Search results for " sequencing"

Next generation diagnostic algorithm in non-small cell lung cancer predictive molecular pathology: The KWAY Italian multicenter cost evaluation study

2022

Abstract Aims The KWAY project aims to investigate the economic sustainability of the up-front NGS technologies adoption in the analysis of clinically relevant molecular alterations in NSCLC patients. Methods The diagnostic workflow and the related sustained costs of five Italian referral centers were assessed in four different evolving scenarios were analyzed. For each scenario, two alternative testing strategies were evaluated: the Maximized Standard strategy and the Maximized NGS strategy. Results For each center, the robustness of obtained results was verified through a deterministic sensitivity analysis, observing the variation of total costs based on a variation of ±20 % of the input …

Germline correction of an epimutation related to Silver-Russell syndrome.

2015

Like genetic mutations, DNA methylation anomalies or epimutations can disrupt gene expression and lead to human diseases. However, unlike genetic mutations, epimutations can in theory be reverted through developmental epigenetic reprograming, which should limit their transmission across generations. Following the request for a parental project of a patient diagnosed with Silver-Russell syndrome (SRS), and the availability of both somatic and spermatozoa DNA from the proband and his father, we had the exceptional opportunity to evaluate the question of inheritance of an epimutation. We provide here for the first time evidence for efficient reversion of a constitutive epimutation in the sperm…

Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant.

2021

Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wi…

A G613A missense in the Hutchinson's progeria lamin A/C gene causes a lone, autosomal dominant atrioventricular block.

2014

Background LMNA/C mutations have been linked to the premature aging syndrome Hutchinson’s progeria, dilated cardiomyopathy 1A, skeletal myopathies (such as the autosomal dominant variant of Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy), Charcot-Marie-Tooth disorder type 2B1, mandibuloacral dysplasia, autosomal dominant partial lipodystrophy, and axonal neuropathy. Atrioventricular block (AVB) can be associated with several cardiac disorders and it can also be a highly heritable, primitive disease. One of the most common pathologies associated with AVB is dilated cardiomyopathy (DCM), which is characterized by cardiac dilatation and reduced systolic function. In this …

2014

In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with “cone-first” retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case-control association study with an internal exome data set as the control group. TTLL5, encoding a tubulin glutamylase, was highlighted as the most likely disease-associated gene; 2 of 28 affected subjects harbored presumed loss-of-function…

Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability.

2020

PurposeMarfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan–Fryns syndrome explain no more than 20% of subjects.MethodsTo further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.ResultsWe identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, …

Familial Hemiplegic Migraine with an ATP1A4 Mutation: Clinical Spectrum and Carbamazepine Efficacy

2020

An Italian family with familial hemiplegic migraine (FHM) with the absence of mutations in the known genes associated with this disorder, namely ATP1A2, ATP1A3, CACNA1A, and SCN1A, has recently been reported. Soon afterward, whole exome sequencing allowed the identification of the carrier status of a heterozygous ATP1A4 mutation c.1798 C >T, in four affected members of this family. Here we compare the clinical symptoms of the affected family members with those from the other FHM families linked to mutations in the known genes associated with this disorder. A further two-year follow-up, including clinical response to carbamazepine administered to the proband and the maternal grandmother due …

High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics

2021

ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) st…

CandidaDB: a genome database for Candida albicans pathogenomics.

2004

CandidaDB is accessible at http://genolist.pasteur.fr/CandidaDB.; International audience; CandidaDB is a database dedicated to the genome of the most prevalent systemic fungal pathogen of humans, Candida albicans. CandidaDB is based on an annotation of the Stanford Genome Technology Center C.albicans genome sequence data by the European Galar Fungail Consortium. CandidaDB Release 2.0 (June 2004) contains information pertaining to Assembly 19 of the genome of C.albicans strain SC5314. The current release contains 6244 annotated entries corresponding to 130 tRNA genes and 5917 protein-coding genes. For these, it provides tentative functional assignments along with numerous pre-run analyses th…

Widespread selection for high and low secondary structure in coding sequences across all domains of life

2019

AbstractCodon composition, GC-content and local RNA secondary structures can have a profound effect on gene expression and mutations affecting these parameters, even though they do not alter the protein sequence, are not neutral in terms of selection. Although evidence exists that in some cases selection favors more stable RNA secondary structures, we currently lack a concrete idea of how many genes are affected within a species, and if this is a universal phenomenon in nature.We searched for signs of structural selection in a global manner, analyzing a set of one million coding sequences from 73 species representing all domains of life, as well as viruses, by means of our newly developed s…