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1.
Sci Rep ; 14(1): 20705, 2024 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-39237551

RESUMO

Several reports have presented that balanced chromosomal rearrangements (BCRs) carriers with normal phenotypes may be carriers of complex rearrangements. However, the incidence and PGT clinical outcomes of cryptic complex chromosome rearrangements (CCCRs) in individuals with BCRs is remain unknown. We recruited a cohort of 1,264 individuals with BCR carriers from 2016 to 2021 at the Reproductive and Genetic Hospital of CITIC Xiangya. Peripheral blood was collected for karyotyping and genomic DNA extraction and the PGT-SR clinical outcomes of CCCRs carriers were analyzed and compared with those of BCR carriers. Our findings revealed that 3.6% (45/1,264) of BCR carriers had CCCRs, involving 3-25 breakpoints on 1-3 chromosomes. Furthermore, when mate-pair sequencing was employed, 63.3% (19/30) of CCCR carriers were found to have chromosome rearrangements that were different from those identified by the MicroSeq technique. And the transferable embryo rate of CCCR carriers with 3 chromosomes was significantly lower than that of CCCR carriers with only 1-2 chromosomes. In this research, we revealed that some of the BCR carriers were actually CCCR carriers, and the prognosis of PGT in CCCR carriers with one or two chromosomes is better than that of CCCR carriers with three chromosomes.


Assuntos
Aberrações Cromossômicas , Humanos , Feminino , Masculino , Adulto , Translocação Genética , Cariotipagem , Heterozigoto , Gravidez
2.
Mol Genet Genomic Med ; 12(9): e70004, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39219382

RESUMO

BACKGROUND: Marfan syndrome (MFS) is a complex genetic systemic connective tissue disorder. It is well known that genetic factors play a critical role in the progression of MFS, with nearly all cases attributed to variants in the FBN1 gene. METHODS: We investigated a Chinese family with MFS spanning two generations. Whole exome sequencing, in silico analysis, minigene constructs, transfection, RT-PCR, and protein secondary structure analysis were used to analyze the genotype of the proband and his father. RESULTS: The main clinical manifestations of the proband and his father were subluxation of the left lens and high myopia with pectus deformity. Whole exome sequencing identified a novel single nucleotide variant (SNV) in the FBN1 gene at a non-canonical splice site, c.443-3C>G. This variant resulted in two abnormal mRNA transcripts, leading to a frameshift and an in-frame insertion. Further in vitro experiments indicated that the c.443-3C>G variant in FBN1 was pathogenic and functionally harmful. CONCLUSION: This research identified a novel intronic pathogenic FBN1: c.443-3C>G gene variant, which led to two different aberrant splicing effects. Further functional analysis expands the variant spectrum and provides a strong indication and sufficient basis for preimplantation genetic testing for monogenic disease (PGT-M).


Assuntos
Fibrilina-1 , Heterozigoto , Íntrons , Síndrome de Marfan , Linhagem , Splicing de RNA , Humanos , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Fibrilina-1/genética , Masculino , Adulto , Feminino , Adipocinas
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(9): 1072-1076, 2024 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-39217485

RESUMO

OBJECTIVE: To explore the clinical phenotype and genetic etiology for a Chinese pedigree affected with Autosomal dominant polycystic kidney disease (ADPKD). METHODS: A pedigree with ADPKD diagnosed at the Department of Gynaecology of the First Affiliated Hospital of Zhengzhou University in December 2020 was selected as the study subject. Clinical data of the pedigree was collected, and whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing of the proband and her relatives. RESULTS: Fetal ultrasonography showed increased volume and parenchymal echogenicity in both kidneys. The fetus was found to harbor c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene, which were respectively inherited from its mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1+PM2_supporting+PP3). CONCLUSION: The c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene probably underlay the ADPKD in the fetus. Above finding has provided guidance for the genetic counseling and prenatal diagnosis for this pedigree.


Assuntos
Testes Genéticos , Rim Policístico Autossômico Dominante , Diagnóstico Pré-Natal , Canais de Cátion TRPP , Adulto , Feminino , Humanos , Masculino , Gravidez , População do Leste Asiático/genética , Sequenciamento do Exoma , Heterozigoto , Mutação , Linhagem , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/diagnóstico por imagem , Canais de Cátion TRPP/genética , Ultrassonografia Pré-Natal
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(9): 1105-1109, 2024 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-39217491

RESUMO

OBJECTIVE: To explore the genetic basis for a child with pachygyria. METHODS: A proband who had visited Qinzhou Maternal and Child Health Care Hospital for pachygyria and mental retardation in June 2020 was selected as the study subject. Clinical data was collected. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. RESULTS: The proband, a 4-year-and-6-month-old female, was clinically diagnosed with megagyrus deformity. WES revealed that she has harbored compound heterozygous variants of the ADGRG1 gene, namely c.781G>T (p.E261*) in exon 6 and c.1369A>C (p.S457R) in exon 11, which were verified by Sanger sequencing to be derived from her mother and father, respectively. Her younger sister was also heterozygous for the c.1369A>C (p.S457R) variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PVS1+PM2_ Supporting; PM1+PM2_Supporting+PM3+PP3). CONCLUSION: The c.781G>T (p.E261*) and c.1369A>C (p.S457R) compound heterozygous variants of the ADGRG1 gene probably underlay the pachygyria malformation in this child.


Assuntos
Sequenciamento do Exoma , Humanos , Feminino , Pré-Escolar , Heterozigoto , Mutação , Lisencefalia/genética , Testes Genéticos , Éxons , Deficiência Intelectual/genética , Linhagem
5.
Sci Rep ; 14(1): 21419, 2024 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271799

RESUMO

The Druze are a distinct group known for their close community, traditions, and consanguineous marriages, dating back to the eleventh century. This practice has led to unique genetic variations, impacting both pathology and gene-associated phenotypes. Some Druze clans, particularly those with exceptional long-lived family heads (ELLI), attracted attention. Given that the bulk of these ELLI were men, the d3GHR polymorphism was the first obvious possibility. Among the 73 clan members, 8.2% carried the d3GHR isoform, with nearly 11% being males. There was a significant age-related increase (p = 0.04) in this isoform among males, leading to examination of potential environmental mediators affecting gene regulation among these carriers during life (namely epigenetic). We focused on DNA methylation due to its crucial role in gene regulation, development, and disease progression. We analyzed DNA samples from 14 clan members with different GHR genotypes, finding a significant (p < 0.05) negative correlation between DNA methylation levels and age. Employing a biological age clock, we observed a significant + 4.229 years favoring the d3GHR group over the WT and heterozygous groups. In conclusion, this study highlights the advantage of d3GHR carriers among this unique Druze clan and underscores the importance of genotype-environment interaction in epigenetic regulation and its impact on health.


Assuntos
Metilação de DNA , Epigenoma , Longevidade , Humanos , Masculino , Longevidade/genética , Feminino , Epigênese Genética , Pessoa de Meia-Idade , Heterozigoto , Adulto , Idoso , Idoso de 80 Anos ou mais , Genótipo
6.
J Ovarian Res ; 17(1): 180, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39232764

RESUMO

Pannexin1 (PANX1) is a highly glycosylated membrane channel-forming protein, which has been found to implicate in multiple physiological and pathophysiological functions. Variants in the PANX1 gene have been reported to be associated with oocyte death and recurrent in vitro fertilization failure. In this study, we identified a novel heterozygous PANX1 variant (NM_015368.4 c.410 C > T (p.Ser137Leu)) associated with the phenotype of oocyte death in a non-consanguineous family, followed by an autosomal dominant (AD) mode. We explored the molecular mechanism of the novel variant and the variant c.976_978del (p.Asn326del) that we reported previously. Both of the variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, affected ATP release and membrane electrophysiological properties, which resulted in mouse and human oocyte death in vitro. For the first time, we presented the direct evidence of the effect of the PANX1 variants on human oocyte development. Our findings expand the variant spectrum of PANX1 genes associated with oocyte death and provide new support for the genetic diagnosis of female infertility.


