Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management.

Background: BRCA1:c.5017_5019del (p.His1673del) is a founder variant relatively frequent in Northern Italy.

A case series of non-small cell lung cancer patients with or exon 20 insertion in Li Fraumeni syndrome.

Introduction: Germline pathogenic mutations in gene are associated with a cancer predisposition syndrome known as Li Fraumeni syndrome. Albeit infrequently, non-small cell lung cancer, especially as oncogene-addicted disease, may be diagnosed in young patients with Li Fraumeni syndrome.

Case Description: We report three cases of patients affected by Li Fraumeni syndrome who developed non-small cell lung cancer with or exon 20 insertions.

Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Once Daily Empagliflozin 25 mg for the Treatment of Postprandial Hypoglycemia After Roux-en-Y Gastric Bypass.

To investigate the effect of empagliflozin on glucose dynamics in individuals suffering from postbariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). Twenty-two adults with PBH after RYGB were randomized to empagliflozin 25 mg or placebo once daily over 20 days in a randomized, double-blind, placebo-controlled, crossover trial. The primary efficacy outcome was the amplitude of plasma glucose excursion (peak to nadir) during a mixed-meal tolerance test (MMTT).

Fostering physical activity-related health competence after bariatric surgery with a multimodal exercise programme: A randomised controlled trial.

Regular physical activity (PA) supports the long-term success of bariatric surgery. However, integrating health-enhancing physical activity in daily life requires specific competences. In this study, we evaluated a multimodal exercise programme to build these competences.

Gingival Overgrowths Revealing Hamartoma Tumor Syndrome: Report of Novel Pathogenic Variants.

PTEN hamartoma tumor syndrome (PHTS), is a spectrum of disorders caused by mutations of PTEN, in which non-cancerous growths, called hamartomas, develop in different areas of the body, often including the oral mucosa. PHTS also implies a recognized increased risk of malignancies, as PTEN is a tumor suppressor gene capable of inhibiting progression of several cancers. One of the main and most common clinical manifestation of PHTS are gingival overgrowths presenting as warty lumps.

Counter-regulatory responses to postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia vs surgical and non-surgical control individuals.

Aims/hypothesis: Post-bariatric hypoglycaemia is an increasingly recognised complication of bariatric surgery, manifesting particularly after Roux-en-Y gastric bypass. While hyperinsulinaemia is an established pathophysiological feature, the role of counter-regulation remains unclear. We aimed to assess counter-regulatory hormones and glucose fluxes during insulin-induced postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia after Roux-en-Y gastric bypass vs surgical and non-surgical control individuals.

Diagnostics of -Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience.

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 () lead to tumor predisposition syndrome (-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of -TPDS, along with a clinical update and cascade genetic testing of previously reported -TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected -TPDS and validated pathogenic variants (PVs) by assessing somatic loss in matching tumor specimens.

Primary hyperoxaluria in Italy: the past 30 years and the near future of a (not so) rare disease.

Background: Primary hyperoxalurias (PHs) are rare autosomal recessive diseases of the glyoxylate metabolism; PH1 is caused by mutations in the AGXT gene, PH2 in GRHPR and PH3 in HOGA1.

Methods: Here we report the first large multi-center cohort of Italian PH patients collected over 30 years (1992-2020 median follow-up time 8.5 years).

Malignant pleural mesothelioma: Germline variants in DNA repair genes may steer tailored treatment.

Introduction: Malignant pleural mesothelioma (MPM) is a tumour associated with asbestos exposure. Approximately, 10% of patients with MPM carry a germline pathogenic variant (PV), mostly in DNA repair genes, suggesting the occurrence of inherited predispositions.

Aim: This article aimed to 1) search for new predisposing genes and assess the prevalence of PVs in DNA repair genes, by next-generation sequencing (NGS) analysis of germline DNA from 113 unselected patients with MPM and 2) evaluate whether these patients could be sensitive to tailored treatments.

The impact of postbariatric hypoglycaemia on driving performance: A randomized, single-blind, two-period, crossover study in a driving simulator.

Postbariatric hypoglycaemia (PBH) is an increasingly recognized complication of bariatric surgery, but its effect on daily functioning remains unclear. In this randomized, single-blind, crossover trial we assessed driving performance in patients with PBH. Ten active drivers with PBH (eight females, age 38.

Clinical exome sequencing is a powerful tool in the diagnostic flow of monogenic kidney diseases: an Italian experience.

Background: A considerable minority of patients on waiting lists for kidney transplantation either have no diagnosis (and fall into the subset of undiagnosed cases) because kidney biopsy was not performed or histological findings were non-specific, or do not fall into any well-defined clinical category. Some of these patients might be affected by a previously unrecognised monogenic disease.

