A novel mutation in the TMC1 gene causes non-syndromic hearing loss in a Moroccan family

International audience

Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability

International audience

A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability

International audience

Frequency of Genotype With ΔF508 Mutation in CFTR Gene Among Iranian Cystic Fibrosis Patients With Pancreatic Insufficiency

Background: Cystic fibrosis (CF) is the most prevalent lethal autosomal recessive disease with a broad spectrum of phenotypes. Mutation of ΔF508 in the CFTR gene is the most important and lethal mutation in CF, which contains 70% of all predisposing mutations for CF worldwide. Objectives: Determining frequency of genotypes with ΔF508 mutation in CFTR gene, and evaluation of correlation between genotype and phenotype of Iranian patients with CF. Patients and Methods: Thirty six patients were included in this cross sectional study. ΔF508 mutations in both alleles of the CFTR gene were checked. Results: Among 36 pediatric patients, ΔF508 mutation was detected in 9 (25%) patients; 2 patients were heterozygous, and 7 patients homozygous for this mutation. From overall 72 tracked alleles, 11 (15.2%) were found to have ΔF508 mutations. Differences in prevalence of dyspnea and bronchiectasis were significant in homozygote group, compared with non-mutated group for ΔF508. Conclusions: It seems that more ΔF508 mutated alleles lead to more severe symptoms of CF.

Novel Mutation in the ATP-Binding Cassette Transporter A3 (ABCA3) Encoding Gene Causes Respiratory Distress Syndrome in A Term Newborn in Southwest Iran

Introduction: ABCA3 glycoprotein belongs to the ATP-binding cassette (ABC) superfamily of transporters, which utilize the energy derived from hydrolysis of ATP for the translocation of a wide variety of substrates across the plasma membrane. Mutations in the ABCA3 gene are knowingly causative for fatal surfactant deficiency, particularly respiratory distress syndrome (RDS) in term babies. Case Presentation: In this study, Sanger sequencing of the whole ABCA3 gene (NCBI NM_001089) was performed in a neonatal boy with severe RDS. A homozygous mutation has been identified in the patient. Parents were heterozygous for the same missense mutation GGA > AGA at position 202 in exon 6 of the ABCA3 gene (c.604G > A; p.G202R). Furthermore, 70 normal individuals have been analyzed for the mentioned change with negative results. Conclusions: Regarding Human Genome Mutation Database (HGMD) and other literature recherche, the detected change is a novel mutation and has not been reported before. Bioinformatics mutation predicting tools prefer it as pathogenic.

Analysis of the LRRK2 p.G2019S mutation in Colombian Parkinson’s Disease Patients

Introduction: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2 or Dardarin) are considered to be a common cause of autosomal dominant and sporadic Parkinson´s disease, but the prevalence of these mutations varies among populations. Objective: To analyzed the frequency of the LRRK2 p.G2019S mutation (c.6055G>A transition) in a sample of Colombian patients. Methods: In the present study we have analyzed the frequency of the LRRK2 p.G2019S mutation in 154 patients with familial or sporadic Parkinson Disease, including early and late onset patients, and 162 normal controls. Results: Our results show occurrence of this mutation in two cases (2/154, 1.3%) with classical Parkinson´s signs, and one completely asymptomatic control (1/162, 0.6%). Conclusion: The p.G2019S mutation is not an important causal factor of Parkinson Disease in Colombia having similar frequencies to those reported in other Latin American populations.

Charcot Marie Tooth disease (CMT4A) due to GDAP1 mutation: report of a colombian family

Background: Mutations of GDAP1 gene cause autosomal dominant and autosomal recessive Charcot-Marie-Tooth disease and more than 40 different mutations have been reported. The recessive Q163X mutation has been described in patients of Spanish ancestry, and a founder mutation in South American patients, originating in Spain has been demonstrated. Objective: We describe physical and histological features, and the molecular impact of mutation Q163X in a Colombian family. Methods: We report two female patients, daughters of consanguineous parents, with onset of symptoms within the first two years of life, developing severe functional impairment, without evidence of dysmorphic features, hoarseness or diaphragmatic paralysis. Electrophysiology tests showed a sensory and motor neuropathy with axonal pattern. Sequencing of GDAP1 gene was requested and the study identified a homozygous point mutation (c.487 C>T) in exon 4, resulting in a premature stop codon (p.Q163X). This result confirms the diagnosis of Charcot-Marie-Tooth disease, type 4A. Results: The patients were referred to Physical Medicine and Rehabilitation service, in order to be evaluated for ambulation assistance. They have been followed by Pulmonology service, for pulmonary function assessment and diaphragmatic paralysis evaluation. Genetic counseling was offered. The study of the genealogy of the patient, phenotypic features, and electrophysiological findings must be included as valuable tools in the clinical approach of the patient with Charcot-Marie-Tooth disease, in order to define a causative mutation. In patients of South American origin, the presence of GDAP1 gene mutations should be considered, especially the Q163X mutation, as the cause of CMT4A disease.

