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1.
Genet Sel Evol ; 54(1): 57, 2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36057564

RESUMO

BACKGROUND: Compared to national evaluations, international collaboration projects further improve accuracies of estimated breeding values (EBV) by building larger reference populations or performing a joint evaluation using data (or proxy of them) from different countries. Genomic selection is increasingly adopted in beef cattle, but, to date, the benefits of including genomic information in international evaluations have not been explored. Our objective was to develop an international beef cattle single-step genomic evaluation and investigate its impact on the accuracy and bias of genomic evaluations compared to current pedigree-based evaluations. METHODS: Weaning weight records were available for 331,593 animals from seven European countries. The pedigree included 519,740 animals. After imputation and quality control, 17,607 genotypes at a density of 57,899 single nucleotide polymorphisms (SNPs) from four countries were available. We implemented two international scenarios where countries were modelled as different correlated traits: an international genomic single-step SNP best linear unbiased prediction (SNPBLUP) evaluation (ssSNPBLUPINT) and an international pedigree-based BLUP evaluation (PBLUPINT). Two national scenarios were implemented for pedigree and genomic evaluations using only nationally submitted phenotypes and genotypes. Accuracies, level and dispersion bias of EBV of animals born from 2014 onwards, and increases in population accuracies were estimated using the linear regression method. RESULTS: On average across countries, 39 and 17% of sires and maternal-grand-sires with recorded (grand-)offspring across two countries were genotyped. ssSNPBLUPINT showed the highest accuracies of EBV and, compared to PBLUPINT, led to increases in population accuracy of 13.7% for direct EBV, and 25.8% for maternal EBV, on average across countries. Increases in population accuracies when moving from national scenarios to ssSNPBLUPINT were observed for all countries. Overall, ssSNPBLUPINT level and dispersion bias remained similar or slightly reduced compared to PBLUPINT and national scenarios. CONCLUSIONS: International single-step SNPBLUP evaluations are feasible and lead to higher population accuracies for both large and small countries compared to current international pedigree-based evaluations and national evaluations. These results are likely related to the larger multi-country reference population and the inclusion of phenotypes from relatives recorded in other countries via single-step international evaluations. The proposed international single-step approach can be applied to other traits and breeds.


Assuntos
Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Animais , Bovinos/genética , Genoma , Genótipo , Linhagem , Fenótipo , Desmame
2.
Sci Rep ; 12(1): 14984, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056154

RESUMO

Research on working dogs is growing rapidly due to increasing global demand. Here we report genome scanning of the risk of puppies being eliminated for behavioral reasons prior to entering the training phase of the US Transportation Security Administration's (TSA) canine olfactory detection breeding and training program through 2013. Elimination of dogs for behavioral rather than medical reasons was based on evaluations at three, six, nine and twelve months after birth. Throughout that period, the fostered dogs underwent standardized behavioral tests at TSA facilities, and, for a subset of tests, dogs were tested in four different environments. Using methods developed for family studies, we performed a case-control genome wide association study (GWAS) of elimination due to behavioral observation and testing results in a cohort of 528 Labrador Retrievers (2002-2013). We accounted for relatedness by including the pedigree as a covariate and maximized power by including individuals with phenotype, but not genotype, data (approximately half of this cohort). We determined genome wide significance based on Bonferroni adjustment of two quasi-likelihood score tests optimized for either small or nearly-fully penetrant effect sizes. Six loci were significant and five suggestive, with approximately equal numbers of loci for the two tests and frequencies of loci with single versus multiple mapped markers. Several loci implicate a single gene, including CHD2, NRG3 and PDE1A which have strong relevance to behavior in humans and other species. We briefly discuss how expanded studies of canine breeding programs could advance understanding of learning and performance in the mammalian life course. Although human interactions and other environmental conditions will remain critical, our findings suggest genomic breeding selection could help improve working dog populations.


