Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

: Genetics of Familial Hypercholesterolemia (FH) is ascribable to pathogenic variants in genes encoding proteins leading to an impaired LDL uptake by the LDL receptor (LDLR). Two forms of the disease are possible, heterozygous (HeFH) and homozygous (HoFH), caused by one or two pathogenic variants, respectively, in the three main genes that are responsible for the autosomal dominant disease: LDLR, APOB and PCSK9 genes. The HeFH is the most common genetic disease in humans, being the prevalence about 1:300. Variants in the LDLRAP1 gene causes FH with a recessive inheritance and a specific APOE variant was described as causative of FH, contributing to increase FH genetic heterogeneity. In addition, variants in genes causing other dyslipidemias showing phenotypes overlapping with FH may mimic FH in patients without causative variants (FH-phenocopies; ABCG5, ABCG8, CYP27A1 and LIPA genes) or act as phenotype modifiers in patients with a pathogenic variant in a causative gene. The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. This review aims to report the updates on the genetic and molecular bases of FH with their implication for molecular diagnosis

Caries Severity, Decayed First Permanent Molars and Associated Factors in 6-7 Years Old Schoolchildren Living in Palermo (Southern Italy).

To date, there are very few epidemiologic studies on caries disease in 6-7 year old children living in Sicily (Southern Italy). The first permanent molar (FPM) is the most commonly affected tooth in this target population, and a one-unit increase in the number of decayed FPMs is predictive of caries in other teeth and in adulthood. The primary aim of this research is to estimate the prevalence of caries in 6-7 year old schoolchildren living in Palermo and, as a secondary aim, to estimate the prevalence of affected FPMs. It was designed as a cluster cross-sectional survey on 995 children from 16 schools, selected based on their geographical location, in one of the eight city districts. Caries data were recorded using the International Caries Detection and Assessment System for each tooth surface. The relation between socio-economic status, behavioural determinants, and clinical information and the number of teeth with initial caries (IC), moderate caries (MC), or extensive caries (SC) was analysed through the ordinal logistic regression. Among the 995 schoolchildren, 662 (66.5%) had at least one lesion and 742 (74.6%) had FPMs. Of the latter, 238 (32.0%) were affected by IC, 86 (11.6%) were affected by MC, and only 3 (0.4%) were affected by SC. During multivariable analysis, there was evidence of an increased risk of MC and SC related to the deprivation of the district in which the children lived and went to school, as well as to the protective role of parental education and employment. The same significant determinants were found for IC and MC FPMs. The study showed the important role of socio-economic determinants, unhealthy behaviours, and social deprivation related to the increased risk of moderate and extensive caries in 6-7 year old schoolchildren. Investigating this target population is very important, as early development of caries in FPMs may have serious consequences in the prognostics of oral health in an adult

Sequence Analysis of the UCP1 Gene in a Severe Obese Population from Southern Italy

Brown adipose tissue, where Uncoupling Protein 1 (UCP1) activity uncouples mitochondrial respiration, is an important site of facultative energy expenditure. This tissue may normally function to prevent obesity. Our aim was to investigate by sequence analysis the presence of UCP1 gene variations that may be associated with obesity. We studied 100 severe obese adults (BMI > 40 kg/m2) and 100 normal-weight control subjects (BMI range = 19–24.9 kg/m2). We identified 7 variations in the promoter region, 4 in the intronic region and 4 in the exonic region. Globally, 72% of obese patients bore UCP1 polymorphisms. Among UCP1 variants, g.IVS4−208T>G SNP was associated with obesity (OR: 1.77; 95% CI = 1.26–2.50; P = .001). Further, obese patients bearing the g.−451C>T (CT+TT) or the g.940G>A (GA+AA) genotypes showed a higher BMI than not polymorphic obese patients (P = .008 and P = .043, resp.). In conclusion, UCP1 SNPs could represent “thrifty” factors that promote energy storage in prone subjects

Human Papilloma Virus (HPV) Detection in Oral Rinse vs. Oral Sponge: A Preliminary Accuracy Report in Oral Cancer Patients

