Showing papers in "Genetic Testing and Molecular Biomarkers in 2010"
TL;DR: Although SIFT and PolyPhen may be useful in prioritizing changes that are likely to cause a loss of protein function, their low specificity means that their predictions should be interpreted with caution and further evidence to support/refute pathogenicity should be sought before reporting novel missense changes.
Abstract: Context: The interpretation of novel missense variants is a challenge with increasing numbers of such variants being identified and a responsibility to report the findings in the context of all available scientific evidence. Various in silico bioinformatic tools have been developed that predict the likely pathogenicity of missense variants; however, their utility within the diagnostic setting requires further investigation. Aim: The aim of our study was to test the predictive value of two of these tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), in a set of 141 missense variants (131 pathogenic, 8 benign) identified in the ABCC8, GCK, and KCNJ11 genes. Methods: Sixty-six of the mutations caused a gain of protein function, while 67 were loss-of-function mutations. The evolutionary conservation at each residue was also investigated using multiple sequence alignments from the UCSC genome browser. Results: The sensitivity of SIFT and PolyPhen was reasonably high (69% and...
352 citations
TL;DR: Investigation of polymorphisms of the vitamin D receptor (VDR) and aggrecan genes and degenerative disc disease in young Turkish patients revealed that they are associated with disc degeneration and herniation.
Abstract: The aim of this study was to investigate the association between the polymorphisms of the vitamin D receptor (VDR) and aggrecan genes and degenerative disc disease in young Turkish patients. Aggrecan and VDR proteins are the main components of bone and cartilage. In our study, the polymorphisms of the VDR and aggrecan genes were investigated in a total of 300 individuals regarding disc degeneration and herniation. An association was found in the patients having VDR gene TT, Tt, FF, and Ff genotypes with the protrusion type of disc herniation, whereas the patients having tt and ff genotypes were associated with extrusion/sequestration types of the disease. Also, an association was observed between TT and FF genotypes of the VDR gene and mild forms of disc degeneration; and tt, ff, and Ff genotypes and severe forms of the disease. There was also an association between shorter, normal, and longer alleles of the aggrecan gene and a protrusion type of disc herniation. An association was found between short all...
77 citations
TL;DR: Although some of the experiences cited by parents are common to families raising a child with a diagnosed condition, lack of diagnosis adds a layer of complexity.
Abstract: Aim: The aim of this study was to explore the parental experiences of raising a child without a diagnosis. Method: Qualitative semistructured interviews were conducted with 14 parents recruited through a large Regional Genetics Centre in the United Kingdom. The interview guide was designed to examine issues such as when and why parents started searching for a diagnosis, whether they were still searching, and what psychosocial issues had arisen as a result of not having a diagnosis. Data were analyzed using the Grounded Theory method. Results: The parental experience can be viewed as a journey, which comprises of two distinct components: the inner, emotional experience, and the outer, sociological experience. Issues that comprise the emotional journey include the realization that there is a problem, the experience of testing, reasons for wanting a diagnosis, the emotional impact, and active coping mechanisms. Social issues include the experience with professionals, the various support networks accessed by ...
60 citations
TL;DR: It is proposed that carriers of ABCC6 loss-of-function mutations benefit from CAD prevention therapy, after a significant association of carrier status and CAD was observed.
Abstract: Loss-of-function mutations of ABCC6 cause pseudoxanthoma elasticum (PXE). This Mendelian disorder is characterized by elastic calcification leading to dermal, ocular, and cardiovascular symptoms like coronary artery disease (CAD) and stroke. Although PXE is a recessive disease, microscopic dermal lesions, serum alterations, and higher anecdotal incidence of stroke or CAD among carriers were reported. Here we investigated the association of the c.3421C>T loss-of-function mutation of ABCC6 and CAD and stroke. A previous study demonstrated the association of the c.3421C>T mutation with CAD; however, the frequency found in the control population was unexpectedly high, contradicting, thus, the prevalence of PXE. In the present study, genomic DNA from 749 healthy blood donors was used as control, while 363 and 361 patients suffering from stroke and CAD were investigated, respectively. One carrier was found in our control group, which is in accordance with the reported prevalence of this mutation. No significant...
55 citations
TL;DR: This clinical case series suggests that approximately half of clinical geneticists who saw patients after DTC-GT judged that testing was clinically useful, especially the BRCA1/2 testing.
Abstract: Background: Direct-to-consumer genetic testing (DTC-GT) provides personalized genetic risk information directly to consumers. Little is known about how and why consumers then communicate the results of this testing to health-care professionals. Aim: To query specialists in clinical genetics about their experience with individuals who consulted them after DTC-GT. Methods: Invitations to participate in a questionnaire were sent to three different groups of genetic professionals, totaling 4047 invitations, asking questions about individuals who consulted them after DTC-GT. For each case reported, respondents were asked to describe how the case was referred to them, the patient's rationale for DTC-GT, and the type of DTC-GT performed. Respondents were also queried about the consequences of the consultations in terms of additional testing ordered. The costs associated with each consultation were estimated. A clinical case series was compiled based upon clinician responses. Results: The invitation resulted in 1...