Assuntos
Cruzamento , Estudo de Associação Genômica Ampla , Animais , Cães , Genoma , Genótipo , Humanos , Mamíferos , Linhagem
3.
Artigo em Chinês | MEDLINE | ID: mdl-36058666

RESUMO

Objective: To diagnose a large family of patients with hereditary angioedema, and to study its inheritance pattern and gene locus. Methods: A retrospective analysis was carried out from August 2021 to February 2022 in a proband (female, 48 years old) and 12 family members who underwent medical history collection and laboratory examinations in the Department of Otorhinolaryngology and Head and Neck Surgery, the Second Hospital of Shanxi Medical University. The clinical data of members and non-affected members [including 7 males and 5 females, aged 12-78 (median 24) years old], were drawn a family map while confirming the diagnosis. Whole exome sequencing technology was used to detect the genetic sequence of the proband and to verify its family members to map the genetic pedigree of the mutation. Results: The inheritance pattern of the family was autosomal dominant, and 8 members of the family were diagnosed with hereditary angioedema by laboratory examination, including 7 cases of type I and 1 case of type Ⅱ. Whole exome sequencing analysis was performed on 2 patients with 2 phenotypes, and it was found that they both carried the same pathogenic mutation locus, which was c.890-2A>G. The family members were verified by next-generation sequencing, and it was found that all members of the family who had a history of edema contained this mutation site, while the younger brother of the proband who had no history of edema did not have this mutation. Conclusion: Both type Ⅰ and type Ⅱ phenotypes are present in this hereditary angioedema family, and the mutation of SERPING1 gene c.890-2A>G causes the onset of each patient in this family.


Assuntos
Angioedemas Hereditários , Angioedemas Hereditários/genética , Asiáticos , Feminino , Humanos , Masculino , Mutação , Linhagem , Estudos Retrospectivos
4.
Trop Anim Health Prod ; 54(5): 279, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36074276

RESUMO

The purpose of the present study was to estimate the inbreeding coefficient and its effects on various growth traits in Beetal goat using pedigree records of 963 kids born to 38 sires and 287 dams over the period of 2004 to 2019. The inbreeding coefficients for each individual were obtained under animal model. The effects of inbreeding along with other fixed effects such as year of birth, sex of kid, type of birth, and dam's weight at kidding on growth traits viz., weight at birth (BWT), 3 (WT3), 6 (WT6), 9 (WT9), and 12 (WT12) months of age were studied using least-squares analysis. Additionally, average daily gain and Kleiber ratio up to weaning age (90 days) were studied under the same model. The overall inbreeding coefficient was low in magnitude (1.42%) and ranged from 0 to 25% over the study period. The significant (P < 0.05) increase in average inbreeding coefficient (%) over the years was observed among the studied population. Although, the effects of various factors had significant (P < 0.05) influence on growth traits under least-squares model, the regression of targeted traits on inbreeding were non-significant (P > 0.05) and the same ranged from - 0.06 to 0.04. The present findings indicated that there was no inbreeding depression among the growth traits of Beetal goat. However, as inbreeding (%) raised in recent years only, the scientific efforts must be taken to avoid inbreeding at resourced population by introducing new germplasms at earliest.


Assuntos
Cabras , Endogamia , Animais , Cabras/genética , Linhagem , Fenótipo , Desmame
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(9): 925-931, 2022 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-36082559

RESUMO

OBJECTIVE: To summarize the genetic characteristics of 671 Chinese pedigrees affected with Duchenne/Becker muscular dystrophy (DMD/BMD). METHODS: Clinical data of the pedigrees were collected. Multiplex PCR, multiple ligation dependent probe amplification (MLPA), next generation sequencing (NGS), Sanger sequencing and long read sequencing were used to detect the variant of DMD gene in the probands and their mothers, and prenatal diagnosis was provided for high risk pregnant women. RESULTS: Among 178 pedigrees analyzed by multiplex PCR, 44 variants of the DMD gene were detected, with the genetic diagnosis attained in 110 pedigrees. Among 493 pedigrees analyzed by MLPA in combination with NGS or Sanger sequencing, 294 pathogenic/possible pathogenic variants were identified, among which 45 were unreported previously, and the genetic diagnosis attained in 484 pedigrees. Structural variants of the DMD gene were identified in two pedigrees by long-read sequencing. Among 444 probands, 341 have inherited the DMD gene variant from their mothers (76.8%). Among 390 women with a high-risk, 339 have opted to have natural pregnancy and 51 chose preimplantation genetic testing for monogenetic disease (PGT-M). The detection rate of neonatal patients and carriers following natural pregnancy was significantly higher than that for PGT-M. CONCLUSION: Combined application of MLPA, NGS, Sanger sequencing and long-read sequencing is an effective strategy to detect DMD/BMD. PGT-M can effectively reduce the risk of fetuses. Above finding has expanded the spectrum of DMD gene variants and provided a basis for reproductive intervention for pregnancies with a high risk for DMD/BMD.