Methods: Through a multidisciplinary cooperative effort, we built an analytical pipeline to identify patients with chronic kidney disease (CKD) with a clinical suspicion of a monogenic condition or without a well-defined diagnosis.

The ILE56 mutation on different genetic backgrounds of alanine:glyoxylate aminotransferase: Clinical features and biochemical characterization.

Primary Hyperoxaluria type I (PH1) is a rare disease caused by mutations in the AGXT gene encoding alanine:glyoxylate aminotransferase (AGT), a liver enzyme involved in the detoxification of glyoxylate, the failure of which results in accumulation of oxalate and kidney stones formation. The role of protein misfolding in the AGT deficit caused by most PH1-causing mutations is increasingly being recognized. In addition, the genetic background in which a mutation occurs is emerging as a critical risk factor for disease onset and/or severity.

Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants.

Background: Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown.

Methods: We applied a combination of systematic experimental and bioinformatic methods to improve the molecular diagnosis of 39 patients with multiple congenital abnormalities and/or intellectual disability harboring apparent de novo SVs, most with an inconclusive diagnosis after regular genetic testing.

Ventricular conduction delay as marker of risk in Brugada Syndrome. Results from the analysis of clinical and electrocardiographic features of a large cohort of patients.

Background: Brugada Syndrome is a genetic arrhythmogenic disease with a variable clinical spectrum. The role of clinical and ECG parameters in the risk stratification is still uncertain.

Aims: In a large cohort of Brugada patients we analysed clinical and ECG features to determine the variables with prognostic value for the occurrence of a first documented arrhythmic event and for recurrences.

Genotype-Phenotype Correlation in a Family with Brugada Syndrome Harboring the Novel p.Gln371* Nonsense Variant in the Gene.

Brugada syndrome (BrS) is marked by coved ST-segment elevation and increased risk of sudden cardiac death. The genetics of this syndrome are elusive in over half of the cases. Variants in the gene are the single most common known genetic unifier, accounting for about a third of cases.

The Role of Genetic Factors in Characterizing Extra-Intestinal Manifestations in Crohn's Disease Patients: Are Bayesian Machine Learning Methods Improving Outcome Predictions?

(1) Background: The high heterogeneity of inflammatory bowel disease (IBD) makes the study of this condition challenging. In subjects affected by Crohn's disease (CD), extra-intestinal manifestations (EIMs) have a remarkable potential impact on health status. Increasing numbers of patient characteristics and the small size of analyzed samples make EIMs prediction very difficult.

Workload measurement for molecular genetics laboratory: A survey study.

Genetic testing availability in the health care system is rapidly increasing, along with the diffusion of next-generation sequencing (NGS) into diagnostics. These issues make imperative the knowledge-drive optimization of testing in the clinical setting. Time estimations of wet laboratory procedure in Italian molecular laboratories offering genetic diagnosis were evaluated to provide data suitable to adjust efficiency and optimize health policies and costs.

Novel mutation of PPOX gene in a patient with abdominal pain and syndrome of inappropriate antidiuresis.

Purpose: Acute porphyrias are metabolic disorders of heme biosynthesis characterized by acute life-threatening attacks. The diagnosis is often missed since clinical presentation is aspecific mimicking other medical and surgical conditions. Variegate porphyria (VP) is an autosomal dominant inherited disease with incomplete penetrance due to decreased activity of the Protoporphyrinogen Oxydase (PPOX) gene; most VP mutations are family specific.

Mapping and phasing of structural variation in patient genomes using nanopore sequencing.

Despite improvements in genomics technology, the detection of structural variants (SVs) from short-read sequencing still poses challenges, particularly for complex variation. Here we analyse the genomes of two patients with congenital abnormalities using the MinION nanopore sequencer and a novel computational pipeline-NanoSV. We demonstrate that nanopore long reads are superior to short reads with regard to detection of de novo chromothripsis rearrangements.

Primary Hyperoxaluria Type 1 with Homozygosity for a Double-mutated Allele in a 2-year-old Child.

Primary hyperoxaluria (PH) Type 1 is a rare, genetic disorder caused by deficiency of the liver enzyme alanine-glyoxylate aminotransferase, which is encoded by gene. We report a 2-year-old South Indian Tamil child with nephrocalcinosis due to PH Type 1, in whom a homozygous genotype for two missense mutations in the gene was found: first, a C to G transversion (c. 32C>G) in exon 1 resulting in the amino acid substitution p.