Charcot Marie Tooth disease (CMT4A) due to GDAP1 mutation: report of a colombian family

Background: Mutations of GDAP1 gene cause autosomal dominant and autosomal recessive Charcot-Marie-Tooth disease and more than 40 different mutations have been reported. The recessive Q163X mutation has been described in patients of Spanish ancestry, and a founder mutation in South American patients, originating in Spain has been demonstrated. Objective: we describe physical and histological features, and the molecular impact of mutation Q163X in a Colombian family. Methods: We report two female patients, daughters of consanguineous parents, with onset of symptoms within the first two years of life, developing severe functional impairment, without evidence of dysmorphic features, hoarseness or diaphragmatic paralysis. Electrophysiology tests showed a sensory and motor neuropathy with axonal pattern. Sequencing of GDAP1 gene was requested and the study identified a homozygous point mutation (c.487 C>T) in exon 4, resulting in a premature stop codon (p.Q163X). This result confirms the diagnosis of Charcot-Marie-Tooth disease, type 4A. Results: The patients were referred to Physical Medicine and Rehabilitation service, in order to be evaluated for ambulation assistance. They have been followed by Pulmonology service, for pulmonary function assessment and diaphragmatic paralysis evaluation. Genetic counseling was offered. The study of the genealogy of the patient, phenotypic features, and electrophysiological findings must be included as valuable tools in the clinical approach of the patient with Charcot-Marie-Tooth disease, in order to define a causative mutation. In patients of South American origin, the presence of GDAP1 gene mutations should be considered, especially the Q163X mutation, as the cause of CMT4A disease.

CALR mutation profile in Irish patients with myeloproliferative neoplasms

Insertion and/or deletion mutations of the CALR gene have recently been demonstrated to be the second most common driver mutations in the myeloproliferative neoplasms (MPNs) of essential thrombocythemia (ET) and primary myelofibrosis (PMF). Given the diagnostic and emerging prognostic significance of these mutations, in addition to the geographical heterogeneity reported, the incidence of CALR mutations was determined in an Irish cohort of patients with MPNs with a view to incorporate this analysis into a prospective screening program. A series of 202 patients with known or suspected ET and PMF were screened for the presence of CALR mutations. CALR mutations were detected in 58 patients. Type 1 and Type 1-like deletion mutations were the most common (n = 40) followed by Type 2 and Type 2-like insertion mutations (n = 17). The CALR mutation profile in Irish ET and PMF patients appears similar to that in other European populations. Establishment of this mutational profile allows the introduction of a rational, molecular diagnostic algorithm in cases of suspected ET and PMF that will improve clinical management.

L’ingénieur et le patrimoine. Savoirs techniques, amenagement du teritoire et mutation du paysage

Le présent volume est l’aboutissement éditorial d’un travail sur les patrimoines de l’ingénierie qui s’était initialement concrétisé par la journée d’études internationale du 6 juillet 2012, à l’Université de Paris I Panthéon-Sorbonne. Cette journée a été organisée dans le cadre des activités des jeunes chercheurs et doctorants du master Erasmus Mundus TPTI, c’est-à-dire « Techniques, patrimoine, territoires de l’industrie », qui réunit un consortium universitaire international autour de ces questions, en offrant d’intéressantes opportunités d’échanges aux jeunes chercheurs. Les grands ouvrages de génie civil ont eu d’importantes conséquences paysagères et sociales. La mutation du paysage est aussi en lien direct avec la mise en place des grands systèmes techniques et avec l’aménagement des territoires de l’industrie. Ce patrimoine technique suscite un intérêt croissant. Le présent volume interroge les questions de sa protection, sa préservation et de sa valorisation.

Un regard pluriel sur le patrimoine de l’ingénierie : savoir technique, aménagement du territoire et mutation du paysage

Un regard pluriel sur le patrimoine de l’ingénierie : savoir technique, aménagement du territoire et mutation du paysage Le patrimoine de l’ingénierie : au-delà des travaux publics L’histoire et le patrimoine de l’ingénierie : les enseignements du passé pour améliorer le travail des ingénieurs formés dans le temps présent Approches diversifiées au patrimoine de l’ingénierie