Assuntos
Distrofia Muscular de Duchenne , China , Distrofina/genética , Éxons , Feminino , Testes Genéticos , Humanos , Recém-Nascido , Reação em Cadeia da Polimerase Multiplex , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Mutação , Linhagem , Gravidez , Diagnóstico Pré-Natal
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(9): 932-937, 2022 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-36082560

RESUMO

OBJECTIVE: To detect potential variants in eight Chinese pedigrees affected with autosomal dominant polycystic kidney disease (ADPKD) and provide prenatal diagnosis for two of them. METHODS: Whole exome sequencing and high-throughput sequencing were carried out to detect variants of PKD1 and PKD2 genes in the probands. Sanger sequencing was used to validate the variants, and their pathogenicity was predicted by searching the ADPKD and protein variation databases. RESULTS: Eight PKD1 variants were detected, which have included five nonsense mutations and three missense mutations. Among these, four nonsense variants (PKD1: c.7555C>T, c.7288C>T, c.4957C>T, c.11423G>A) were known to be pathogenic, whilst one missense variant (PKD1: c.2180T>G) was classified as likely pathogenic. Three novel variants were detected, which included c.6781G>T (p.Glu2261*), c.109T>G (p.Cys37Gly) and c.8495A>G (p.Asn2832Ser). Prenatal testing showed that the fetus of one family has carried the same mutation as the proband, while the fetus of another family did not. CONCLUSION: PKD1 variants, including three novel variants, have been identified in the eight pedigrees affected with ADPKD. Based on these results, prenatal diagnosis and genetic counseling have been provided.


Assuntos
Rim Policístico Autossômico Dominante , Análise Mutacional de DNA/métodos , Feminino , Humanos , Mutação , Linhagem , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/genética , Gravidez , Diagnóstico Pré-Natal , Canais de Cátion TRPP/genética
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(9): 983-987, 2022 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-36082570

RESUMO

OBJECTIVE: To explore the clinical and genetic characteristics of a Chinese pedigree affected by glycogen storage disease (GSD) type Ia with gout as the first manifestation. METHODS: Clinical and biochemical data of the pedigree were collected. Available members of the pedigree were subjected to gene sequencing, and the result was analyzed by bioinformatics software. The pedigree was followed up for five years. RESULTS: The proband was a young female manifesting recurrent gout flare, hypoglycemia, and hypertriglyceridemia. One of her younger brothers also presented with dysplasia and hepatic adenoma. Gene sequencing revealed that the proband and her younger brother both harbored c.1022T>A (p.I1e341Asn) and c.230+5G>A compound heterozygous variants of the G6PC gene , which were inherited from their father and mother, respectively. Among these, the c.230+5G>A is an intron region variant which was unreported previously, and bioinformatics analysis showed that it may impact mRNA splicing of the gene. The proband was treated with raw corn starch, allopurinol, and fenofibrate. Gout was well controlled, and she had given birth to a baby girl without GSD. CONCLUSION: GSD Ia should be considered among young gout patients with hypoglycemia and hepatomegaly, for which gene sequencing is warranted. GSD Ia has a good prognosis after comprehensive treatment with diet and medicine.


Assuntos
Gota , Hipoglicemia , China , Feminino , Doença de Depósito de Glicogênio Tipo I , Gota/genética , Humanos , Masculino , Linhagem , Exacerbação dos Sintomas
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(9): 1016-1020, 2022 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-36082577

RESUMO

OBJECTIVE: To explore the clinical and genetic characteristics of a Chinese pedigree affected with hereditary dentinogenesis imperfecta (DGI) type II. METHODS: Clinical data of the pedigree members were collected. Genomic DNA was extracted from peripheral blood samples and subjected to whole exome sequencing. RESULTS: Clinical characteristics of the affected family members have included amber teeth along with significant attrition, constricted roots and dentine hypertrophy leading to pulpal obliteration, which were suggestive of DGI type II. All of the affected members were found to have harbored a novel heterozygous c.2837delA (p.Asp946Valfs*368) variant of the DSPP gene which was predicted to be likely pathogenic. CONCLUSION: The c.2837delA variant of the DSPP gene probably underlay the disease in this pedigree. Above finding has expanded the variant spectrum of DSPP gene and provided a basis for molecular diagnosis and genetic counseling for this pedigree.