Assuntos
Morte Celular , Conexinas , Heterozigoto , Infertilidade Feminina , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso , Oócitos , Humanos , Oócitos/metabolismo , Feminino , Conexinas/genética , Conexinas/metabolismo , Infertilidade Feminina/genética , Animais , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Camundongos , Morte Celular/genética , Linhagem , Adulto , Glicosilação
7.
Pract Radiat Oncol ; 14(5): 435-442, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39218527

RESUMO

PURPOSE: Several international groups have published guidelines to identify low-risk breast cancer (BC) patients who are eligible for partial breast irradiation (PBI). These include the American Society for Radiation Oncology (ASTRO), the European Society for Radiotherapy and Oncology (ESTRO), and ESTRO subgroups such as the Intraoperative radiation (IORT) Task Force and Groupe Européen de Curiethérapie (GEC) -ESTRO. Only ASTRO guidelines recommend against the use of PBI in known carriers of germline pathogenic variants (PVs) in BRCA1/2. The aim of this study was to evaluate the proportion of BC patients, subsequently found to be BRCA1/2 PV carriers who would be eligible for PBI based on clinical-pathologic criteria of the above-mentioned international guidelines. METHODS AND MATERIALS: Data were extracted from the medical records of consecutive BC BRCA1/2 PV carriers treated at a single institution between 2006 and 2023. Data included patient demographics, tumor characteristics, treatment, and disease outcomes. RESULTS: Overall, 498 patients with 518 primary tumors were analyzed. Of these, 282 (12 of them with synchronous bilateral disease) presented with unknown genetic status at diagnosis and formed the study cohort. The median age at diagnosis was 42.7 years (range, 23.8-77.9). Based on the recent ASTRO guidelines (not including conditionally recommended criteria), 17 of 294 (5.8%) of the carriers had tumors that would be eligible for PBI, including 3 Her2-positive tumors and 5 patients diagnosed between ages 40 and 49 years. Using the ESTRO IORT and the ACROP-ESTRO PBI criteria, 9 of 294 (3%) would be eligible, whereas with the GEC-ESTRO low-risk criteria, 31 of 294 (10.5%) of the carriers would be eligible, and their intermediate risk criteria would increase eligibility for PBI by an additional 8.2% (overall 18.7%). CONCLUSIONS: Using clinical-pathologic criteria published in international guidelines, 3% to 18% of BRCA1/2 PV carriers will have tumors eligible for PBI. Therefore, especially in populations who are at high risk for being BRCA1/2 PV carriers, we recommend adhering to stricter guidelines. In our cohort, ASTRO, ESTRO-IORT, and ESTRO PBI had the lowest probability of identifying BRCA1/2 PV carriers as eligible for PBI.


Assuntos
Proteína BRCA1 , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/radioterapia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Adulto , Pessoa de Meia-Idade , Proteína BRCA1/genética , Proteína BRCA2/genética , Idoso , Mutação , Heterozigoto
8.
J Cancer Res Clin Oncol ; 150(9): 417, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39259360

RESUMO

PURPOSE: To support doctors in counselling women with genetic predisposition for breast or gynecologic cancers on endocrine interventions. METHODS: Evidence on the safety of endocrine interventions for fertility treatment, contraception, hormone replacement therapy after risk-reducing salpingo-oophorectomy (RRSO) or treatment of symptoms during peri- and postmenopause was analysed for carriers of probably pathogenic and pathogenic variants in BRCA1 or BRCA2 (BRCA1/2-pV), in other breast and ovarian cancer genes and the Lynch Syndrome. Cancer risks were compared with data on risks for the general population. RESULTS: Data on risk modulation of endocrine interventions in women with genetic predisposition is limited. Ovarian hyperstimulation for fertility treatment may be performed. Oral contraceptives should not be used to reduce ovarian cancer risk in BRCA1/2-pV carriers. Premenopausal BRCA1/2-pV carriers and carriers of pV in Lynch Syndrome genes should be offered hormone replacement therapy (HRT) after RRSO, to prevent diseases caused by estrogen deficiency. CONCLUSION: Effect direction and strength of risk modulation by endocrine interventions is similar to the general population. Participation of individuals at risk in prospective registries is recommended.


