A second kindred linked to DFNA20 (17q25.3) reduces the genetic interval.
Ontology highlight
ABSTRACT:
SUBMITTER: DeWan AT
PROVIDER: S-EPMC6143177 | biostudies-literature | 2003 Jan
REPOSITORIES: biostudies-literature
Publications
A second kindred linked to DFNA20 (17q25.3) reduces the genetic interval.
DeWan A T AT Parrado A R AR Leal S M SM
Clinical genetics 20030101 1
A family ascertained in the United States displays significant evidence of linkage to 17q25.3 (maximum two-point LOD score 6.32). The non-syndromic autosomal-dominant hearing-loss loci DFNA20 and DFNA26 map to this region. The 3-unit support interval and haplotype for this USA kindred falls within the interval for DFNA20 and DFNA26 and reduces the region to 6.05 cM, according to the deCode genetic map. The same gene is probably responsible for both DFNA20/DFNA26. In addition, the USH1G locus map ...[more]
Similar Datasets
Project description:A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538 and 5'-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified.
| S-EPMC1918325 | biostudies-other
Project description:BACKGROUND: Transcriptional profiling of prostate cancer (PC) has unveiled new markers of neoplasia and allowed insights into mechanisms underlying this disease. Genomewide analyses have also identified new chromosomal abnormalities associated with PC. The combination of both classes of data for the same sample cohort might provide better criteria for identifying relevant factors involved in neoplasia. Here we describe transcriptional signatures identifying distinct normal and tumoral prostate tissue compartments, and the inference and demonstration of a new, highly recurrent copy number gain on chromosome 17q25.3. METHODS: We have applied transcriptional profiling to tumoral and non-tumoral prostate samples with relatively homogeneous epithelial representations as well as pure stromal tissue from peripheral prostate and cultured cell lines, followed by quantitative RT-PCR validations and immunohistochemical analysis. In addition, we have performed in silico colocalization analysis of co-regulated genes and validation by fluorescent in situ hybridization (FISH). RESULTS: The transcriptomic analysis has allowed us to identify signatures corresponding to non-tumoral luminal and tumoral epithelium, basal epithelial cells, and prostate stromal tissue. In addition, in silico analysis of co-regulated expression of physically linked genes has allowed us to predict the occurrence of a copy number gain at chromosomal region 17q25.3. This computational inference was validated by fluorescent in situ hybridization, which showed gains in this region in over 65% of primary and metastatic tumoral samples. CONCLUSION: Our approach permits to directly link gene copy number variations with transcript co-regulation in association with neoplastic states. Therefore, transcriptomic studies of carefully selected samples can unveil new diagnostic markers and transcriptional signatures highly specific of PC, and lead to the discovery of novel genomic abnormalities that may provide additional insights into the causes and mechanisms of prostate cancer.
| S-EPMC2585097 | biostudies-literature
Project description:A second kindred has been identified which supports the previously reported location of DFNB9. Linkage has been established to markers closely linked to DFNB9 which is located on 2p22-p23. The hearing impaired individuals in this highly consanguineous kindred from Eastern Turkey have prelingual profound hearing loss which affects all frequencies. A genetic map of the 2p22-p23 region where DFNB9 resides was generated using marker genotypes available from the CEPH database. All markers were placed on this genetic map using a likelihood ratio criterion of 1000:1. This map suggests that the region for DFNB9 is less than 1.08 cM, 95% confidence interval (0-2.59 cM).
| S-EPMC6141006 | biostudies-literature
Project description:Paleogenomic and archaeological studies show that Neolithic lifeways spread from the Fertile Crescent into Europe around 9000 BCE, reaching northwestern Europe by 4000 BCE. Starting around 4500 BCE, a new phenomenon of constructing megalithic monuments, particularly for funerary practices, emerged along the Atlantic façade. While it has been suggested that the emergence of megaliths was associated with the territories of farming communities, the origin and social structure of the groups that erected them has remained largely unknown. We generated genome sequence data from human remains, corresponding to 24 individuals from five megalithic burial sites, encompassing the widespread tradition of megalithic construction in northern and western Europe, and analyzed our results in relation to the existing European paleogenomic data. The various individuals buried in megaliths show genetic affinities with local farming groups within their different chronological contexts. Individuals buried in megaliths display (past) admixture with local hunter-gatherers, similar to that seen in other Neolithic individuals in Europe. In relation to the tomb populations, we find significantly more males than females buried in the megaliths of the British Isles. The genetic data show close kin relationships among the individuals buried within the megaliths, and for the Irish megaliths, we found a kin relation between individuals buried in different megaliths. We also see paternal continuity through time, including the same Y-chromosome haplotypes reoccurring. These observations suggest that the investigated funerary monuments were associated with patrilineal kindred groups. Our genomic investigation provides insight into the people associated with this long-standing megalith funerary tradition, including their social dynamics.