Assuntos
Dentinogênese Imperfeita , Dentinogênese Imperfeita/genética , Proteínas da Matriz Extracelular/genética , Humanos , Mutação , Linhagem , Fosfoproteínas/genética , Sialoglicoproteínas/genética
9.
Int J Mol Sci ; 23(17)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36076978

RESUMO

Palmoplantar keratoderma is a clinically polymorphic disorder with a heterogeneous etiology characterized by marked hyperkeratotic lesions on the surface of palms and soles. Hereditary forms of palmoplantar keratoderma usually have autosomal dominant inheritance and are caused by mutations in dozens of genes, most of which belong to the keratin family. We carried out clinical and molecular genetic analysis of the affected and healthy members of four families with autosomal dominant palmoplantar keratoderma. In three out of four family cases of autosomal dominant palmoplantar keratoderma, the following molecular genetic causes were established: in two families-previously non-described missense mutations in the AQP5 gene (NM_001651.4): c.369C>G (p.(Asn123Lys)) and c.103T>G (p.(Trp35Gly)); in one family-a described splice site mutation in the KRT9 gene (NM_000226.4): c.31T>G. In one family, the possible cause of palmoplantar keratoderma was detected-a variant in the KRT1 gene (NM_006121.4): c.931G>A (p.(Glu311Lys)).


Assuntos
Ceratodermia Palmar e Plantar , Humanos , Queratinas/genética , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Biologia Molecular , Mutação , Mutação de Sentido Incorreto , Linhagem
10.
Transl Psychiatry ; 12(1): 390, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115840

RESUMO

Bipolar disorder (BD) is a complex psychiatric disorder with strong heritability. Identification of new BD risk genes will help determine the mechanism underlying disease pathogenesis. In the present study, we carried out whole genome sequencing for a Chinese BD family with three affected members and three unaffected members, and identified multiple candidate causal variations, including a frameshift mutation in the GOLGB1 gene. Since a GOLGB1 missense mutation was also found in another BD pedigree, we carried out functional studies by downregulating Golgb1 expression in the brain of neonatal mice. Golgb1 deficiency had no effect on anxiety, memory, and social behaviors in young adult mice. However, we found that young adult mice with Golgb1 deficiency exhibited elevated locomotor activity and decreased depressive behaviors in the tail suspension test and the sucrose preference test, but increased depressive behaviors in the forced swim test, resembling the dual character of BD patients with both mania and depression. Moreover, Golgb1 downregulation reduced PSD93 levels and Akt phosphorylation in the brain. Together, our results indicate that GOLGB1 is a strong BD risk gene candidate whose deficiency may result in BD phenotypes possibly through affecting PSD93 and PI3K/Akt signaling.


Assuntos
Transtorno Bipolar , Animais , Transtorno Bipolar/metabolismo , Humanos , Camundongos , Linhagem , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Sacarose
11.
BMC Med Genomics ; 15(1): 197, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115989

RESUMO

BACKGROUND: Leber's congenital amaurosis (LCA) is a severe hereditary retinopathy disease that is characterized by early and severe reduction of vision, nystagmus, and sluggish or absent pupillary responses. To date, the pathogenesis of LCA remains unclear, and the majority of cases are caused by autosomal recessive inheritance. In this study, we explored the variant in the Crumbs homologue 1 (CRB1) gene in a Chinese family with LCA. METHODS: We conducted comprehensive ocular examinations and collected 5 ml of blood samples from members of a Chinese family with LCA. A pathogenic variant was identified by capturing (the panel in NGS) and Sanger sequencing validation. RESULTS: A nonsense variant (c.1499C>G) in the 6th exon of CRB1 gene in a Chinese family with LCA was identified, which predicted a change in the protein p. S500*, may lead to loss of gene function. We summarized the 76 variants reported thus far in CRB1 that caused LCA8. CONCLUSIONS: This study reported a novel variant c.1499C>G (p. S500*) of the CRB1 gene occurred in a Chinese family with LCA, thus expanding the spectrum of CRB1 variants causing LCA.