Assuntos
Neoplasias da Mama , Predisposição Genética para Doença , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Terapia de Reposição Hormonal/efeitos adversos , Terapia de Reposição Hormonal/métodos , Neoplasias dos Genitais Femininos/genética , Heterozigoto , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Alemanha , Proteína BRCA2/genética , Proteína BRCA1/genética
9.
Hear Res ; 452: 109109, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39241555

RESUMO

The genes Ocm (encoding oncomodulin) and Slc26a5 (encoding prestin) are expressed strongly in outer hair cells and both are involved in deafness in mice. However, it is not clear if they influence the expression of each other. In this study, we characterise the auditory phenotype resulting from two new mouse alleles, Ocmtm1e and Slc26a5tm1Cre. Each mutation leads to absence of detectable mRNA transcribed from the mutant allele, but there was no evidence that oncomodulin regulates expression of prestin or vice versa. The two mutants show distinctive patterns of auditory dysfunction. Ocmtm1e homozygotes have normal auditory brainstem response thresholds at 4 weeks old followed by progressive hearing loss starting at high frequencies, while heterozygotes show largely normal thresholds until 6 months of age, when signs of worse thresholds are detected. In contrast, Slc26a5tm1Cre homozygotes have stable but raised thresholds across all frequencies tested, 3 to 42 kHz, at least from 4 to 8 weeks old, while heterozygotes have raised thresholds at high frequencies. Distortion product otoacoustic emissions and cochlear microphonics show deficits similar to auditory brainstem responses in both mutants, suggesting that the origin of hearing impairment is in the outer hair cells. Endocochlear potentials are normal in the two mutants. Scanning electron microscopy revealed normal development of hair cells in Ocmtm1e homozygotes but scattered outer hair cell loss even at 4 weeks old when thresholds appeared normal, indicating that there is not a direct relationship between numbers of outer hair cells present and auditory thresholds.


Assuntos
Alelos , Limiar Auditivo , Potenciais Evocados Auditivos do Tronco Encefálico , Homozigoto , Emissões Otoacústicas Espontâneas , Fenótipo , Transportadores de Sulfato , Animais , Transportadores de Sulfato/genética , Transportadores de Sulfato/metabolismo , Camundongos , Mutação , Heterozigoto , Células Ciliadas Auditivas Externas/metabolismo , Células Ciliadas Auditivas Externas/patologia , Proteínas de Transporte de Ânions/genética , Proteínas de Transporte de Ânions/metabolismo , Proteínas Motores Moleculares/genética , Proteínas Motores Moleculares/metabolismo , Cóclea/metabolismo , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Camundongos Endogâmicos C57BL , Estimulação Acústica
10.
Mol Genet Genomic Med ; 12(9): e70006, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39235128

RESUMO

BACKGROUND: Paired box gene 2 (PAX2) heterozygous mutations can cause renal coloboma syndrome, but its role in patients with focal segmental glomerular sclerosis (FSGS) has been rarely reported. METHODS: Based on the clinical manifestations and renal pathological characteristics of the patient, as well as familial whole exome sequencing, the diagnosis of FSGS related to PAX2 mutation was confirmed. Treatment such as lowering urinary protein and blood pressure was given, and the patient was followed up and observed. RESULTS: There is a familial heterozygous case presented with chronic kidney disease secondary to FSGS, which was related to PAX2 frameshift mutation due to the deletion of G at the position 76 (c.76delG). To our knowledge, this is the first report of PAX2 c.76delG variant related to adult-onset FSGS. CONCLUSION: Here, we further expand the phenotypic spectrum of FSGS. Genetic screening especially PAX2 mutation is recommended in patients with adult-onset FSGS of unknown etiology.