| S-EPMC6511028 | biostudies-literature
Project description:BackgroundEarlier detection of second breast cancers after primary breast cancer (PBC) treatment improves survival, yet mammography is less accurate in women with prior breast cancer. The purpose of this study was to examine women presenting clinically with second breast cancers after negative surveillance mammography (interval cancers), and to estimate the five-year risk of interval-invasive second cancers for women with varying risk profiles.MethodsWe evaluated a prospective cohort of 15 114 women with 47 717 surveillance mammograms diagnosed with stage 0-II unilateral PBC from 1996 through 2008 at facilities in the Breast Cancer Surveillance Consortium. We used discrete time survival models to estimate the association between odds of an interval-invasive second breast cancer and candidate predictors, including demographic, PBC, and imaging characteristics. All statistical tests were two-sided.ResultsThe cumulative incidence of second breast cancers after five years was 54.4 per 1000 women, with 325 surveillance-detected and 138 interval-invasive second breast cancers. The five-year risk of interval-invasive second cancer for women with referent category characteristics was 0.60%. For women with the most and least favorable profiles, the five-year risk ranged from 0.07% to 6.11%. Multivariable modeling identified grade II PBC (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.15 to 3.31), treatment with lumpectomy without radiation (OR = 3.27, 95% CI = 1.91 to 5.62), interval PBC presentation (OR = 2.01, 95% CI 1.28 to 3.16), and heterogeneously dense breasts on mammography (OR = 1.54, 95% CI = 1.01 to 2.36) as independent predictors of interval-invasive second breast cancers.ConclusionsPBC diagnosis and treatment characteristics contribute to variation in subsequent-interval second breast cancer risk. Consideration of these factors may be useful in developing tailored post-treatment imaging surveillance plans.
| S-EPMC4651041 | biostudies-literature
Project description:We review the literature on Tau and TDP-43 proteinopathies in aged human brains and the relevant underlying pathogenetic cascades. Complex interacting pathways are implicated in Alzheimer's disease and related dementias (ADRD), wherein multiple proteins tend to misfold in a manner that is "reactive," but, subsequently, each proteinopathy may contribute strongly to the clinical symptoms. Tau proteinopathy exists in brains of individuals across a broad spectrum of primary underlying conditions-e.g., developmental, traumatic, and inflammatory/infectious diseases. TDP-43 proteinopathy is also expressed in a wide range of clinical disorders. Although TDP-43 proteinopathy was first described in the central nervous system of patients with amyotrophic lateral sclerosis (ALS) and in subtypes of frontotemporal dementia (FTD/FTLD), TDP-43 proteinopathy is also present in chronic traumatic encephalopathy, cognitively impaired persons in advanced age with hippocampal sclerosis, Huntington's disease, and other diseases. We list known Tau and TDP-43 proteinopathies. There is also evidence of cellular co-localization between Tau and TDP-43 misfolded proteins, suggesting common pathways or protein interactions facilitating misfolding in one protein by the other. Multiple pleiotropic gene variants can alter risk for Tau or TDP-43 pathologies, and certain gene variants (e.g., APOE ε4, Huntingtin triplet repeats) are associated with increases of both Tau and TDP-43 proteinopathies. Studies of genetic risk factors have provided insights into multiple nodes of the pathologic cascades involved in Tau and TDP-43 proteinopathies. Variants from a specific gene can be either a low-penetrant risk factor for a group of diseases, or alternatively, a different variant of the same gene may be a disease-driving allele that is associated with a relatively aggressive and early-onset version of a clinically and pathologically specific disease type. Overall, a complex but enlightening paradigm has emerged, wherein both Tau and TDP-43 proteinopathies are linked to numerous overlapping upstream influences, and both are associated with multiple downstream pathologically- and clinically-defined deleterious effects.