Assuntos
Amaurose Congênita de Leber , Asiáticos/genética , China , Proteínas do Olho/genética , Humanos , Amaurose Congênita de Leber/genética , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Linhagem
12.
J Infect Dev Ctries ; 16(8): 1351-1358, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36099380

RESUMO

INTRODUCTION: To identify the specific Anopheles mosquito sibling species responsible for malaria transmission, determine their vectorial potential, and predict suitable control measures, this study investigated genetic identities, human blood feeding, and sporozoite infection rates of endophilic Anopheles mosquitoes in Gaa-Bolorunduro, a cattle rearing community in Kwara State, Nigeria. METHODOLOGY: Monthly pyrethrum spray collections of Anopheles mosquitoes were conducted for one year in addition to PCR characterization of sibling species and ELISA probing of human blood meal and sporozoite infections. Mean numbers and human blood indices (HBI) of the different Anopheles sibling species identified were compared. RESULTS: The total of 668 PCR-identified mosquitoes comprised 50.8% An. arabiensis, 46.7% An. gambiae, and 2.5% An. coluzzii. Annual mean numbers of An. arabiensis was significantly higher (p = 0.001) than An. coluzzii but not An. gambiae (p = 0.602). Proportions of An. arabiensis found with human blood (0.29) were lower compared to An. gambiae (0.72) and An. coluzzii (0.75). However, the annual mean HBI of An. arabiensis was not significantly higher than An. gambiae (p = 0.195) and An. coluzzii (p = 0.249). Plasmodium falciparum sporozoite infection rate was 1.6% in An. gambiae, 0.9% in An. arabiensis and 0% in An. coluzzii. CONCLUSIONS: The prevalent An. arabiensis and An. gambiae mosquitoes found indoors, despite the outdoor cattle population barrier, could be targeted by community-scale utilization of long-lasting insecticide-treated bed nets. Further studies on outdoor mosquito surveillance and bovine blood meal identification are required for the recommendation of suitable complementary vector control measures for the community.


Assuntos
Anopheles , Malária Falciparum , Malária , Animais , Anopheles/genética , Bovinos , Humanos , Malária/epidemiologia , Malária/prevenção & controle , Mosquitos Vetores , Nigéria/epidemiologia , Linhagem , Esporozoítos
13.
Zhonghua Yi Xue Za Zhi ; 102(34): 2702-2706, 2022 Sep 13.
Artigo em Chinês | MEDLINE | ID: mdl-36096698

RESUMO

Mutations in fibrillin-1 (FBN1) were detected in an autosomal dominant Marfan syndrome (MFS) pedigree. The related phenotypes and the significance of mutation screening were discussed. Complete medical and cardiovascular examinations for all pedigree members were performed. Whole exons sequencing (WES) was used to sequence the DNA of the patients and their relatives. The potential pathogenic mutation sites were screened by bioinformatics method. Sanger sequencing was used to verify the mutation sites in the pedigree. The results showed that FBN1 missense mutation was c.6806 T>C in exon 56, resulting in isoleucine being replaced by threonine (p. Ile2269Thr). This mutation has not been reported in Chinese Han population. The occurrence of the mutations strongly correlated with the phenotypes of the patients. The results expand the mutation spectrum of FBN1, and it is helpful to further explore the molecular pathogenesis of MFS and MFS related diseases.


