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1.
Neuromolecular Med ; 26(1): 28, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38954284

RESUMO

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in the NF1 gene. This disorder shows nearly complete penetrance and high phenotypic variability. We used the whole-exome sequencing technique to identify mutations in 32 NF1 cases from 22 Iranian families. A total of 31 variants, including 30 point mutations and one large deletion, were detected. In eight cases, variants were inherited, while they were sporadic in the remaining. Seven novel variants, including c.5576 T > G, c.6658_6659insC, c.2322dupT, c.92_93insAA, c.4360C > T, c.3814C > T, and c.4565_4566delinsC, were identified. The current study is the largest in terms of the sample size of Iranian NF1 cases with identified mutations. The results can broaden the spectrum of NF1 mutations and facilitate the process of genetic counseling in the affected families.


Assuntos
Sequenciamento do Exoma , Genes da Neurofibromatose 1 , Neurofibromatose 1 , Neurofibromina 1 , Humanos , Irã (Geográfico) , Neurofibromatose 1/genética , Neurofibromina 1/genética , Feminino , Masculino , Criança , Linhagem , Adulto , Mutação Puntual , Mutação , Adolescente , Pré-Escolar , Adulto Jovem , Análise Mutacional de DNA , Deleção de Sequência
3.
PLoS One ; 19(7): e0305157, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38959276

RESUMO

The last couple of decades have highlighted the importance of studying hybridization, particularly among primate species, as it allows us to better understand our own evolutionary trajectory. Here, we report on genetic ancestry estimates using dense, full genome data from 881 olive (Papio anubus), yellow (Papio cynocephalus), or olive-yellow crossed captive baboons from the Southwest National Primate Research Center. We calculated global and local ancestry information, imputed low coverage genomes (n = 830) to improve marker quality, and updated the genetic resources of baboons available to assist future studies. We found evidence of historical admixture in some putatively purebred animals and identified errors within the Southwest National Primate Research Center pedigree. We also compared the outputs between two different phasing and imputation pipelines along with two different global ancestry estimation software. There was good agreement between the global ancestry estimation software, with R2 > 0.88, while evidence of phase switch errors increased depending on what phasing and imputation pipeline was used. We also generated updated genetic maps and created a concise set of ancestry informative markers (n = 1,747) to accurately obtain global ancestry estimates.


Assuntos
Papio , Animais , Papio/genética , Linhagem , Masculino , Feminino , Genoma , Papio cynocephalus/genética , Papio anubis/genética , Polimorfismo de Nucleotídeo Único , Hibridização Genética , Software
4.
Cancer Med ; 13(13): e7394, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38970307

RESUMO

BACKGROUND: Germline mutations have been identified in a small number of hereditary cancers, but the genetic predisposition for many familial cancers remains to be elucidated. METHODS: This study identified a Chinese pedigree that presented different cancers (breast cancer, BRCA; adenocarcinoma of the esophagogastric junction, AEG; and B-cell acute lymphoblastic leukemia, B-ALL) in each of the three generations. Whole-genome sequencing and whole-exome sequencing were performed on peripheral blood or bone marrow and cancer biopsy samples. Whole-genome bisulfite sequencing was conducted on the monozygotic twin brothers, one of whom developed B-ALL. RESULTS: According to the ACMG guidelines, bioinformatic analysis of the genome sequencing revealed 20 germline mutations, particularly mutations in the DNAH11 (c.9463G > A) and CFH (c.2314G > A) genes that were documented in the COSMIC database and validated by Sanger sequencing. Forty-one common somatic mutated genes were identified in the cancer samples, displaying the same type of single nucleotide substitution Signature 5. Meanwhile, hypomethylation of PLEK2, MRAS, and RXRA as well as hypermethylation of CpG island associated with WT1 was shown in the twin with B-ALL. CONCLUSIONS: These findings reveal genomic alterations in a pedigree with multiple cancers. Mutations found in the DNAH11, CFH genes, and other genes predispose to malignancies in this family. Dysregulated methylation of WT1, PLEK2, MRAS, and RXRA in the twin with B-ALL increases cancer susceptibility. The similarity of the somatic genetic changes among the three cancers indicates a hereditary impact on the pedigree. These familial cancers with germline and somatic mutations, as well as epigenomic alterations, represent a common molecular basis for many multiple cancer pedigrees.


