedigree.


Assuntos
Genômica , Mães , Feminino , Heterozigoto , Humanos , Mutação , Linhagem
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 877-879, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487535

RESUMO

OBJECTIVE: To explore the genetic basis for a patient diagnosed with tuberous sclerosis complex (TSC). METHODS: Peripheral blood samples of the patient and his parents were collected for the extraction of genomic DNA. Next generation sequencing (NGS) was carried out to detect potential variant, and the result was verified by Sanger sequencing. RESULTS: The patient was found to harbor a heterozygous c.1053delG (p.Glu352SerfsX10) frameshifting variant of the TSC2 gene. The same variant was not found in his unaffected parents and 100 unrelated healthy controls. Based on the American College of Medical Genetics and Genomics guidelines, the variant was predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION: The novel c.1053delG (p.Glu352SerfsX10) frameshifting variant of the TSC2 gene probably underlay the TSC in this patient.


Assuntos
Esclerose Tuberosa , Genômica , Heterozigoto , Humanos , Mutação , Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética
4.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(8): 841-847, 2021 Aug 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34511175

RESUMO

OBJECTIVES: To investigate the distribution of genotypes of thalassemia in children in Guangxi, China. METHODS: A total of 30 417 children with positive results of thalassemia screening in the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region from January 2011 to December 2019 were enrolled. Single-tube multiplex PCR, agarose gel electrophoresis, and reverse dot blot hybridization technique were used for the detection of common α- and ß-thalassemia genes. Gap-PCR or gene sequence analysis was performed for 2 703 children suspected of rare thalassemia. RESULTS: Among the 30 417 children with positive results of thalassemia screening, 23 214 (76.32%) were diagnosed with thalassemia, and the detection rates of α-thalassemia, ß-thalassemia, and α-thalassemia with ß-thalassemia were 47.77%, 23.75%, and 4.80% respectively. A total of 13 types of α-thalassemia alleles (18 480 alleles in total) were detected, mainly --SEA (54.98%), including seven rare alleles, i.e., --THAI (0.43%), HKαα (0.02%), -α30 (0.01%), -α1.0 (0.01%), -α2.4 (0.01%), -α21.9 (0.01%), and HBA2:C272-279 del (0.01%). A total of 17 types of ß-thalassemia alleles (9 168 alleles in total) were detected, mainly CD41-42 (47.79%), followed by CD17 (25.53%), including three rare alleles, i.e., IVS-II-5 (0.02%), IVS-I-2 (0.01%), and Gγ(Aγδß)0 (0.01%). A total of 37 genotypes were detected in 14 531 children with α-thalassemia, among which the most common 6 genotypes were --SEA/αα (52.20%), -α3.7/αα (13.24%), αCSα/αα (7.52%), -α4.2 (6.06%), --SEA/-α3.7 (5.91%), and αWSα/αα (3.41%), accounting for 88.34%. A total of 49 genotypes were detected in 7 223 children with ß-thalassemia, among which the most common 6 genotypes were CD41-42/ßN (45.81%), CD17/ßN (24.30%), IVS-II-654/ßN (7.49%), -28/ßN (5.62%), CD71-72/ßN (4.42%), and CD26/ßN (3.94%), accounting for 91.13%. A total of 137 genotypes were detected in 1 460 children with both α- and ß-thalassemia, mainly --SEA/αα combined with CD41-42/ßN (14.17%) and CD17/ßN (8.35%). A total of 2 050 children were diagnosed with hemoglobin H disease (α0/α+), among whom 134 had ß-thalassemia heterozygote and 12 had Bart hydrops fetalis syndrome (--SEA/--SEA); 355 children were diagnosed with ß-thalassemia double heterozygote, and 128 were diagnosed with ß-thalassemia homozygote, including 93 children with α-thalassemia. CONCLUSIONS: There are diverse gene mutations and rich genotypes of thalassemia among children in Guangxi, and α-thalassemia is more common, with --SEA/αα as the major genotype. There is a high proportion of children with both α- and ß-thalassemia, and there are relatively high incidence rates of ß-thalassemia double heterozygote and homozygote (intermedia and major).