Assuntos
Síndrome de Marfan , Éxons , Fibrilina-1/genética , Humanos , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Mutação de Sentido Incorreto , Linhagem
14.
BMC Pediatr ; 22(1): 528, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064339

RESUMO

BACKGROUND: Brachydactyly type B is an autosomal dominant disorder that is characterized by hypoplasia of the distal phalanges and nails and can be divided into brachydactyly type B1 (BDB1) and brachydactyly type B2 (BDB2). BDB1 is the most severe form of brachydactyly and is caused by truncating variants in the receptor tyrosine kinase-like orphan receptor 2 (ROR2) gene. CASE PRESENTATION: Here, we report a five-generation Chinese family with brachydactyly with or without syndactyly. The proband and her mother underwent digital separation in syndactyly, and the genetic analyses of the proband and her parents were provided. The novel heterozygous frameshift variant c.1320dupG, p.(Arg441Alafs*18) in the ROR2 gene was identified in the affected individuals by whole-exome sequencing and Sanger sequencing. The c.1320dupG variant in ROR2 is predicted to produce a truncated protein that lacks tyrosine kinase and serine/threonine- and proline-rich structures and remarkably alters the tertiary structures of the mutant ROR2 protein. CONCLUSION: The c.1320dupG, p.(Arg441Alafs*18) variant in the ROR2 gene has not been reported in any databases thus far and therefore is novel. Our study extends the gene variant spectrum of brachydactyly and may provide information for the genetic counselling of family members.


Assuntos
Braquidactilia , Sindactilia , Braquidactilia/diagnóstico , Braquidactilia/genética , Ossos do Carpo/anormalidades , Feminino , Deformidades Congênitas do Pé , Deformidades Congênitas da Mão , Humanos , Linhagem , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Estribo/anormalidades , Sinostose , Ossos do Tarso/anormalidades
15.
BMC Med Genomics ; 15(1): 189, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068540

RESUMO

BACKGROUND: Familial dilated cardiomyopathy (DCM) is a genetic cardiomyopathy that is associated with reduced left ventricle function or systolic function. Fifty-one DCM-causative genes have been reported, most of which are inherited in an autosomal dominant manner. However, recessive DCM-causative gene is rarely observed. METHODS: Whole-exome sequencing (WES) was performed in a consanguineous family with DCM to identify candidate variants. Sanger sequencing was utilized to confirm the variant. We then checked the DCM candidate gene in 210 sporadic DCM cases. We next explored BICD2 function in both embryonic and adult bicd2-knockout zebrafish models. In vivo cardiac function of bicd2-knockout fish was detected by echocardiography and RNA-seq. RESULTS: We identified an autosomal recessive and evolutionarily conserved missense variant, NM_001003800.1:c.2429G > A, in BICD2, which segregated with the disease phenotype in a consanguineous family with DCM. Furthermore, we confirmed the presence of BICD2 variants in 3 sporadic cases. Knockout of bicd2 resulted in partial embryonic lethality in homozygotes, suggesting a vital role for bicd2 in embryogenesis. Heart dilation and decreased ejection fraction, cardiac output and stroke volume were observed in bicd2-knockout zebrafish, suggesting a phenotype similar to human DCM. Furthermore, RNA-seq confirmed a larger transcriptome shift in in bicd2 homozygotes than in heterozygotes. Gene set enrichment analysis of bicd2-deficient fish showed the enrichment of altered gene expression in cardiac pathways and mitochondrial energy metabolism. CONCLUSIONS: Our study first shows that BICD2 is a novel candidate gene associated with familial DCM, and our findings will facilitate further insights into the molecular pathological mechanisms of DCM.


Assuntos
Cardiomiopatia Dilatada , Adulto , Animais , Cardiomiopatia Dilatada/patologia , Consanguinidade , Exoma , Humanos , Proteínas Associadas aos Microtúbulos , Linhagem , Peixe-Zebra/genética
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(9): 969-973, 2022 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-36082567

RESUMO

OBJECTIVE: To analyze the clinical and genetic characteristics of a Chinese pedigree affected with developmental and epileptic encephalopathy 9. METHODS: N048: epilepsy full version gene detection panel-V2 and genome wide copy number variation analysis were carried out on the genomic DNA extracted from the peripheral blood samples. Amniotic fluid was also sampled for single nucleoticle polymorphism array (SNP-array) analysis. RESULTS: Both the mother and her daughter were found to have loss of heterozygosity at Xq21.31q22.1, with which exons of protocadherin 19 (PCDH19) gene was deleted. SNP-array showed the fetus to be a female and had arr[hg19]Xq21.31q22.1 (89 558 626-99 701 006)x1. The mother, daughter and fetus of this family all had developmental and epileptic encephalopathy 9. CONCLUSION: Variant of the PCDH19 gene probably underlay the Developmental and epileptic encephalopathy 9 in this pedigree.