Assuntos
Mutação da Fase de Leitura , Glomerulosclerose Segmentar e Focal , Fator de Transcrição PAX2 , Humanos , Fator de Transcrição PAX2/genética , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Adulto , Masculino , Feminino , Linhagem , Heterozigoto
11.
Taiwan J Obstet Gynecol ; 63(5): 771-776, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39266164

RESUMO

OBJECTIVE: To present the ultrasound imaging and genetic diagnosis of a fetus with prenatal lethal form of Gaucher disease. CASE REPORT: A 37-year-old primiparous woman was pregnant at her 23 weeks of gestation and the prenatal fetal ultrasound revealed hydrops fetalis, cerebellum hypoplasia, and fetal immobility. The pregnancy was terminated due to major fetal anomaly, and whole exome sequencing (WES) analysis of fetal tissue and parental blood unveiled a pathogenic variant in exon 10 of the GBA gene (NM_001005741.3: c.1265T > G: p.L422R) originating from the mother. Additionally, a novel CNV (chr1: 155204785-155205635 deletion, 0.85 kb) spanning exon 10-12 in the GBA gene was identified from the father. This compound heterozygosity confirmed the diagnosis of prenatal lethal form of Gaucher disease and was informative for genetic counseling. CONCLUSION: WES is a powerful tool to detect pathogenic variants among fetuses with nonimmune hydrops fetalis and complex abnormality from prenatal ultrasound. Compound heterozygosity consisted of single nucleotide variants (SNV) and copy number variations (CNVs) may lead rare inherited metabolic disorders including prenatal lethal form of Gaucher disease.


Assuntos
Cerebelo , Variações do Número de Cópias de DNA , Sequenciamento do Exoma , Doença de Gaucher , Hidropisia Fetal , Ultrassonografia Pré-Natal , Humanos , Feminino , Doença de Gaucher/genética , Doença de Gaucher/diagnóstico , Doença de Gaucher/complicações , Gravidez , Adulto , Hidropisia Fetal/genética , Hidropisia Fetal/diagnóstico , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Heterozigoto , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/diagnóstico , Polimorfismo de Nucleotídeo Único , Glucosilceramidase/genética , Deficiências do Desenvolvimento
12.
Cell Mol Biol (Noisy-le-grand) ; 70(8): 57-63, 2024 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-39262262

RESUMO

The diagnosis of familial Mediterranean fever (FMF) is primarily based on clinical standards. The purpose of this study was to investigate the relevance of Mediterranean fever (MEFV) genetic testing in the diagnosis of FMF as well as to identify the most frequent variant alleles and their relationship to clinical symptoms in Egyptian patients. Egyptian patients with a clinical suspicion of having FMF were studied in order to determine MEFV genotypes. Each patient was meticulously evaluated through an extensive collection of their medical history, a thorough clinical examination, and a series of laboratory tests, encompassing CBC, ESR, and CRP measurements. The MEFV variant screening procedure included the use of reverse dot blot hybridization. The average age of our patients when they were given a diagnosis was 22.8 ± 1.404 years old. The predominant clinical manifestations identified were abdominal pain, fever, and arthralgia.  Molecular interrogation of the MEFV gene unveiled that a significant proportion of the cohort, constituting 72 individuals (60%), displayed heterozygosity, whereas a smaller fraction, comprising 12 subjects (10%), demonstrated homozygosity and an equivalent number (10%) exhibited compound heterozygosity. Pertaining to the distribution of allele variants, E148Q emerged as the most prevalent, succeeded by M694I, accounting for 12.5% of the cases, and M680I (G/A), representing 10.41%. This notable prevalence of heterozygous genotypes among the Egyptian demographic, preliminarily identified as potential FMF cases, underscores the imperative for molecular diagnostics to enhance the precision of FMF identification.


Assuntos
Febre Familiar do Mediterrâneo , Pirina , Humanos , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/diagnóstico , Pirina/genética , Feminino , Masculino , Adulto Jovem , Adulto , Alelos , Egito/epidemiologia , Polimorfismo Genético , Genótipo , Heterozigoto , Frequência do Gene/genética , Adolescente
13.
Mol Genet Genomic Med ; 12(9): e2495, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39268837