Background/Objectives: Human Papillomavirus (HPV) is a significant etiological factor in the development of oropharyngeal carcinogenesis. The detection of HPV in oral squamous cell carcinoma (OSCC) could be also crucial for diagnosis, prognosis, and treatment planning. This study compares the efficacy and accuracy of two non-invasive sampling methods, oral rinse, and oral sponge, in detecting HPV DNA in patients with OSCC. Methods: Twenty-six patients with histologically confirmed OSCCs were recruited (M/F = 15/11; mean age 68.6). From each patient, two self-collected oral specimens, in the form of an oral rinse and a salivary sponge (i.e., LolliSponge), were collected, and subsequently processed, utilizing INNO-LiPA HPV Genotyping Extra II for HPV DNA detection; Results: Oral sponge detection showed high specificity (100%), sensitivity (85.7%), and accuracy (96.2%) compared to the oral rinse sampling, also demonstrating an area AUC for its diagnostic performance significantly greater than 0.5 (0.93 vs. 0.5, p < 0.0001). Conclusions: This study supports that oral sponge sampling offers valuable non-invasive alternatives for HPV detection in patients with OSCC, with the potentiality to facilitate saliva sampling in patients that may exhibit functional deficit due to OSCC. Further research is recommended to validate these findings in larger cohorts and to explore the integration of these methods into routine clinical practice for the management of HPV-related OSCC

Association of USF1 and APOA5 polymorphisms with familial combined hyperlipidemia in an Italian population.

Familial combined hyperlipidemia (FCH) is a polygenic and multifactorial disease characterized by a variable phenotype showing increased levels of triglycerides and/or cholesterol. The aim of this study was to identify single nucleotides (SNPs) in lipid-related genes associated with FCH. METHODS AND RESULTS: Twenty SNPs in lipid-related genes were studied in 142 control subjects and 165 FCH patients after excluding patients with mutations in the LDLR gene and patients with the E2/E2 genotype of APOE. In particular, we studied the 9996G > A (rs2073658) and 11235C > T (rs3737787) variants in the Upstream Stimulatory Factor 1 gene (USF1), and the -1131T > C (rs662799) and S19W (rs3135506) variants in the Apolipoprotein A-V gene (APOA5). We found that the frequencies of these variants differed between patients and controls and that are associated with different lipid profiles. At multivariate logistic regression SNP S19W in APOA5 remained significantly associated with FCH independently of age, sex, BMI, cholesterol and triglycerides. CONCLUSIONS: Our results show that the USF1 and APOA5 polymorphisms are associated with FCH and that the S19W SNP in the APOA5 gene is associated to the disease independently of total cholesterol, triglycerides and BMI. However, more extensive studies including other SNPs such as rs2516839 in USF1, are required

Ultrasound tissue characterization detectspreclinical myocardial structural changes inchildren affected by Duchenne muscular dystrophy

AbstractObjectivesOur goal was to identify early changes in myocardial physical properties in children with Duchenne muscular dystrophy (DMDch).BackgroundDuchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, which triggers complex molecular and biological events in skeletal and cardiac muscle tissues. Although about 30% of patients display overt signs of cardiomyopathy in the late stage of the disease, it is unknown whether changes in myocardial physical properties can be detected in the early (preclinical) stages of the disease.MethodsWe performed an ultrasonic tissue characterization (UTC) analysis of myocardium in DMDch with normal systolic myocardial function and no signs of cardiomyopathy. Both the cyclic variation of integrated backscatter (cvIBS) and the calibrated integrated backscatter (cIBS) were assessed in 8 myocardial regions of 20 DMDch, age 7 ± 2 years (range 4 to 10 years), and in 20 age-matched healthy controls.ResultsWe found large differences in the UTC data between DMDch and controls; the mean value of cvIBS was 4.4 ± 1.5 dB versus 8.8 ± 0.8 dB, whereas the mean value of cIBS was 36.4 ± 7.1 dB versus 26.9 ± 2.0 dB (p < 10−6for both). In DMDch, all eight sampled segments showed cIBS mean values to be significantly higher and cvIBS mean values to be significantly lower than those in the controls. Finally, interindividual differences were greater in DMDch than in controls for both parameters.ConclusionsThe myocardium in DMDch displays UTC features different from those in healthy controls. These results show that lack of dystrophin is commonly associated with changes in myocardial features well before the onset of changes of systolic function and overt cardiomyopathy