Assuntos
Metilação de DNA , Sequenciamento do Exoma , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Linhagem , Humanos , Masculino , Feminino , Sequenciamento Completo do Genoma , Pessoa de Meia-Idade , Genômica/métodos , Adulto , Epigênese Genética , Ilhas de CpG , Epigenômica/métodos , Dineínas do Axonema/genética
5.
Med Sci Monit ; 30: e944294, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38970244

RESUMO

BACKGROUND Non-syndromic cleft lip with cleft palate (NSCLP) is one of the most common congenital birth defects worldwide; it causes lifelong problems and imposes burdens on patients and their families. This study aimed to describe the genomic analysis and identification of de novo regulated endocrine-specific protein 18 (RESP18) rs2385404 and rs2385405 gene polymorphisms associated with NSCLP in a southern Chinese family and to improve prevention, treatment, and prognosis of NSCLP. MATERIAL AND METHODS We performed a genome-wide association study (GWAS) to investigate the association of NSCLP phenotype with gene mutation. We investigated a 5-persons NSCLP family to screen the genetic variation of Han nationality in southern Chinese. Whole-genome sequencing (WGS) was used to detect all candidate genetic variants, and whole-exome sequencing (WES) was implemented to further verify mutations. The Clinical Variation Data Base (ClinVar) was employed for screening gene mutations. Finally, Sanger sequencing was applied to verify gene variations. RESULTS The combined analysis of WGS, WES, and ClinVar showed that a total of 9 variation positions overlapped among the 3 study cohorts. Sanger sequencing verified Glu amino acid variation in 2 mutation sites (rs2385404, rs2385405) from the RESP18 gene, which caused abnormal RESP18 function and was associated with hereditary NSCLP. CONCLUSIONS The combined genomic results showed that 2 mutations (rs2385404 and rs2385405) of the RESP18 gene were related to NSCLP in the family. The RESP18 gene may play an important role in the etiology and pathogenesis of cleft lip and palate.


Assuntos
Povo Asiático , Fenda Labial , Fissura Palatina , Estudo de Associação Genômica Ampla , Mutação , Linhagem , Humanos , Fenda Labial/genética , Fissura Palatina/genética , Feminino , Mutação/genética , Masculino , Povo Asiático/genética , China , Polimorfismo de Nucleotídeo Único/genética , Predisposição Genética para Doença/genética , Sequenciamento do Exoma/métodos , Sequenciamento Completo do Genoma/métodos , Fenótipo , População do Leste Asiático
6.
Mol Genet Genomic Med ; 12(7): e2482, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38958168

RESUMO

BACKGROUND: Marfan syndrome (MFS) is a hereditary connective tissue disorder involving multiple systems, including ophthalmologic abnormalities. Most cases are due to heterozygous mutations in the fibrillin-1 gene (FBN1). Other associated genes include LTBP2, MYH11, MYLK, and SLC2A10. There is significant clinical overlap between MFS and other Marfan-like disorders. PURPOSE: To expand the mutation spectrum of FBN1 gene and validate the pathogenicity of Marfan-related genes in patients with MFS and ocular manifestations. METHODS: We recruited 318 participants (195 cases, 123 controls), including 59 sporadic cases and 88 families. All patients had comprehensive ophthalmic examinations showing ocular features of MFS and met Ghent criteria. Additionally, 754 cases with other eye diseases were recruited. Panel-based next-generation sequencing (NGS) screened mutations in 792 genes related to inherited eye diseases. RESULTS: We detected 181 mutations with an 84.7% detection rate in sporadic cases and 87.5% in familial cases. The overall detection rate was 86.4%, with FBN1 accounting for 74.8%. In cases without FBN1 mutations, 23 mutations from seven Marfan-related genes were identified, including four pathogenic or likely pathogenic mutations in LTBP2. The 181 mutations included 165 missenses, 10 splicings, three frameshifts, and three nonsenses. FBN1 accounted for 53.0% of mutations. The most prevalent pathogenic mutation was FBN1 c.4096G>A. Additionally, 94 novel mutations were detected, with 13 de novo mutations in 14 families. CONCLUSION: We expanded the mutation spectrum of the FBN1 gene and provided evidence for the pathogenicity of other Marfan-related genes. Variants in LTBP2 may contribute to the ocular manifestations in MFS, underscoring its role in phenotypic diversity.