Assuntos
Talassemia alfa , Talassemia beta , Criança , China/epidemiologia , Genótipo , Heterozigoto , Humanos , Mutação , Talassemia alfa/epidemiologia , Talassemia alfa/genética , Talassemia beta/diagnóstico , Talassemia beta/epidemiologia , Talassemia beta/genética
5.
Science ; 373(6557): 918-922, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34413236

RESUMO

Zoonotic avian influenza A virus (IAV) infections are rare. Sustained transmission of these IAVs between humans has not been observed, suggesting a role for host genes. We used whole-genome sequencing to compare avian IAV H7N9 patients with healthy controls and observed a strong association between H7N9 infection and rare, heterozygous single-nucleotide variants in the MX1 gene. MX1 codes for myxovirus resistance protein A (MxA), an interferon-induced antiviral guanosine triphosphatase known to control IAV infections in transgenic mice. Most of the MxA variants identified lost the ability to inhibit avian IAVs, including H7N9, in transfected human cell lines. Nearly all of the inactive MxA variants exerted a dominant-negative effect on the antiviral function of wild-type MxA, suggesting an MxA null phenotype in heterozygous carriers. Our study provides genetic evidence for a crucial role of the MX1-based antiviral defense in controlling zoonotic IAV infections in humans.


Assuntos
Subtipo H7N9 do Vírus da Influenza A , Influenza Humana/genética , Influenza Humana/virologia , Proteínas de Resistência a Myxovirus/genética , Doenças dos Trabalhadores Agrícolas/genética , Doenças dos Trabalhadores Agrícolas/virologia , Animais , Linhagem Celular , Predisposição Genética para Doença , Variação Genética , Heterozigoto , Humanos , Subtipo H7N9 do Vírus da Influenza A/fisiologia , Vírus da Influenza A/fisiologia , Mutação de Sentido Incorreto , Proteínas de Resistência a Myxovirus/química , Proteínas de Resistência a Myxovirus/metabolismo , Aves Domésticas , Zoonoses Virais , Sequenciamento Completo do Genoma
6.
J Immunol ; 207(4): 1150-1164, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34341167

RESUMO

CARD11 is a multidomain scaffold protein required for normal activation of NF-κB, JNK, and mTOR during Ag receptor signaling. Germline CARD11 mutations cause at least three types of primary immunodeficiency including CARD11 deficiency, B cell expansion with NF-κB and T cell anergy (BENTA), and CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS). CADINS is uniquely caused by heterozygous loss-of-function CARD11 alleles that act as dominant negatives. CADINS patients present with frequent respiratory and skin infections, asthma, allergies, and atopic dermatitis. However, precisely how a heterozygous dominant negative CARD11 allele leads to the development of this CADINS-specific cluster of symptoms remains poorly understood. To address this, we generated mice expressing the CARD11 R30W allele originally identified in patients. We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency. CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis. CARD11R30W/+ mice display reduced regulatory T cell numbers, but not the Th2 expansion observed in other mice with diminished CARD11 activity. Interestingly, the presence of mixed CARD11 oligomers in CARD11R30W/+ mice causes more severe signaling defects in T cells than in B cells, and specifically impacts IFN-γ production by NK cells, but not NK cell cytotoxicity. Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms.


Assuntos
Linfócitos B/imunologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Imunoglobulina E/imunologia , Células Matadoras Naturais/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Alelos , Animais , Heterozigoto , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL
7.
FASEB J ; 35(9): e21752, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369602

RESUMO

Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1ß coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1ß [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro-thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria-rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ-specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.


Assuntos
Tecido Adiposo/metabolismo , Mitocôndrias/genética , Proteínas Nucleares/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fatores de Transcrição/genética , Envelhecimento/genética , Animais , Modelos Animais de Doenças , Metabolismo Energético/genética , Heterozigoto , Resistência à Insulina/genética , Masculino , Camundongos , Obesidade/genética , Termogênese/genética , Transcriptoma/genética
8.
J Int Med Res ; 49(8): 3000605211038133, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34396835

RESUMO

Congenital nephrotic syndrome (CNS) is a rare autosomal recessive disorder that occurs in the first 0 to 3 months of life. The course of CNS is progressive, often leading to end-stage renal disease within 2 to 3 years. Most patients with CNS are resistant to glucocorticoids and immunosuppressive drugs. We report a girl aged 1 month and 20 days who was admitted to hospital with a history of abdominal distension and palpebral edema. She was diagnosed with CNS and administered a glucocorticoid (methylprednisolone) for 2 years. Targeted high-throughput next-generation sequencing showed mutations in the NPHS1 gene. She had a favorable outcome after 2 years of treatment. She has remained in complete remission for the last 6 months. From a clinical point of view, the outcome of CNS may be associated with end-stage renal disease or even death. Appropriate pharmacotherapy is beneficial to maintain a normal function and integrity of the glomerular barrier. An aggressive treatment plan is required to save the life of patients with CNS, even if a heterozygous mutation is detected by genetic analysis.