Assuntos
Epilepsia Generalizada , Epilepsia , Caderinas/genética , China , Variações do Número de Cópias de DNA , Epilepsia/diagnóstico , Epilepsia/genética , Feminino , Humanos , Mutação , Linhagem , Protocaderinas
17.
Eur J Med Genet ; 65(10): 104599, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36067927

RESUMO

Polydactyly is a human inherited disorder caused by to anomalies in the genes involved in autopod development. The disorder segregates in both autosomal recessive and autosomal dominant form. Up till now, eleven genes causing non-syndromic polydactyly, have been identified. This includes ZNF141, GLI3, ZRS in LMBR1, MIPOL1, PITX1, IQCE, GLI1, FMA92A1, KIAA0825, STKLD1, and DACH1. In the present study, we have investigated a large consanguineous family of Pakistani origin segregating polydactyly in autosomal recessive pattern. Clinical examination of affected individuals revealed a non-syndromic form of the disorder. Genetic study based on homozygosity mapping and Sanger sequencing using DNA of the normal and affected individuals found a novel homozygous missense sequence variant [NM_005269.3: c.1133C > T, p.(Ser378Leu)] in the GLI1 located on human chromosome 12q13.3. In silico analysis of the identified variant showed a significant change in the secondary structure of the mutant protein that affects its function. Findings of the present study expand the mutation spectrum of the GLI1. In addition, the study will help in prevention of the disorder through carrier testing and bringing awareness among families affected with polydactyly.


Assuntos
Polidactilia , Consanguinidade , Dedos/anormalidades , Humanos , Linhagem , Fenótipo , Polidactilia/complicações , Polidactilia/genética , Dedos do Pé/anormalidades , Proteína GLI1 em Dedos de Zinco/genética
18.
PLoS One ; 17(9): e0274335, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36083974

RESUMO

BACKGROUND: Primary congenital glaucoma (PCG) is a heterogeneous rare recessively inherited disorder prevalent in regions with high consanguinity. Disease phenotype is associated with increased intra ocular pressure and is a major cause of childhood blindness. Sequence variations in Cytochrome P450 1B1 (CYP1B1) gene are a major cause of PCG. Current study was conducted to screen CYP1B1 gene in highly consanguineous PCG affected families from Pakistani population consistent with the autosomal recessive pattern of PCG inheritance. METHODS: For this study, patients and controls (clinically unaffected individuals of each family) from 25 consanguineous families belonging to Punjab, Baluchistan and Khyber Pakhtunkhwa, Pakistan were recruited through ophthalmologists. DNA was isolated from collected blood samples. Genetic screening of CYP1B1 gene was done for all enrolled families. In-silico analysis was performed to identify and predict the potential disease-causing variations. RESULTS: Pathogenicity screening revealed sequence variants segregating with disease phenotype in homozygous or compound heterozygous form in eleven out of 25 analyzed families. We identified a total of sixteen disease causing variants among which five frameshift i.e., c.629dup (p.Gly211Argfs*13), c.287dup (p.Leu97Alafs*127), c.662dup (p.Arg222Profs*2), c.758_759insA (p.Val254Glyfs*73) and c.789dup (p.Leu264Alafs*63), two silent c.1314G>A, c.771T>G and six missense variations c.457C>G (p.Arg153Gly), c.516C>A (p.Ser172Arg), c.722T>A (p.Val241Glu), c.740T>A (p.Leu247Gln), c.1263T>A (p.Phe421Leu), and c.724G>C (p.Asp242His) are previously un reported. However two frameshift c.868dup (p.Arg290Profs*37), c.247del (p.Asp83Thrfs*12) and one missense variant c.732G>A (p.Met244Ile), is previously reported. Furthermore, six polymorphisms c.1347T>C, c.2244_2245insT, c.355G>T, c.1294G>C, c.1358A>G and c.142C>G were also identified. In the intronic region, a novel silent polymorphism i.e., g.35710_35711insT was found in homozygous state. All the newly detected disease-causing variants were negative in 96 ethnically matched controls. CONCLUSION: Among twenty-five screened families, eight families (PCG50, 52-54, 58, 59, 63 and 67) were segregating disease causing variants in recessive manner. Two families (PCG049 and PCG062) had compound heterozygosity. Our data confirms genetic heterogeneity of PCG in Pakistani population however we did not find molecular variants segregating with PCG in fifteen families in coding exons and intron-exon boundaries of CYP1B1 gene. Genetic counseling was provided to families to refrain from practicing consanguinity and perform premarital screening as a PCG control measure in upcoming generations.