Assuntos
Fibrilina-1 , Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Marfan , Mutação , Humanos , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Feminino , Masculino , Fibrilina-1/genética , Adulto , Criança , Adolescente , Pessoa de Meia-Idade , Pré-Escolar , Oftalmopatias/genética , Oftalmopatias/patologia , Linhagem , População do Leste Asiático , Adipocinas
7.
Mol Genet Genomic Med ; 12(7): e2488, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38963008

RESUMO

BACKGROUND: This study aimed to identify disease-causing variants within a Chinese family affected by Birt-Hogg-Dubé syndrome (BHDS), which arises from an autosomal dominant inheritance pattern attributed to variants in the folliculin (FLCN) gene, recognized as a tumor suppressor gene. METHODS: A Chinese proband diagnosed with BHDS due to renal tumors underwent next-generation sequencing (NGS), revealing a novel variant in the FLCN gene. Sanger sequencing was subsequently performed on blood samples obtained from family members to confirm the presence of this variant. RESULTS: A novel germline frameshift variant (NM_144997.5:c.977dup) was identified in five individuals among the screened family members, marking the first report of this variant. Additionally, a somatic frameshift variant (NM_144997.5:c.1252del) was detected in the renal tumors of the proband. No variant was detected in unaffected family members. CONCLUSIONS: A novel heterozygous variant was identified in exon 9 of the FLCN gene, which broadens the spectrum of FLCN variants. We recommend that molecular analysis of the FLCN gene be performed in patients with suspected BHDS and their families.


Assuntos
Síndrome de Birt-Hogg-Dubé , Mutação da Fase de Leitura , Linhagem , Proteínas Proto-Oncogênicas , Proteínas Supressoras de Tumor , Humanos , Síndrome de Birt-Hogg-Dubé/genética , Síndrome de Birt-Hogg-Dubé/patologia , Proteínas Supressoras de Tumor/genética , Proteínas Proto-Oncogênicas/genética , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Neoplasias Renais/genética , Neoplasias Renais/patologia , Mutação em Linhagem Germinativa , Heterozigoto , População do Leste Asiático
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(7): 807-811, 2024 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-38946362

RESUMO

OBJECTIVE: To analyze the genetic variant and molecular pathogenesis in a Chinese pedigree affected with Multiple epiphyseal dysplasia (MED). METHODS: A MED pedigree which had presented at the Beijing Jishuitan Hospital Affiliated to Capital Medical University on September 13, 2020 was selected as the study subject. Clinical data of the pedigree were collected. Peripheral blood samples were drawn from pedigree members for the extraction of genomic DNA. Whole exome sequencing (WES) was carried out for the pedigree. Candidate variant was verified by Sanger sequencing. Wild type and mutant SLC26A2 expression plasmids were constructed and transfected into human primary chondrocytes. The effect of the variants on the protein localization and cell proliferation was determined by immunofluorescence and CCK8 assays. RESULTS: WES and Sanger sequencing revealed that the proband has harbored compound heterozygous variants of the SLC26A2 gene, including a paternally derived c.484G>T (p.Val162Leu) missense variant and a maternally derived c.485_486delTG (p.Val162Glyfs*12) frameshifting variant. The SLC26A2WT and its mutant SLC26A2Val162Leu and SLC26A2Val162Glyfs*12 expression plasmids were distributed in the nuclei and cytoplasm of human primary chondrocytes. Compared with SLC26A2WT, the expressions of SLC26A2Val162Leu and SLC26A2Val162Glyfs*12 were decreased, along with reduced proliferation of human primary chondrocytes. CONCLUSION: The c.484G>T and c.485_486delTG compound heterozygous variants of the SLC26A2 gene may affect the proliferation of human primary chondrocytes and underlay the pathogenesis of MED in this pedigree.


Assuntos
Povo Asiático , Osteocondrodisplasias , Linhagem , Transportadores de Sulfato , Humanos , Transportadores de Sulfato/genética , Transportadores de Sulfato/metabolismo , Osteocondrodisplasias/genética , Masculino , Feminino , Povo Asiático/genética , Condrócitos/metabolismo , Sequenciamento do Exoma , Adulto , China , Mutação , Variação Genética , Proliferação de Células , População do Leste Asiático
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(7): 821-824, 2024 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-38946365