Assuntos
Síndrome Nefrótica , Feminino , Testes Genéticos , Heterozigoto , Humanos , Lactente , Proteínas de Membrana/genética , Mutação , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/genética
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1266-1270, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362514

RESUMO

OBJECTIVE: To analyze the genotypes and distribution of thalassemia in children in Quanzhou Region so as to provide reference for the prevention and control of thalassemia. METHODS: A total of 1 302 children with suspected thalassemia were collected from January 2014 to April 2020 in Quanzhou Region. The deletional α-thalassemia was detected by Gap-PCR, and DNA reverse dot blot (RDB) hybridization was used to detect α- and ß-thalassemia mutations. RESULTS: In the 1 302 cases, 667 cases were identified as thalassemia carriers, and the positive detection rate was about 51.23%. Among them, 380 cases of α-thalassemia gene were detected, and --SEA/αα was the most common genotype with the composition rate about 69.21%. Forty-two cases were identified as HbH disease, and -α3.7/--SEA was the most common genotype. While, 274 cases were identified as ß-thalassemia, and ßIVS-Ⅱ-654/ßN (35.40%) and ßCD41-42/ßN (33.94%) were the most common genotypes. Seventeen cases of ß-thalassemia major/intermedia were identified, and the most common genotypes were ßIVS-Ⅱ-654/ßIVS-Ⅱ-654 and ßIVS-Ⅱ-654/ßCD17. Meanwhile, 13 cases of α- complex ß- thalassemia were detected. Among them, 1 case of ß-thalassemia gene rare mutation Term CD+32 was firstly detected in Fujian Province, and 1 case of CD14-15 mutation was firstly detected in Quanzhou Region. In addition, 3 cases of abnormal hemoglobin disease were identified, in which 2 cases were Hb Q-Thailand and 1 case was Hb G-Honolulu. CONCLUSION: There are various genotypes of thalassemia in children in Quanzhou Region, and many children with thalassemia major or intermedia. Therefore, further prevention and control of thalassemia need to be strengthened for reducing the birth of thalassemia major or intermedia.


Assuntos
Talassemia alfa , Talassemia beta , Criança , China , Testes Genéticos , Genótipo , Heterozigoto , Humanos , Mutação , Talassemia alfa/genética , Talassemia beta/genética
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 731-734, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365612

RESUMO

OBJECTIVE: To identify the pathogenesis in two patients of restrictive cardiomyopathy (RCM) using high-throughput sequencing. METHODS: Peripheral blood samples from the two patients and their parents were collected and genomic DNAs were extracted to conduct targeted next generation sequencing or whole exome sequencing. Bioinformation analysis was performed to identify the pathogenic variants in genes associated with cardiomyopathy, which were further validated by Sanger sequencing. RESULTS: By high throughput sequencing, we detected a de novo heterozygous variant c.549+1G>T in TNNI3 gene in patient 1. The variant has not been reported previously and was predicted to be pathogenic in line with American College of Medical Genetics and Genomics (ACMG) guidelines (PVS1+PS2+PM2). Another heterozygous variant c.433C>T (p.Arg145Trp) in TNNI3 gene was identified in patient 2 and his father. The variant had been reported as pathogenic variant in Clinvar and HGMD databases; based on ACMG guidelines, the variant was predicted to be likely pathogenic (PS3+PM1+PP3). CONCLUSION: TNNI3 variants may be the causative gene responsible for restrictive cardiomyopathy in the two patients. High throughput sequencing results provide bases for the diagnosis of restrictive cardiomyopathy.


Assuntos
Cardiomiopatia Restritiva , Cardiomiopatia Restritiva/genética , Criança , Genômica , Heterozigoto , Humanos , Mutação , Sequenciamento Completo do Exoma
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 740-744, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365614

