Search results for "Germline mutation"
showing 10 items of 91 documents
Hereditary Cancers and Genetics
2021
The study of hereditary syndromes is fundamentally based on the finding and identification of susceptibility genes underlying the pathology. Although hereditary tumors account for only a small fraction of all the tumors, the knowledge of underlying genetics changed the clinical management of affected patients and their families, also providing important information on the molecular mechanisms involved in the development of sporadic tumors. In the subjects who inherit a germline mutation, all the cells of the organism are carriers of that mutation, predisposing such subject to develop neoplasm more easily and earlier compared to the general population. The identification of individuals with …
Mutational analysis ofBRCA1andBRCA2in Mediterranean Spanish women with early-onset breast cancer: Identification of three novel pathogenic mutations
2003
In Spain, the contribution of BRCA mutations to the population incidence of early-onset breast cancer was unknown. We carried out a mutational analysis of the BRCA1 and BRCA2 genes in 124 Spanish women diagnosed with breast cancer before the age 41 and who were not selected for a family history of this disease. The genetic study was performed by PCR-SSCP analysis and DNA sequencing. We identified 6 pathogenic BRCA mutations in 7 unrelated probands (5.6%; 95% CI=2.3% to 11.3%): 1 BRCA1 (c.2080delA) and 5 BRCA2 (p.Y3006X, p.Q1994X, c.9204_9217del14, c.9254_9258del5 and c.295+2T>C). Three out of 6 mutations were novel (BRCA2 p.Y3006X, c.9204_9217del14, and c.295+2T>C), and two further mutation…
Analysis ofBRCA1andBRCA2genes in Spanish breast/ovarian cancer patients: A high proportion of mutations unique to Spain and evidence of founder effec…
2003
We screened index cases from 410 Spanish breast/ovarian cancer families and 214 patients (19 of them males) with breast cancer for germ-line mutations in the BRCA1 and BRCA2 genes, using SSCP, PTT, CSGE, DGGE, and direct sequencing. We identified 60 mutations in BRCA1 and 53 in BRCA2. Of the 53 distinct mutations observed, 11 are novel and 12 have been reported only in Spanish families (41.5%). The prevalence of mutations in this set of families was 26.3%, but the percentage was higher in the families with breast and ovarian cancer (52.1%). The lowest proportion of mutations was found in the site-specific female breast cancer families (15.4%). Of the families with male breast cancer cases, …
Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development
2018
AbstractDe novo germline mutations in the RNA helicase DDX3X account for 1-3% of unexplained intellectual disability (ID) cases in females, and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here we use human and mouse genetics, and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n=78), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes.…
Megalencephaly Syndromes and Activating Mutations in the PI3K-AKT Pathway: MPPH and MCAP
2013
The megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus (MPPH) and megalencephaly‐capillary malformation (MCAP) syndromes are highly recognizable and partly overlapping disorders of brain overgrowth (megalencephaly). Both syndromes are characterized by congenital or early postnatal megalencephaly, with a high risk for progressive ventriculomegaly leading to hydrocephalus and cerebellar tonsillar ectopia leading to Chiari malformation, and cortical brain abnormalities, specifically polymicrogyria. MCAP is further characterized by distinct cutaneous capillary malformations, finger or toe syndactyly, postaxial polydactyly, variable connective tissue dysplasia and mild focal or segmental bo…
Detection of a novel germline mutation in the von Hippel-Lindau tumour-suppressor gene by fluorescence-labelled base excision sequence scanning (F-BE…
1999
The von Hippel Lindau (VHL) syndrome is an inherited multi-tumour disorder characterised by clinical heterogeneity and high penetrance. The VHL gene has been shown to be a tumour-suppressor gene. A carrier of a germline mutation will be predisposed to a high variety of benign and malign tumours affecting different organ systems. As treatment of VHL malformations in presymptomatic stages will improve significantly the clinical outcome and the patient's quality of life, early and unambiguous detection of a germline mutation is mandatory. Direct sequencing especially of large genes might be laborious and time consuming. Therefore, most laboratories apply single strand conformational polymorphi…
Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers
2012
Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and di…
Absence of germline CDKN2A mutation in Sicilian Patients with Familial Malignant Melanoma: could it be a population-specific genetic signature?
2015
Germline CDKN2A mutations have been described in 25% to 40% of melanoma families from several countries. Sicilian population is genetically different from the people of Europe and Northern Italy because of its historical background, therefore familial melanoma could be due to genes different from high-penetrance CDKN2A gene. Four hundred patients with cutaneous melanoma were observed in a 6-years period at the Plastic Surgery Unit of the University of Palermo. Forty-eight patients have met the criteria of the Italian Society of Human Genetics (SIGU) for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 mutations. Mutation testing revealed that none of the families car…
Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder
2017
AbstractGenetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. We systematically evaluated PMMs by leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection. We found evidence that 11% of published single nucleotide variant (SNV)de novomutations are potentially PMMs. We then developed a robust SNV PMM calling approach that leverages complementary callers, logistic regression modeling, and additional heuristics. Using this approach, we recalled SNVs and found that 22% ofde novomutations like…
The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation.
2014
The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared …