Search results for "germline"

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…

Piwi proteins and piRNAs in mammalian oocytes and early embryos: From sample to sequence

2015

AbstractThe role of the Piwi/piRNA pathway during mammalian oogenesis has remained enigmatic thus far, especially since experiments with Piwi knockout mice did not reveal any phenotypic defects in female individuals. This is in striking contrast with results obtained from other species including flies and zebrafish. In mouse oocytes, however, only low levels of piRNAs are found and they are not required for their function. We recently demonstrated dynamic expression of PIWIL1, PIWIL2, and PIWIL3 during mammalian oogenesis and early embryogenesis. In addition, small RNA analysis of human, crab-eating macaque and cattle revealed that piRNAs are also expressed in the female germline and closel…

SNVSniffer: An integrated caller for germline and somatic SNVs based on Bayesian models

2015

The discovery of single nucleotide variants (SNVs) from next-generation sequencing (NGS) data typically works by aligning reads to a given genome and then creating an alignment map to interpret the presence of SNVs. Various approaches have been developed to call whether germline SNVs (or SNPs) in normal cells or somatic SNVs in cancer/tumor cells. Nonetheless, efficient callers for both germline and somatic SNVs have not yet been extensively investigated. In this paper, we present SNVSniffer, an integrated caller for germline and somatic SNVs from NGS data based on Bayesian probabilistic models. In SNVSniffer, our germline SNV calling models allele counts per site as a multinomial condition…

Germline JAK2 L611S mutation in a child with thrombocytosis

2018

Conserved and ubiquitous expression of piRNAs and PIWI genes in mollusks antedates the origin of somatic PIWI/piRNA expression to the root of bilater…

2018

AbstractPIWI proteins and a specific class of small non-coding RNAs, termed Piwi interacting RNAs (piRNAs), suppress transposon activity in animals on the transcriptional and post-transcriptional level, thus protecting genomes from detrimental insertion mutagenesis. While in vertebrates the PIWI/piRNA system appears to be restricted to the germline, somatic expression of piRNAs directed against transposons is widespread in arthropods, likely representing the ancestral state for this phylum. Here, we show that somatic expression of PIWI genes and piRNAs directed against transposons is conserved in mollusks, suggesting that somatic PIWI/piRNA expression was already realized in an early bilate…

Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K‐AKT‐mTOR signaling path…

2021

To describe clinical and molecular findings in a French multicenter cohort of fetuses with prenatal diagnosis of congenital abnormality and suspicion of a localized overgrowth disorder (LOD) suggestive of genetic variants in the PI3K-AKT-mTOR signaling pathway.We analyzed retrospectively data obtained between 1 January 2013 and 1 May 2020 from fetuses with brain and/or limb overgrowth referred for molecular diagnosis of PI3K-AKT-mTOR pathway genes by next-generation sequencing (NGS) using pathological tissue obtained by fetal autopsy. We also assessed the diagnostic yield of amniotic fluid.During the study period, 21 subjects with LOD suspected of being secondary to a genetic variant of the…

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…

A20 deficiency in B cells enhances B-cell proliferation and results in the development of autoantibodies.

2011

A20/TNFAIP3 is an ubiquitin-editing enzyme, important for the regulation of the NF-κB pathway. Mutations in the TNFAIP3 gene have been linked to different human autoimmune disorders. In human B-cell lymphomas, the inactivation of A20 results in constitutive NF-κB activation. Recent studies demonstrate that in mice the germline inactivation of A20 leads to early lethality, due to inflammation in multiple organs of the body. In this report, we describe a new mouse strain allowing for the tissue-specific deletion of A20. We show that B-cell-specific deletion of A20 results in a dramatic reduction in marginal zone B cells. Furthermore, A20-deficient B cells display a hyperactive phenotype repre…

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…