RESUMO

OBJECTIVE: To explore the genetic basis for a child featuring facial dysmorphism and intellectual disabilities. METHODS: A child who was diagnosed at Linyi People's Hospital on January 5 2023 due to "mental retardation" was selected as the study subject. Peripheral blood samples of the child and his parents, in addition with an amniotic fluid sample from the his mother were collected for the extraction of genomic DNA. Whole exome sequencing was carried out for the child, and candidate variant was verified by Sanger sequencing of his family members. RESULTS: The child was found to harbor a hemizygous c.1123dupG (p.E375Gfs*4) variant of the NEXMIF gene, for which both of his parents and the fetus were of the wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PVS1+PS2-P+PM2-P). A healthy infant was subsequently born. CONCLUSION: The hemizygous c.1123dupG (p.E375Gfs*4) variant of the NEXMIF gene probably underlay the disease in this child. Based on his clinical phenotype and genotype, the child was ultimately diagnosed with X-linked intellectual developmental disorder-98. Above finding has also enriched the mutational spectrum of the NEXMIF gene.


Assuntos
Deficiência Intelectual , Humanos , Masculino , Deficiência Intelectual/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação , Sequenciamento do Exoma , Testes Genéticos , Feminino , Criança , Linhagem , Lactente , Pré-Escolar , Proteínas do Tecido Nervoso
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(7): 849-852, 2024 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-38946371

RESUMO

OBJECTIVE: To investigate the clinical and genetic features of a child with Dyschromatosis symmetrica hereditaria (DSH) and variant of the ADAR1 gene. METHODS: A child who was admitted to the Department of Dermatology of the First Affiliated Hospital of Zhengzhou University in June 2020 due to irregular pigmented maculopapular rash on the dorsum of hands was selected as the study subject. Whole exome sequencing (WES) was carried out for the child and his similarly affected father, and Sanger sequencing was used to verify the candidate variant. SWISS-MODEL was used to predict the secondary and tertiary structures of the wild-type and mutant ADAR1 proteins. RESULTS: The child, a 13-year-old boy, had symmetrical hyperpigmented and depigmented spots on the back of his hands and was clinically diagnosed with DSH. WES and Sanger sequencing results showed that he and his father had both harbored a heterozygous c.2858dup (p.T954Dfs*20) truncating variant in exon 10 of the ADAR1 gene. Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was predicted as pathogenic (PVS1+PM2_Supporting+PM1+PP3). CONCLUSION: The c.2858dup (p.T954Dfs*20) variant of the ADAR1 gene probably underlay the DSH in this pedigree.


Assuntos
Adenosina Desaminase , Transtornos da Pigmentação , Proteínas de Ligação a RNA , Humanos , Masculino , Adenosina Desaminase/genética , Transtornos da Pigmentação/genética , Transtornos da Pigmentação/congênito , Proteínas de Ligação a RNA/genética , Adolescente , Mutação , Sequenciamento do Exoma , Éxons , Testes Genéticos , Linhagem
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(7): 840-843, 2024 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-38946369

RESUMO

OBJECTIVE: To explore the clinical phenotype and genetic basis of a child with Neutral lipid storage disease with myopathy (NLSDM). METHODS: A child who was admitted to the First Affiliated Hospital of Zhengzhou University in February 2021 for a history of elevated creatine kinase (CK) for over 2 months was selected as the study subject. Clinical and laboratory examinations were carried out, and the child was subjected to whole exome sequencing. Candidate variants were validated by Sanger sequencing of her family members. RESULTS: The patient, a 9-year-old female, had exhibited weakness in the lower limbs, elevated CK level, and refractory cardiomyotrophy. Genetic testing revealed that she has harbored c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene, which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PM1+PM2_Supporting+PP3+PP4). CONCLUSION: The c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene probably underlay the myasthenia gravis and elevated creatine kinase in this child.


Assuntos
Lipase , Erros Inatos do Metabolismo Lipídico , Doenças Musculares , Humanos , Feminino , Criança , Doenças Musculares/genética , Erros Inatos do Metabolismo Lipídico/genética , Lipase/genética , Mutação , Testes Genéticos , Sequenciamento do Exoma , Creatina Quinase/sangue , Linhagem , Fenótipo , Aciltransferases
12.
Sci Rep ; 14(1): 15141, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956129