RESUMO

BACKGROUND: This study aimed to conduct molecular diagnostics among individuals with hemophilia B (HB) and carriers of hemophilia in Mongolia. METHODS: Eight patients (six severe, two mild) with HB and their 12 female relatives were enrolled from eight families. Sanger sequence was performed for mutation identification. The questionnaire survey was conducted to evaluate carrier symptoms in female relatives. RESULTS: Two families had a history of HB. A total of five different variants (c.223C > T; c.344A > G; c.464G > C; c.187_188del; and c.1314_1314delA) were identified in six patients with severe HB. Of these, two (c.187_188del and c.1314_1314delA) were novel. No variant in the entire F9 was found in two patients with mild HB. Nonsense c.223C > T (p.Arg75*) mutation was detected in two unrelated patients. Carrier testing identified five mothers as carriers, while one younger sister was a non-carrier. The carrier status of six female relatives of the two mild patients remained undetermined. By questionnaire survey, only one of the five genetically identified carriers displayed noticeable symptoms of being a carrier. CONCLUSION: The novel variants c.187_188del and c.1314_1314delA can cause severe hemophilia B. This study did not observe a significant association between symptoms and carrier status in the five carriers.


Assuntos
Hemofilia B , Linhagem , Humanos , Feminino , Hemofilia B/genética , Mongólia , Adulto , Masculino , Mutação , Fator IX/genética , Heterozigoto , Criança , Adolescente , Pessoa de Meia-Idade
15.
Proc Natl Acad Sci U S A ; 121(38): e2401379121, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39269774

RESUMO

Family-based genome-wide association studies (GWASs) are often claimed to provide an unbiased estimate of the average causal effects (or average treatment effects; ATEs) of alleles, on the basis of an analogy between the random transmission of alleles from parents to children and a randomized controlled trial. We show that this claim does not hold in general. Because Mendelian segregation only randomizes alleles among children of heterozygotes, the effects of alleles in the children of homozygotes are not observable. This feature will matter if an allele has different average effects in the children of homozygotes and heterozygotes, as can arise in the presence of gene-by-environment interactions, gene-by-gene interactions, or differences in linkage disequilibrium patterns. At a single locus, family-based GWAS can be thought of as providing an unbiased estimate of the average effect in the children of heterozygotes (i.e., a local average treatment effect; LATE). This interpretation does not extend to polygenic scores (PGSs), however, because different sets of SNPs are heterozygous in each family. Therefore, other than under specific conditions, the within-family regression slope of a PGS cannot be assumed to provide an unbiased estimate of the LATE for any subset or weighted average of families. In practice, the potential biases of a family-based GWAS are likely smaller than those that can arise from confounding in a standard, population-based GWAS, and so family studies remain important for the dissection of genetic contributions to phenotypic variation. Nonetheless, their causal interpretation is less straightforward than has been widely appreciated.


Assuntos
Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Humanos , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Modelos Genéticos , Heterozigoto , Alelos , Homozigoto , Família , Interação Gene-Ambiente
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(9): 1100-1104, 2024 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-39217490

RESUMO

OBJECTIVE: To explore the genetic etiology of a child with Primary hypertrophic osteoarthropathy. METHODS: A child who was admitted to Zhongnan Hospital of Wuhan University on July 27, 2021 was selected as the study subject. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to whole exome sequencing. Suspected splicing variant was verified by Sanger sequencing of family members. In vitro function was validated through a minigene assay, whilst the suspected exonic deletion was validated by long-fragment PCR. RESULTS: Whole exome sequencing revealed that the child has harbored compound heterozygous variants of HPGD gene, including a heterozygous deletion (exon 3 del) derived from his father and a splicing variant (c.421+1G>T) derived from his mother. Long-fragment PCR verified that the child and his father had both harbored a 7 565 bp heterozygous deletion (c.218-1304_324+6156del), whilst the minigene assay proved that the splicing variant has resulted in skipping of exon 4. CONCLUSION: The heterozygous c.218-1304_324+6156del deletion and the c.421+1G>T splicing variant of the HPGD gene probably underlay the pathogenesis in this child. Above finding has enriched the mutational spectrum of the HPGD gene and provided a basis for genetic counseling and prenatal diagnosis for this family.


