Performance evaluation of deleteriousness prediction methods for intronic SNVs in next generation sequences

Introduction: Alterations in splicing sites (ss) are estimated to explain approximately 10% of human disease causal variants. Mutations outside the ss but affecting ?regulatory elements? can be up to 25%. Accurate deleteriousness prediction for intronic variants is crucial for diagnostic purposes. Many deleteriousness prediction methods have been developed, but their relative values are still unclear in practical applications. We comprehensively evaluated the predictive performance of two complementary deleteriousness-scoring methods using information from real patients. Material and Methods: We selected the dbscSNV (both ADA and RF scores) and SPIDEX algorithms, that study variants in splicing consensus regions or in regulatory regions respectively. The tools, either alone or in combination, were tested on 29294 gene intronic SNVs that have previously been characterised by ClinVar as either ?pathogenic? (430) or ?benign? (28864). The sensitivity, specificity and positive and negative predictive values were calculated. Moreover, we applied the algorithms to WES data from undiagnosed patients, and we analysed the mRNA sequence from genes that fitted the patient?s phenotype. Results: The highest sensitivity corresponds to dbscSNV with 96.55% while the best specificity is for SPIDEX with 95.78%. When considering the 3 scores (SPIDEX, dbscSNV ADA and RF Score), the sensitivity and specificity values were 60.7% and 94.6%. The Positive and Negative Predictive Value were 14.45% and 99.39%. The results for 20 undiagnosed cases are presented. Conclusions: Besides the low positive predictive value, the combination of both algorithms leads less than 1% of false negatives, so their routine use can be recommended for diagnostic purposes

Variable expressivity familial cherubism: Woman transmitting cherubism without suffering the disease

Cherubism is classified within the group of benign osteo-fibrous lesions. Aside from facial deformities, it may account for major complications. It has been observed that the disease is caused by a mutation in the gene SH3BP2 (SH3-domain binding protein 2), which is located at chromosome 4pl6.3. Here we present two cases of familial cherubism, uncle and nephew, with variable clinical involvement ("Expressivity"), and one case of a woman (sister and mother, respectively), who transmitted cherubism without suffering the disease. In this article we have shown that, in familial cherubism cases, the mutation is inherited through an autosomal dominant transmission. Mutations affecting gene SH3BP2 cause variable clinical involvement (variable expressivity), involvement can be moderate, severe or may result merely in asymptomatic carriers. Since the possibility of transmission reaches 50% of chances, we believe that it is important to develop genetic counseling for both patients and carriers, in order to prevent or minimize new affected offspring

Microarrays de DNA en el cáncer oral

Uno de los principales objetivos en la investigación sobre el cáncer en la actualidad es el estudio de marcadores que puedan predecir el pronóstico o la respuesta al tratamiento de forma individual. El número de genes implicados en los distintos pasos de la carcinogénesis oral aumenta a medida que se investiga sobre el tema. Los microarrays de DNA permiten el análisis simultáneo de la expresión de cientos de genes de un tejido en un solo experimento. El formato paralelo del ensayo permite el estudio de diferencias en la expresión genética entre células normales y enfermas, puesto que la actividad de cada gen en el microarray puede ser comparada en dos poblaciones celulares distintas. El objetivo de este trabajo es hacer una breve revisión de los estudios realizados por diversos autores que han intentado identificar genes relacionados con el cáncer oral, así como clasificarlo en subgrupos según los patrones de expresión genética; lo que permitirá una precoz detección, mejor diagnóstico y pronóstico del cáncer oral.One of the principal aims of modern cancer research is to identify markers allowing individual prediction of prognosis or response to treatment. In this connection, the number of genes thought to be involved in the different stages of different types of oral cancer increases apace. DNA microarrays allow simultaneous evaluation of the expression of hundreds of genes in a single assay. The parallel format of microassay slides is designed to allow rapid comparison of gene expression between two samples, for example tumor cells and healthy cells. This article reviews studies that have aimed to identify genes related to oral cancer, and to classify these genes into groups that are commonly co-expressed. These studies suggest that DNA microarrays are set to become routine tools in the detection, diagnosis, characterization and treatment of oral cancers

The role of p21Waf 1/CIP1 as a Cip/Kip type cell-cycle regulator in oral squamous cell carcinoma: review