| S-EPMC6609463 | biostudies-literature
Project description:BackgroundThe objective of this study was to describe the clinical and molecular features of the first South African family with X-linked hyper-IgM syndrome (HIGM1).MethodsDiagnoses were based on immunoglobulin results and the absence of CD40 ligand (CD40L) expression on activated T-cells. Complete molecular characterisation involved CD40L cDNA sequencing, and genomic DNA analysis by polymerase chain reaction amplification, restriction enzyme digestion and sequencing. A PCR-based diagnostic assay was established for carrier detection and prenatal diagnosis in this family.ResultsThere were originally six children, three males and three females. The eldest boy died after being diagnosed with hypogammaglobulinaemia, before HIGM1 was considered. This disorder was diagnosed in the second eldest boy at the age of 5 years, after failing to detect CD40L expression on his activated T-cells. A deficiency of CD40L was also confirmed in the youngest male at the age of 5 years. Both younger brothers have since died of infections relating to HIGM1. Molecular investigation showed that exon 3 was deleted from the CD40L mRNA of the affected males. Genomic DNA analysis identified a 1.5 kilobase deletion, spanning exon 3 and including extended flanking intronic sequence. Carrier status in the mother was confirmed by RT-PCR of her CD40L mRNA. Genetic analysis of the three female children was deferred because they were below the legal consenting age of 18 years. A PCR-based assay for genomic DNA was established for easy identification of female carriers and affected males in the future.ConclusionsThis study confirmed the diagnosis of HIGM1 in the first South African family to be investigated and identified a novel mutation in the CD40L gene.
| S-EPMC317313 | biostudies-literature
Project description:X-linked Intellectual Disability (XLID) is a group of genetically heterogeneous disorders caused by mutations in genes on the X chromosome. Deleterious mutations in ~10% of X chromosome genes are implicated in causing XLID disorders in ~50% of known and suspected XLID families. The remaining XLID genes are expected to be rare and even private to individual families. To systematically identify these XLID genes, we sequenced the X chromosome exome (X-exome) in 56 well-established XLID families (a single affected male from 30 families and two affected males from 26 families) using an Agilent SureSelect X-exome kit and the Illumina HiSeq 2000 platform. To enrich for disease-causing mutations, we first utilized variant filters based on dbSNP, the male-restricted portions of the 1000 Genomes Project, or the Exome Variant Server datasets. However, these databases present limitations as automatic filters for enrichment of XLID genes. We therefore developed and optimized a strategy that uses a cohort of affected male kindred pairs and an additional small cohort of affected unrelated males to enrich for potentially pathological variants and to remove neutral variants. This strategy, which we refer to as Affected Kindred/Cross-Cohort Analysis, achieves a substantial enrichment for potentially pathological variants in known XLID genes compared to variant filters from public reference databases, and it has identified novel XLID candidate genes. We conclude that Affected Kindred/Cross-Cohort Analysis can effectively enrich for disease-causing genes in rare, Mendelian disorders, and that public reference databases can be used effectively, but cautiously, as automatic filters for X-linked disorders.
| S-EPMC4332666 | biostudies-literature
Project description:X-linked neutropenia (XLN, OMIM #300299) is a rare form of severe congenital neutropenia. It was originally described in a three-generation family with five affected members that had an L270P mutation in the GTP-ase binding domain (GBD) of the Wiskott-Aldrich syndrome protein (WASP) [Devriendt et al (2001) Nature Genetics, Vol. 27, 313-317]. Here, we report and describe a large three-generation family with XLN, with 10 affected males and eight female carriers. A c.882T>C mutation was identified in the WAS gene, resulting in an I294T mutation. The infectious course is variable and mild in view of the profound neutropenia. In addition to the original description, low-normal IgA levels, low to low-normal platelet counts and reduced natural killer (NK)-cell counts also appear as consistent XLN features. However, inverted CD4/CD8 ratios were not found in this family, nor were cases identified with myelodysplastic syndrome or acute myeloid leukaemia. Female carriers exhibited a variable attenuated phenotype. Like L270P WASP, I294T WASP is constitutively active towards actin polymerization. In conclusion, this largest XLN kindred identified to date provides new independent genetic evidence that mutations disrupting the auto-inhibitory GBD of WASP are the cause of XLN. Reduced NK cells, low to low normal platelet counts and low to low-normal IgA levels are also features of XLN.
| S-EPMC3125974 | biostudies-literature
Project description:IntroductionGenetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations.MethodsA genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies.Results13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14.DiscussionVariants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.
| S-EPMC10514237 | biostudies-literature