Assuntos
Glaucoma , Citocromo P-450 CYP1B1/genética , Análise Mutacional de DNA , Glaucoma/congênito , Glaucoma/genética , Humanos , Mutação , Paquistão , Linhagem
19.
J Oral Pathol Med ; 51(8): 755-761, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36087272

RESUMO

BACKGROUND: Molecular etiology of lingual hamartoma is poorly understood. This study aims to identify potentially deleterious mutations for lingual hamartoma and analyze its molecular profile by a combination of whole-exome sequencing and RNA-sequencing. METHODS: Whole-exome sequencing was conducted on the proband presenting lingual hamartoma and patient's unaffected family members. Potentially pathogenic mutations were identified after filtration. The pathogenicity of the identified variants was predicted by in silico algorithms and conservative analysis. RNA-sequencing was performed to further explore the molecular profile of lingual hamartoma. RESULTS: Whole-exome sequencing of the proband and patients' unaffected brother and parents identified a de novo mutation c.931C>T_p.Pro311Ser in the DYNC2H1 gene (NM_001080463.2). The DYNC2H1 mutation was predicted to be disease-causing for affecting highly conserved amino acid by PolyPhen2 and Mutation Taster. RNA-sequencing analysis showed that the DYNC2H1 gene was significantly down-regulated in lingual hamartoma. Gene set enrichment analysis revealed cilium assembly and Hedgehog signaling pathway were significantly affected. CONCLUSION: The study expanded our knowledge on the clinical and genetic spectrum of lingual hamartoma by identifying causal variants in a Chinese pedigree. DYNC2H1 is likely to participate in tongue development and its pathologic mutation may underlie the etiology of lingual hamartoma.


Assuntos
Hamartoma , Proteínas Hedgehog , China , Dineínas do Citoplasma , Hamartoma/genética , Humanos , Masculino , Linhagem , RNA
20.
Zhonghua Yi Xue Za Zhi ; 102(31): 2441-2445, 2022 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-36000373

RESUMO

Objective: To analyze the clinical phenotype and detect the pathogenic gene in a Chinese pedigree with autosomal dominant polycystic kidney disease(ADPKD). Methods: The proband of this study was hospitalized in Dongguan City People's Hospital on October 10, 2017, due to "left maxillary apical cyst". Clinical phenotypes were noted, imaging examinations and determination of biochemical indicators were carried out for the clinical diagnosis of the proband. Genomic DNA was extracted from peripheral venous blood. Whole-exome genotyping of the proband was performed with the next generation sequencing technology, and the candidate mutation site of the patient and his family members was verified by PCR and Sanger sequencing technology. The mutation site was further screened in 150 unrelated healthy Chinese controls. Mutation frequency within human populations and bioinformatics analysis were predicted with softwares including ExAC, dbSNP, HGMD, 1000 genomes, ClinVar, PKDB, Mutation Taster and PhyloP. Results: The proband, a 46-year-old male, was diagnosed with hypertension, positive urine occult blood and elevated blood creatinine. B-ultrasound and CT examinations showed that he had bilateral polycystic kidney with left kidney stones and polycystic liver. The gene analysis showed that the c.11017-10C>A heterozygous splice mutation in PKD1 gene was identified in the proband, his second younger brother, younger sister, daughter and niece, but absent in 150 healthy controls. Bioinformatics analysis showed it has been reported in the dbSNP, ClinVar, HGMD, PKDB and Mutation Taster databases. Some databases predicted it has a harmful function for probably leading to production of a truncated polycystin1(PC1) protein. Conclusion: c.11017-10C>A underlies the Chinese ADPKD pedigree and expands mutation spectrum of PKD1.


Assuntos
Rim Policístico Autossômico Dominante , Canais de Cátion TRPP/genética , Asiáticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/genética
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