Molecular target therapy and immunotherapy of rare lung tumors

Lung cancer is an heterogeneous disease, with 1-2% of rare histology. New molecular profiling technologies, such as next generation sequencing (NGS), haverevolutionized the assessment of molecular alteration in clinical practice. We analyzed a cohort of 1408 NSCLC-A patients treated at the Sant'Orsola- Malpighi University Hospital from 2019 to 2021. This analysis was performed using the oncomine focus thermo fischer panel. Of them, 410 (29%) had rare alteration (RET 3%, NTRK 0,2%,FGFR1 2%, MET exon14 skipping 3%, BRAF V600 4%, ALK fusion EGFR exon 20 2%) and 36 (2%)had a uncommon mutation. We enrolled 7 RET- rearranged patients in CRETA and J2G-MC-JZJC clinical trials assessing respectively unselective and selective RET-inhibitors , another 7 patients tested positive for the BRAF V6006 mutation and have been enrolled in the Array clinical trial assessing a novel combination of anti-BRAF and anti-mek agents . Other molecular alterations found are KRAS (Gly12Cys), FGFR1-4 mutation, MET skipping ex14 mutations, respectively eligible for other ongoing open studies such as Amgen 20190009 comparing efficacy of sotorasib vs docetaxel, Fight-207 assessing activity of pemigatinib and CINC280J12201 assessing activity of the novel met inhibitor capmatinib. In 2018 we joined the CHANCE clinical trial,a multicenter study evaluating the efficacy and safety of atezolizumab in patients withrare lung cancer histologies where and 14 patients have been so far enrolled in the Bologna site. Our studies underline the need of tailored approach to NSCLC patients and our results showed that precision medicine is feasible and is an effective approach to cancer treatment.

Magnetic Resonance Imaging-Derived biomarkers of Isocitrate-Dehydrogenase mutation in diffuse gliomas: a conventional MR and Diffusion Weighted Imaging study.

The introduction of molecular criteria into the classification of diffuse gliomas has added interesting practical implications to glioma management. This has created a new clinical need for correlating imaging characteristics with glioma genotypes, also known as radiogenomics or imaging genomics. Whilst many studies have primarily focused on the use of advanced magnetic resonance imaging (MRI) techniques for radiogenomics purposes, conventional MRI sequences still remain the reference point in the study and characterization of brain tumours. Moreover, a different approach may rely on diffusion-weighted imaging (DWI) usage, which is considered a “conventional” sequence in line with recently published directions on glioma imaging. In a non-invasive way, it can provide direct insight into the microscopic physical properties of tissues. Considering that Isocitrate-Dehydrogenase gene mutations may reflect alterations in metabolism, cellularity, and angiogenesis, which may manifest characteristic features on an MRI, the identification of specific MRI biomarkers could be of great interest in managing patients with brain gliomas. My study aimed to evaluate the presence of specific MRI-derived biomarkers of IDH molecular status through conventional MRI and DWI sequences.

Ruolo delle tecniche di sequenziamento di ultima generazione nella gestione dei pazienti con carcinoma colorettale metastatico

L'utilità clinica dell’uso routinario delle tecniche di sequenziamento di nuova generazione (NGS) nei pazienti con cancro colorettale metastatico andrebbe approfondita. In questo studio, è stato valutato l'impatto di un pannello NGS da 52 geni utilizzato nella pratica clinica di routine. Abbiamo analizzato i risultati dei test molecolari multigenici in pazienti con carcinoma colorettale metastatico (mCRC) in uno studio osservazionale, retrospettivo e monocentrico su pazienti affetti da carcinoma colorettale metastatico consecutivamente testati presso un centro oncologico italiano tra giugno 2019 e dicembre 2020. Le analisi di sopravvivenza sono state effettuate con il metodo Kaplan-Meier, test log-rank e modello di Cox. Complessivamente sono stati inclusi 179 pazienti con mCRC. Il follow-up mediano è stato di 33 mesi (IQR: 28,45–NR). I quattro geni più frequentemente mutati sono stati: KRAS (48,6%), PIK3CA (22,4%), BRAF (14,5%) e APC (8,4%). È stata trovata un'associazione positiva tra la sopravvivenza globale (OS) e le mutazioni KRAS con un'alta frequenza allelica variante (VAF) [HR: 0,60 (0.36 – 0.99), P=0.047]. La mutazione BRAF era associata a OS inferiore [HR: 2,62 (1,59-4,32), P <0,001]. Il panello NGS ha consentito a otto pazienti di accedere a terapie a bersaglio molecolare non ancora registrate per il cancro colorettale. In conclusione, i pannelli NGS in mCRC sono fattibili nella pratica clinica in laboratori di riferimento per consentire un impatto inferiore sui costi e un aggiornamento regolare. La mutazione di BRAF risulta associata a una prognosi peggiore. Le mutazioni di KRAS con un’elevata variazione di frequenza allelica erano associate a una sopravvivenza globale superiore rispetto ai pazienti KRAS non mutati. Sono necessari studi più approfonditi per analizzare meglio i fattori prognostici.