Oral Squamous Cell Carcinoma (OSCC) is biologically characterized by the accumulation of multiple genetic and molecular alterations that end up clinically characterized as a malignant neoplasm through a phenomenon known as multistep. The members of the Cip/Kip family, specifically p21 Waf 1/CIP1 , are responsible for cell cycle control, blocking the transition from phase G1 to phase S. We made a search of articles of peer-reviewed Journals in PubMed/ Medline, crossing the keywords. The goal of this paper is to determine the relationship between p21 Waf 1/ CIP1 expression and several clinical and pathological aspects of OSCC, their relationship with p53 and HPV, as well as genetic alterations in their expression pattern, their use as a prognosis market in the evolution of precancer - ous lesions and their roles in anticancer treatments. The results of p21 WA F1/C I P1 expression in OSCC showed mixed results in terms of positivity/negativity throughout different studies. It seems that, although p21 Waf 1/CIP1 expression is controlled in a p53-dependent manner, coexpression of both in OSCC is not intrinsically related. Although the presence of HPV viral oncoproteins increases p21 Waf 1/CIP1 levels, the small number of studies, have forced us to disregard the hypothesis that HPV infected lesions that present better prognosis are due to a p21 Waf 1/CIP1 -dependent control. The role of p21 WA F1/C I P1 as cell-cycle regulator has been well described; however, its relationship to OSCC, the clinical and pathological variables of tumors, HPV and different treatments are not entirely clear. Thus, it would be very interesting to pursue further study of this protein, which may have a significant value for the diagnosis, prog nosis and therapy of this type of tumors

V232D Mutation in Patients With Cystic Fibrosis: Not So Rare, Not So Mild

The frequency of some Cystic Fibrosis (CF) Transmembrane Conductance Regulator gene (CFTR) mutations varies between populations. Genetic testing during newborn screening (NBS) for CF can identify less common mutations with low clinical expression in childhood and previously considered mild but not fully characterized, such as the mutation p.Val232Asp (c.695T > A). The aim of this study was to describe CF patients with the V232D mutation. We identify CF children with the V232D mutation detected by NBS and compare them with CF adults with this mutation whose diagnosis was prompted by clinical symptoms in the same period. We studied clinical, biochemical, spirometric, and prognostic features in both populations. NBS program tested 276,523 children during a period of 14 years (2003-2017) and identified 54 cases of CF. Six children (11%) had the V232D mutation. Over the same period, 5 adults (age 37.6 ± 16.29 years old) with symptoms of CF and this mutation were also diagnosed. Follow-up duration was mean 10.1 years for adults and mean 6.5 years for children. In the adult group, lung function was impaired at diagnosis in all patients (Forced Expiratory Volume1-FEV1-67.12% ± 13.09) and worsened in children tested during evolution (FEV1first: 113%; FEV1last: 64%). Pancreatic insufficiency was present in adult group, with recurrent pancreatitis in 1 present. Although with less clinical expression in children, V232D is associated with pulmonary and pancreatic involvement during adulthood and CF cannot be considered mild. This mutation is present in 11% of all patients diagnosed with CF in our region. Its inclusion in some NBS programs should be taken into account in order to improve the prognosis of affected children.S

Quantitative determination of c-myc facilitates the assessment of prognosis of OSCC patients

Myc genes are a family of proto-oncogenes whose proteins are implicated in the regulation of cell proliferation, differentiation and apoptosis, and in regulating the activity of genes involved in cell division. The aim of the present study was to establish a quantitative description of the expression of c-myc and evaluate its relationship with other clinical and prognostic factors, as well as to establish a multivariate survival prediction model. This is a retrospective study of 68 patients diagnosed with oral squamous cell carcinoma (OSCC). We constructed a tissue microarray for investigating the expression of c-myc by immunohistochemistry. Statistical analyses were carried out, and a multivariate model that predicts survival was established. The average expression of c-myc was 50.32 (SD, 26.05) with a range from 6.60 to 99.48; similar for initial and advanced tumor stages. Non-smoking patients had higher levels of c-myc, showing statistically significant differences (Kruskal-Wallis chi2=5.975; p=0.05). We found no statistically significant relationship between the quantitative expression of c-myc and any other clinical or pathological parameters. For each unit of increase of c-myc, the risk increased by 1.15 (p<0.001; HR, 1.150; 95% CI, 1062-1245). Further study of this protein, which may have a significant diagnostic, prognostic and therapeutic value is warranted. Its determination can be valuable when used together with other markers to assess the prognosis of OSCC patients

Mowat-Wilson Syndrome with a deletion of the ZEB2 gene previously undescribed

Dismorfología y Genética ClínicaMowat-Wilson syndrome –MWS- (MIM 235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 (Zinc finger E-box-binding homeobox 2 gene) gene, that codifies the SIP1 (Smad interacting protein 1) localized within the 2q22-q23 chromosomal region. It conforms a syndrome of multiple congenital anomalies, characterized by a typical facial phenotype, moderate to severe mental retardation, epilepsy and different congenital malformations including Hirschsprung disease, congenital cardiopathy, agenesis of the corpus callosum, genitourinary and eye anomalies. We present a patient suffering MWS with a heterozigotic deletion of a base in the 461 position of the codifying sequence for the ZFB2 gene, corresponding to the codon 157, which alters the reading frame and causes the appearance of a stopping codon, 17 positions later. Genotype: c.461 delA (p.Glu157GlufsX17)/normal. This mutation does not appear described in the literature but its presence justifies the reported clinical manifestations. The genetic studies performed to the parents were normal, confirming a de novo mutation.N