54 citations
TL;DR: The spectrum of mutations associated with cardiac septal defects is expanded and two novel putative mutations identified in five patients with atrial or ventricular septals that were not seen in control subjects do not support GATA4 mutations as a common cause of CHD.
Abstract: Congenital heart disease (CHD) represents one of the most common birth defects, but the genetic causes remain largely unknown. Mutations in GATA4, encoding a zinc finger transcription factor with a pivotal role in heart development, have been associated with CHD in several familial cases and a small subset of sporadic patients. To estimate the pathogenetic role of GATA4 in CHD, we screened for mutations in 357 unrelated patients with different congenital heart malformations. In addition to nine synonymous changes, we identified two known (A411V and D425N) and two novel putative mutations (G69D and P163R) in five patients with atrial or ventricular septal defects that were not seen in control subjects. The four mutations did not show altered GATA4 transcriptional activity in synergy with the transcription factors NKX2-5 and TBX20. Our data expand the spectrum of mutations associated with cardiac septal defects but do not support GATA4 mutations as a common cause of CHD.
51 citations
TL;DR: The carriers of the variant genotype of OGG1 did not associate with the increased risk of cancer progression, despite the increased oxidative stress in cancer patients, and serum albumin concentrations of cancer patients were significantly lower than those of the controls.
Abstract: The contribution of polymorphisms of DNA repair genes OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln in developing colorectal carcinoma is controversial. Whether the group 1A carcinogen Helicobacter pylori is a risk factor or not in these patients could not be clearly elucidated. One hundred ten colorectal cancer patients and 116 cancer-free individuals constituted the test and control groups, respectively. The association of OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln polymorphisms and the susceptibility to colorectal carcinoma with or without oxidative stress were evaluated. DNA was extracted from peripheral blood cells and genotypes were determined using polymerase chain reaction–restriction fragment length polymorphism. For serum nitric oxide and total antioxidant status assay, spectrophotometric analyses were used. Serum albumin measurements were performed using an autoanalyzer. H. pylori IgG was measured by ELISA. The serum albumin concentrations of cancer patients were significantly lower th...
49 citations
TL;DR: This cohort represents the largest CHARGE syndrome sample size to date and is intended to serve as a resource for clinicians, genetic counselors, researchers, and other diagnostic laboratories.
Abstract: CHARGE syndrome is an autosomal dominant multisystem disorder caused by mutation in the CHD7 gene, encoding chromodomain helicase DNA-binding protein 7. Molecular diagnostic testing for CHD7 mutation has been available in a clinical setting since 2005. We report here the results from the first 642 unrelated proband samples submitted for testing. Thirty-two percent (n = 203) of patient samples had a heterozygous pathogenic variant identified. The lower mutation rate than that published for well-characterized clinical samples is likely due to referral bias, as samples submitted for clinical testing may be for "rule-out" diagnoses, rather than solely to confirm clinical suspicion. We identified 159 unique pathogenic mutations, and of these, 134 mutations were each seen in a single individual and 25 mutations were found in two to five individuals (n =69). Of the 203 mutations, only 9 were missense, with 107 nonsense, 69 frameshift, and 15 splice-site mutations likely leading to haploinsufficiency at the cellular level. An additional 72 variations identified in the 642 tested samples (11%) were considered to have unknown clinical significance. Copy number changes (deletion/duplication of the entire gene or one/several exons) were found to account for a very small number of cases (n = 3). This cohort represents the largest CHARGE syndrome sample size to date and is intended to serve as a resource for clinicians, genetic counselors, researchers, and other diagnostic laboratories.
47 citations
TL;DR: The first study on the association of GST polymorphisms and aerodigestive tract cancers in the high-risk region of NE India found tobacco smoking and betel quid chewing were found to be high risk factors for oral and lung cancers but not for gastric cancer, whereas tobacco chewing was finding to be a risk factor for oral cancer but notFor gastric or lung cancer.
Abstract: Background: Widespread use of tobacco and betel quid consumption and a high incidence of tobacco-associated aerodigestive tract cancers have been reported in different ethnic groups from several regions of Northeast (NE) India. This study was done to explore the possibility of phase II metabolic enzymes being responsible for the high prevalence of cancers in this region of India. Methods: Samples from 370 cases with oral, gastric, and lung cancers and 270 controls were analyzed for polymorphism of glutathione-S-transferase (GST) genes using polymerase chain reaction–restriction fragment length polymorphism-based methods. Results and Conclusions: Tobacco smoking and betel quid chewing were found to be high risk factors for oral and lung cancers but not for gastric cancer, whereas tobacco chewing was found to be a risk factor for oral cancer but not for gastric or lung cancer. The variant genotypes of GSTP1 were not associated with any of the aerodigestive tract cancers. GSTT1 and GSTM1 null genotypes appea...