RESUMO

OBJECTIVE: To identify genetic variants among patients with methylmalonic acidemia and provide genetic evidence for prenatal diagnosis. METHODS: Thirty-one probands and their parents were subjected to next generation sequencing (NGS). Suspected variants were verified by Sanger sequencing. RESULTS: 25 probands or their parents were found to harbor previously known pathogenic or likely pathogenic variants, and three probands were found to carry heterozygous MMACHC exonic deletion. The overall diagnostic yield was 90.32%. CONCLUSION: NGS can improve the detection rate for methylmalonic acidemia for its accuracy and efficiency, yet the detection of exonic deletion is required to further improve the diagnostic yield. The identification of specific variants provided evidence for prenatal diagnosis.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Sequenciamento de Nucleotídeos em Larga Escala , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Feminino , Heterozigoto , Humanos , Mutação , Oxirredutases , Gravidez , Diagnóstico Pré-Natal
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 765-767, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365620

RESUMO

OBJECTIVE: To explore the genetic basis for a case of Lamb-Shaffer syndrome. METHODS: Genomic DNA was extracted from peripheral blood samples and subjected to whole exome sequencing(WES). Suspected variant was verified by Sanger sequencing. RESULTS: The patients was found to harbor a heterozygous c.1495delA(p.Thr499Glnfs*5) frameshift variant of the SOX5 gene by WES. Sanger sequencing confirmed that the same variant was a de novo variant. Based on the American College of Medical Genetics and Genomics guidelines, c.1495delA(p.Thr499Glnfs*5) variant of the SOX5 gene was predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION: The c.1495delA(p.Thr499Glnfs*5) variant of the SOX5 gene probably underlies the Lamb-Shaffer syndrome in this patient.


Assuntos
Genômica , Fatores de Transcrição SOXD , Animais , Heterozigoto , Humanos , Mutação , Fatores de Transcrição SOXD/genética , Ovinos , Sequenciamento Completo do Exoma
14.
J Theor Biol ; 528: 110849, 2021 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-34331961

RESUMO

Meiotic recombination and the factors affecting its rate and fate in nature have inspired many studies in theoretical evolutionary biology. Classical theoretical models have inferred that recombination can be favored under a rather restricted parameter range. Thus, the ubiquity of recombination in nature remains an open question. However, these models assumed constant recombination with an equal rate across all individuals within the population, whereas empirical evidence suggests that recombination may display certain sensitivity to ecological stressors and/or genotype fitness. Models assuming condition-dependent recombination show that such a strategy can often be favored over constant recombination. Moreover, in our recent model with panmictic populations subjected to purifying selection, fitness-dependent recombination was quite often favored even when any constant recombination was rejected. By using numerical modeling, we test whether such a 'recombination-rescuing potential' of fitness dependence holds also beyond panmixia, given the recognized effect of mating strategy on the evolution of recombination. We show that deviations from panmixia generally increase the recombination-rescuing potential of fitness dependence, with the strongest effect under intermediate selfing or high clonality. We find that under partial clonality, the evolutionary advantage of fitness-dependent recombination is determined mostly by selection against heterozygotes and additive-by-additive epistasis, while under partial selfing, additive-by-dominance epistasis is also a driver.


Assuntos
Modelos Genéticos , Reprodução , Genótipo , Heterozigoto , Humanos
15.
Stem Cell Res ; 54: 102449, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34216980

RESUMO

Induced pluripotent stem cell (iPSC) lines were generated from two patients with RDH12 variants. UCLi014-A is from a patient with heterozygous frameshift mutation c.759del p.(Phe254Leufs*24), associated with autosomal dominant retinitis pigmentosa. UCLi015-A is from a patient with homozygous missense mutation c.619A > G p.(Asn207Asp), associated with Leber congenital amaurosis. Fibroblasts were derived from skin biopsies and reprogrammed using integration free episomal reprogramming plasmids. The iPSC lines expressed pluripotency markers, exhibited differentiation potential in vitro and displayed normal karyotypes. These cell lines will act as a tool for disease modelling, enabling comparison of disease mechanisms, identification of therapeutic targets and drug screening.


Assuntos
Células-Tronco Pluripotentes Induzidas , Amaurose Congênita de Leber , Retinite Pigmentosa , Oxirredutases do Álcool/genética , Linhagem Celular , Heterozigoto , Humanos , Amaurose Congênita de Leber/genética , Mutação , Retinite Pigmentosa/genética
16.
Nat Genet ; 53(7): 1006-1021, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34211179

RESUMO

SPTBN1 encodes ßII-spectrin, the ubiquitously expressed ß-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal ßII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect ßII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of ßII-spectrin in the central nervous system.