RESUMO

Pediatric cardiomyopathies are mostly attributed to variants in sarcomere-related genes. Unfortunately, the genetic architecture of pediatric cardiomyopathies has never been previously studied in Jordan. We sought to uncover the genetic landscape of 14 patients from nine families with several subtypes of pediatric cardiomyopathies in Jordan using Exome sequencing (ES). Our investigation identified pathogenic and likely pathogenic variants in seven out of nine families (77.8%), clustering in sarcomere-related genes. Surprisingly, phenocopies of sarcomere-related hypertrophic cardiomyopathies were evident in probands with glycogen storage disorder and mitochondrial-related disease. Our study underscored the significance of streamlining ES or expanding cardiomyopathy-related gene panels to identify plausible phenocopies of sarcomere-related cardiomyopathies. Our findings also pointed out the need for genetic testing in patients with cardiomyopathy and their at-risk family members. This can potentially lead to better management strategies, enabling early interventions, and ultimately enhancing their prognosis. Finally, our findings provide an initial contribution to the currently absent knowledge about the molecular underpinnings of cardiomyopathies in Jordan.


Assuntos
Cardiomiopatias , Linhagem , Sarcômeros , Humanos , Jordânia , Masculino , Feminino , Sarcômeros/genética , Criança , Cardiomiopatias/genética , Cardiomiopatias/diagnóstico , Pré-Escolar , Sequenciamento do Exoma , Lactente , Fenótipo , Adolescente , Mutação , Testes Genéticos/métodos
13.
Med Sci (Paris) ; 40(6-7): 563-565, 2024.
Artigo em Francês | MEDLINE | ID: mdl-38986104

RESUMO

Many human DNA sequences have been obtained from ancient remains dating back from several millennia. However, these have low coverage and may contain many errors; this has limited their usefulness for many analyses, in particular the search for Identical By Descent (IBD) segments that is very powerful for detection of kinship. A new method, using imputation from database data and sophisticated statistical analysis, proves able to detect IBD segments (and thus parenthood) in low-quality DNA sequences from individuals linked only by sixth degree parenthood, opening a whole new field of investigation using ancient DNA.


Assuntos
DNA Antigo , Humanos , DNA Antigo/análise , Análise de Sequência de DNA/métodos , Linhagem
14.
BMC Med Genomics ; 17(1): 181, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978054

RESUMO

BACKGROUND: Alport syndrome (AS) is an inherited nephropathy caused by mutations in the type IV collagen genes. It is clinically characterized by damage to the eyes, ears and kidneys. Diagnosis of AS is hampered by its atypical clinical picture, particularly when the typical features, include persistent hematuria and microscopic changes in the glomerular basement membrane (GBM), are the only clinical manifestations in the patient. METHODS: We screened 10 families with suspected AS using whole exome sequencing (WES) and analyzed the harmfulness, conservation, and protein structure changes of mutated genes. In further, we performed in vitro functional analysis of two missense mutations in the COL4A5 gene (c.2359G > C, p.G787R and c.2605G > A, p.G869R). RESULTS: We identified 11 pathogenic variants in the type IV collagen genes (COL4A3, COL4A4 and COL4A5). These pathogenic variants include eight missense mutations, two nonsense mutations and one frameshift mutation. Notably, Family 2 had digenic mutations in the COL4A3 (p.G1170A) and UMOD genes (p.M229K). Family 3 had a digenic missense mutation (p.G997E) in COL4A3 and a frameshift mutation (p.P502L fs*151) in COL4A4. To our knowledge, four of the 11 mutations are novel mutations. In addition, we found that COL4A5 mutation relation mRNA levels were significantly decreased in HEK 293 T cell compared to control, while the cellular localization remained the same. CONCLUSIONS: Our research expands the spectrum of COL4A3-5 pathogenic variants, which is helpful for clinical and scientific research.


Assuntos
Autoantígenos , Colágeno Tipo IV , Nefrite Hereditária , Linhagem , Humanos , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Colágeno Tipo IV/genética , Autoantígenos/genética , Feminino , Masculino , Adulto , Mutação , Sequenciamento do Exoma , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Células HEK293
15.
Mol Genet Genomic Med ; 12(7): e2446, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38980994