Assuntos
Osteoartropatia Hipertrófica Primária , Humanos , Masculino , Osteoartropatia Hipertrófica Primária/genética , Éxons , Criança , Heterozigoto , Sequenciamento do Exoma , Feminino , Sequência de Bases , Linhagem , Deleção de Sequência , Testes Genéticos , Mutação
17.
Mol Immunol ; 174: 41-46, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39182279

RESUMO

Colony stimulating factor 1 receptor (CSF1R) is an essential receptor for both colony stimulating factor 1 (CSF1) and interleukin (IL) 34 signaling expressed on monocyte precursors and myeloid cells, including monocytes, dendritic cells (DC), and microglia. In humans, dominant heterozygous pathogenic variants in CSF1R cause a neurological condition known as CSF1R-related disorder (CSF1R-RD), typically with late onset, previously referred to as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). CSF1R-RD is characterized by microglia reduction and altered monocyte function; however, the impact of pathogenic CSF1R variants on the human DC lineage remains largely unknown. We previously reported that cord blood CD34+ stem cell-derived DCs generated in vitro originate specifically from CSF1R expressing precursors. In this study, we examined the DC lineage of four unrelated patients with late-onset CSF1R-RD who carried heterozygous missense CSF1R variants (c.2330G>A, c.2375C>A, c.2329C>T, and c.2381T>C) affecting different amino acids in the protein tyrosine kinase domain of CSF1R. CD34+ stem cells and CD14+ monocytes were isolated from peripheral blood and subjected to an in vitro culture protocol to differentiate towards conventional DCs and monocyte-derived DCs, respectively. Flow cytometric analysis revealed that monocytes from patients with late-onset CSF1R-RD were still able to differentiate into monocyte-derived DCs in vitro, whereas the ability of CD34+ stem cells to differentiate into conventional DCs was impaired. Strikingly, the peripheral blood of patients contained all naturally occurring DC subsets. We conclude that the in vitro abrogation of DC-development in patients with heterozygous pathogenic missense CSF1R variants does not translate to an impairment in DC development in vivo and speculate that CSF1R signalling in vivo is compensated, which needs further study.


Assuntos
Antígenos CD34 , Diferenciação Celular , Células Dendríticas , Mutação de Sentido Incorreto , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Humanos , Células Dendríticas/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Antígenos CD34/metabolismo , Diferenciação Celular/genética , Feminino , Masculino , Pessoa de Meia-Idade , Heterozigoto , Adulto , Idoso , Monócitos/metabolismo , Células Cultivadas , Receptor de Fator Estimulador de Colônias de Macrófagos
18.
Neurobiol Aging ; 143: 41-52, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39213809

RESUMO

Apolipoprotein E ε4 (APOE4) is a strong genetic risk factor of Alzheimer's disease and metabolic dysfunction. However, whether APOE4 and markers of metabolic dysfunction synergistically impact the deterioration of white matter (WM) integrity in older adults remains unknown. In the UK Biobank data, we conducted a multivariate analysis to investigate the interactions between APOE4 and 249 plasma metabolites (measured using nuclear magnetic resonance spectroscopy) with whole-brain WM integrity (measured by diffusion-weighted magnetic resonance imaging) in a cohort of 1917 older adults (aged 65.0-81.0 years; 52.4 % female). Although no main association was observed between either APOE4 or metabolites with WM integrity (adjusted P > 0.05), significant interactions between APOE4 and metabolites with WM integrity were identified. Among the examined metabolites, higher concentrations of low-density lipoprotein and very low-density lipoprotein were associated with a lower level of WM integrity (b=-0.12, CI=-0.14,-0.10) among APOE4 carriers. Conversely, among non-carriers, they were associated with a higher level of WM integrity (b=0.05, CI=0.04,0.07), demonstrating a significant moderation role of APOE4 (b =-0.18, CI=-0.20,-0.15, P<0.00001).


Assuntos
Apolipoproteína E4 , Heterozigoto , Lipoproteínas LDL , Substância Branca , Humanos , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Apolipoproteína E4/genética , Feminino , Masculino , Idoso , Lipoproteínas LDL/sangue , Idoso de 80 Anos ou mais , Estudos de Coortes , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Imagem de Difusão por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Fatores de Risco
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