Assuntos
Genes Dominantes , Predisposição Genética para Doença , Variação Genética , Transtornos do Neurodesenvolvimento/genética , Espectrina/genética , Animais , Estudos de Associação Genética/métodos , Heterozigoto , Humanos , Camundongos , Transtornos do Neurodesenvolvimento/diagnóstico , Fenótipo , Espectrina/metabolismo
17.
Lancet Neurol ; 20(8): 615-626, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34302786

RESUMO

BACKGROUND: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease. METHODS: We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30-61 years) were analysed for markers of amyloid ß (Aß1-40, Aß1-42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups. FINDINGS: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30-61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aß1-42 to Aß1-40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aß and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms). FUNDING: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Síndrome de Down/líquido cefalorraquidiano , Adulto , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Encefalite/líquido cefalorraquidiano , Feminino , Genótipo , Gliose/líquido cefalorraquidiano , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano
18.
Int J Hematol ; 114(3): 307-318, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34195938

RESUMO

This study investigated prenatal diagnosis of α-thalassemia and ß-thalassemia in 3049 families in 18 regions of Hainan Province. Molecular diagnosis was performed in 3049 couples with thalassemia in Hainan Province. Genomic DNA was extracted from peripheral blood of the couples and villus, amniotic fluid, or cord blood of fetuses. DNA-based diagnosis was performed using polymerase chain reaction. The most commonly detected mutation for α-thalassemia was- SEA/αα (31.53%), followed by - α4.2/αα (11.15%) and - α3.7/αα (11.02%). The most common mutation for ß-thalassemia was CD41/42 (30.27%), followed by - 28 (2.56%). Prevalence was highest in the coastal regions and lowest in the Wenchang, Lingao, and Ding'an regions. We also found that the most common gene mutations in Han people and other minority groups were not homogeneous. Prenatal diagnosis showed 556 normal fetuses, 116 with α-thalassemia hydrops, and 134 with ß-thalassemia major. Our findings provide important information for clinical genetic counseling regarding prenatal diagnosis for thalassemia major in Hainan Province.


Assuntos
Mutação , alfa-Globinas/genética , Talassemia alfa/epidemiologia , Talassemia alfa/genética , Globinas beta/genética , Talassemia beta/epidemiologia , Talassemia beta/genética , China/epidemiologia , Feminino , Genótipo , Geografia Médica , Heterozigoto , Humanos , Masculino , Gravidez , Prevalência , Talassemia alfa/diagnóstico , Talassemia beta/diagnóstico
19.
Eur Heart J ; 42(32): 3063-3073, 2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34263907

RESUMO

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.


Assuntos
Cardiomiopatia Hipertrófica , Cardiomiopatia Hipertrófica/genética , Heterozigoto , Humanos , Mutação , Proteínas Quinases/genética , Sarcômeros
20.
Int J Colorectal Dis ; 36(10): 2199-2204, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34244858

RESUMO

PURPOSE: The carrier frequency of MUTYH pathogenic variants in the population may be as high as one in 45. Some studies have found an increased risk of colorectal cancer (CRC) in monoallelic carriers of MUTYH pathogenic variants, but the role of early surveillance colonoscopy is not conclusive. This study aimed to assess the outcomes of colonoscopy surveillance in MUTYH carriers. METHODS: Patients, with a monoallelic pathogenic variant in MUTYH, found at cascade testing, were identified from the St Mark's Hospital Polyposis Registry database. Findings at surveillance colonoscopy were reviewed. RESULTS: Two hundred and forty-nine carriers were identified, of whom 125 had undergone at least one surveillance colonoscopy. Twenty-eight patients (22%) developed at least one adenoma; all adenomas had low-grade dysplasia (LGD). The median age at first colonoscopy was 36 years (range 16-75 years). The median age at first adenoma detection was 43 years (range 22-75 years). The cumulative incidence of adenoma development by age 30, 40, 50, 60 and 70 years was 3.2%, 8.8%, 15.2%, 18.4% and 20.8%, respectively. No CRCs were observed. CONCLUSIONS: Our cohort of monoallelic carriers of MUTYH pathogenic variants is a relatively younger group than adults entering population screening colonoscopy, but a high adenoma rate was not observed. No CRCs were detected, suggesting that current guidance that these individuals should be managed in the same way as the general population is reasonable.


Assuntos
Adenoma , Polipose Adenomatosa do Colo , Neoplasias Colorretais , DNA Glicosilases , Adenoma/epidemiologia , Adenoma/genética , Adolescente , Adulto , Idoso , Neoplasias Colorretais/genética , DNA Glicosilases/genética , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Adulto Jovem
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