RESUMO

BACKGROUND: Deafness autosomal dominant 2A (DFNA2A) is related to non-syndromic genetic hearing impairment. The KCNQ4 (Potassium Voltage-Gated Channel Subfamily Q Member 4) can lead to DFNA2A. In this study, we report a case of autosomal dominant non-syndromic hearing loss with six family members as caused by a novel variant in the KCNQ4 gene. METHODS: The whole-exome sequencing (WES) and pure tone audiometry were performed on the proband of the family. Sanger sequencing was conducted on family members to determine if the novel variant in the KCNQ4 gene was present. Evolutionary conservation analysis and computational tertiary structure protein prediction of the wild-type KCNQ4 protein and its variant were then performed. In addition, voltage-gated channel activity of the wild-type KCNQ4 protein and its variant were tested using whole-cell patch clamp. RESULTS: It was observed that the proband had inherited autosomal dominant, non-syndromic sensorineural hearing loss as a trait. A novel co-segregating heterozygous missense variant (c.902C>A, p.Ala301Asp) of the KCNQ4 gene was identified in the proband and other five affected family members. This variant was predicted to cause an alanine-to-aspartic acid substitution at position 301 in the KCNQ4 protein. The alanine at position 301 is well conserved across different species. Whole-cell patch clamp showed that there was a significant difference between the WT protein currents and the mutant protein currents in the voltage-gated channel activity. CONCLUSION: In the present study, performing WES in conjunction with Sanger sequencing enhanced the detection of a novel, potentially causative variant (c301 A>G; p.Ala301Asp) in exon 6 of the KCNQ4 gene. Therefore, our findings contributed to the mutation spectrum of the KCNQ4 gene and may be useful in the diagnosis and gene therapy of deafness autosomal dominant 2A.


Assuntos
Perda Auditiva Neurossensorial , Canais de Potássio KCNQ , Mutação de Sentido Incorreto , Linhagem , Humanos , Canais de Potássio KCNQ/genética , Masculino , Feminino , Adulto , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Pessoa de Meia-Idade , População do Leste Asiático
16.
Theor Appl Genet ; 137(8): 181, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38985188

RESUMO

KEY MESSAGES: We investigate a method of extracting and fitting synthetic environmental covariates and pedigree information in multilocation trial data analysis to predict genotype performances in untested locations. Plant breeding trials are usually conducted across multiple testing locations to predict genotype performances in the targeted population of environments. The predictive accuracy can be increased by the use of adequate statistical models. We compared linear mixed models with and without synthetic covariates (SCs) and pedigree information under the identity, the diagonal and the factor-analytic variance-covariance structures of the genotype-by-location interactions. A comparison was made to evaluate the accuracy of different models in predicting genotype performances in untested locations using the mean squared error of predicted differences (MSEPD) and the Spearman rank correlation between predicted and adjusted means. A multi-environmental trial (MET) dataset evaluated for yield performance in the dry lowland sorghum (Sorghum bicolor (L.) Moench) breeding program of Ethiopia was used. For validating our models, we followed a leave-one-location-out cross-validation strategy. A total of 65 environmental covariates (ECs) obtained from the sorghum test locations were considered. The SCs were extracted from the ECs using multivariate partial least squares analysis and subsequently fitted in the linear mixed model. Then, the model was extended accounting for pedigree information. According to the MSEPD, models accounting for SC improve predictive accuracy of genotype performances in the three of the variance-covariance structures compared to others without SC. The rank correlation was also higher for the model with the SC. When the SC was fitted, the rank correlation was 0.58 for the factor analytic, 0.51 for the diagonal and 0.46 for the identity variance-covariance structures. Our approach indicates improvement in predictive accuracy with SC in the context of genotype-by-location interactions of a sorghum breeding in Ethiopia.


Assuntos
Genótipo , Modelos Genéticos , Linhagem , Melhoramento Vegetal , Sorghum , Sorghum/genética , Melhoramento Vegetal/métodos , Etiópia , Meio Ambiente , Modelos Lineares , Fenótipo
17.
Genet Sel Evol ; 56(1): 53, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987703

RESUMO

BACKGROUND: The Franches-Montagnes (FM) is the last native horse breed of Switzerland, established at the end of the 19th century by cross-breeding local mares with Anglo-Norman stallions. We collected high-density SNP genotype data (Axiom™ 670 K Equine genotyping array) from 522 FM horses, including 44 old-type horses (OF), 514 European Warmblood horses (WB) from Sweden and Switzerland (including a stallion used for cross-breeding in 1990), 136 purebred Arabians (AR), 32 Shagya Arabians (SA), and 64 Thoroughbred (TB) horses, as introgressed WB stallions showed TB origin in their pedigrees. The aim of the study was to ascertain fine-scale population structures of the FM breed, including estimation of individual admixture levels and genomic inbreeding (FROH) by means of Runs of Homozygosity. RESULTS: To assess fine-scale population structures within the FM breed, we applied a three-step approach, which combined admixture, genetic contribution, and FROH of individuals into a high-resolution network visualization. Based on this approach, we were able to demonstrate that population substructures, as detected by model-based clustering, can be either associated with a different genetic origin or with the progeny of most influential sires. Within the FM breed, admixed horses explained most of the genetic variance of the current breeding population, while OF horses only accounted for a small proportion of the variance. Furthermore, we illustrated that FM horses showed high TB admixture levels and we identified inconsistencies in the origin of FM horses descending from the Arabian stallion Doktryner. With the exception of WB, FM horses were less inbred compared to the other breeds. However, the relatively few but long ROH segments suggested diversity loss in both FM subpopulations. Genes located in FM- and OF-specific ROH islands had known functions involved in conformation and behaviour, two traits that are highly valued by breeders. CONCLUSIONS: The FM remains the last native Swiss breed, clearly distinguishable from other historically introgressed breeds, but it suffered bottlenecks due to intensive selection of stallions, restrictive mating choices based on arbitrary definitions of pure breeding, and selection of rare coat colours. To preserve the genetic diversity of FM horses, future conservation managements strategies should involve a well-balanced selection of stallions (e.g., by integrating OF stallions in the FM breeding population) and avoid selection for rare coat colours.


Assuntos
Endogamia , Polimorfismo de Nucleotídeo Único , Cavalos/genética , Animais , Linhagem , Masculino , Cruzamento/métodos , Feminino , Suíça , Genótipo , Homozigoto
18.
BMC Med Genomics ; 17(1): 178, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965556

RESUMO

BACKGROUND: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene. METHODS: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing. RESULTS: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein. CONCLUSION: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition.


Assuntos
Consanguinidade , Proteínas de Transporte de Nucleosídeos , Linhagem , Humanos , Feminino , Proteínas de Transporte de Nucleosídeos/genética , Masculino , Adolescente , Criança , Mutação , Histiocitose/genética , Histiocitose/patologia , Simulação por Computador , Hipertricose/genética , Sequenciamento do Exoma , Contratura , Perda Auditiva Neurossensorial
19.
Genome Med ; 16(1): 87, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982518

RESUMO

BACKGROUND: Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end. METHODS: To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes. RESULTS: Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical-histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets. CONCLUSIONS: Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments.


Assuntos
Sequenciamento do Exoma , Estudos de Associação Genética , Fenótipo , Humanos , Masculino , Feminino , Predisposição Genética para Doença , Mutação , Exoma/genética , Linhagem , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/diagnóstico , Doenças Musculares/genética , Doenças Musculares/diagnóstico , Doenças Musculares/congênito , Criança , Adulto
20.
Sci Rep ; 14(1): 16342, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39014189

RESUMO

Indigenous goats are important to many livelihoods. Despite this, they are subjected to indiscriminate crossbreeding. This affects their genetic variability which is needed to survive in current regime of climate change. The study assessed population structure and genetic diversity of Galla and Small East African goats (SEA) using pedigree information. A total of 7384 animals, 5222 of the Galla and 2162 of the SEA breeds, born between the years 1983 and 2022, were utilized. Individuals with known parents were defined as reference population. From the results, the maximum generation traced for Galla and SEA populations was 14.6 and 14.5, respectively. However, only 6 and 5 generations for Galla and SEA were complete. Pedigree completeness increased with the increasing number of generations. The average generation interval (GI) for Galla and SEA was 3.84 ± 0.04 and 4.4 ± 0.13 years. The average increase in the rate of inbreeding per generation for Galla and SEA was 0.04 and 0.05, with the effective ancestors and founders (fa/fe) ratio being same (1.00) for both breeds. Fifty percent (50%) of the genetic variability in the populations was contributed by 3 and 1 ancestor for Galla SEA, respectively. The effective population size (Ne) was 5.19 and 4.77 for Galla and SEA. Therefore, the current breeding programs should be changed to avoid future genetic bottlenecks in this population. These findings offer an opportunity to enhance the current genetic status and management of Kenyan native goats and other regions with similar production systems.


Assuntos
Variação Genética , Cabras , Animais , Cabras/genética , Quênia , Linhagem , Genética Populacional , Cruzamento , Endogamia , Masculino , Feminino , Densidade Demográfica
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