44 citations
TL;DR: Severe to profound sensorineural hearing loss was observed in all subjects with homozygous mutations except for two members of a family who were homozygously for the p.Y289X mutation in the N-terminal extension domain and had considerable residual hearing.
Abstract: The identities and frequencies of MYO15A mutations associated with hearing loss in different populations remained largely unknown. We screened the MYO15A gene for mutations in 104 unrelated multiplex and consanguineous Turkish families with autosomal recessive nonsyndromic sensorineural hearing loss using autozygosity mapping. The screening of MYO15A in 10 families mapped to the DFNB3 locus revealed five previously unreported mutations: p.Y289X (1 family), p.V1400M (1 family), p.S1481P (1 family), p.R1937TfsX10 (3 families), and p.S3335AfsX121 (2 families). Recurrent mutations were associated with conserved haplotypes suggesting the presence of founder effects. Severe to profound sensorineural hearing loss was observed in all subjects with homozygous mutations except for two members of a family who were homozygous for the p.Y289X mutation in the N-terminal extension domain and had considerable residual hearing. We estimate the prevalence of homozygous MYO15A mutations in autosomal recessive nonsyndromic deafness in Turkey as 0.062 (95% confidence interval is 0.020-0.105).
42 citations
TL;DR: The p.R34X mutation is the most frequent known mutation in the transmembrane channel-like gene 1 (TMC1) and is indicated in the genetic evaluation of persons with ARNSHL from North African and Southwest Asia.
Abstract: Founder mutations, particularly 35delG in the GJB2 gene, have to a large extent contributed to the high frequency of autosomal recessive nonsyndromic hearing loss (ARNSHL). Mutations in transmembrane channel-like gene 1 (TMC1) cause ARNSHL. The p.R34X mutation is the most frequent known mutation in the TMC1 gene. To study the origin of this mutation and determine whether it arose in a common ancestor, we analyzed 21 polymorphic markers spanning the TMC1 gene in 11 unrelated individuals from Algeria, Iran, Iraq, Lebanon, Pakistan, Tunisia, and Turkey who carry this mutation. In nine individuals, we observed significant linkage disequilibrium between p.R34X and five polymorphic markers within a 220 kb interval, suggesting that p.R34X arose from a common founder. We estimated the age of this mutation to be between 1075 and 1900 years, perhaps spreading along the third Hadramaout population movements during the seventh century. A second founder effect was observed in Turkish and Lebanese individuals with mark...
TL;DR: The HLA-DQA1 and AB0 allele frequencies were used to estimate forensic population parameters for these loci, and data were used in comparative studies to determine predisposition to tuberculosis, lymphoma, and leukemia in adults and to childhood acute leukemia.
Abstract: Xenobiotic-metabolizing genes (eg, Cytochromes P450, GST, NAT2, and NQO1), folate metabolism genes (eg, MTHFR and MTRR), and major histocompatibility complex genes (eg, HLA-DQA1) play multiple roles in the organism functioning In addition, AB0 is the most clinically significant high-polymorphic gene in transfusion and transplantation medicine Epidemiological data show that allele frequencies of these genes exhibit ethnic and geographic diversity Besides, little is known about frequency distribution of the major polymorphic variants in native Russians We developed biological microchips that allow us to analyze a spectrum of allelic variants in 12 different genes: CYP1A1, CYP2D6, CYP2C9, CYP2C19, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0 Using this composite methodological platform we have studied 352 DNA samples from healthy native Russian volunteers The allelic frequencies of gene polymorphisms obtained are close to allelic frequencies observed in some European populations, as p
TL;DR: An online survey of corresponding authors of genetic/genomic studies conducted in the United States and published in 2006-2007 found that issues associated with clinical validity and respect for participants dominated concerns of time and expense.
Abstract: Background/Aims: As genetic and genomic research proliferates, debate has ensued about returning results to participants. In addition to consideration of the benefits and harms to participants, researchers must also consider the logistical and financial feasibility of returning research results. However, little data exist of actual researcher practices. Methods: We conducted an online survey of 446 corresponding authors of genetic/genomic studies conducted in the United States and published in 2006–2007 to assess the frequency with which they considered, offered to, or actually returned research results, what factors influenced these decisions, and the method of communicating results. Results: The response rate was 24% (105/446). Fifty-four percent of respondents considered the issue of returning research results to participants, 28% offered to return individual research results, and 24% actually returned individual research results. Of those who considered the issue of returning research results during the study planning phase, the most common factors considered were whether research results were deemed clinically useful (18%) and respect for participants (13%). Researchers who had a medical degree and conducted studies on children were significantly more likely to offer to return or actually return individual results compared to those with a Ph.D. only. Conclusions: We speculate that issues associated with clinical validity and respect for participants dominated concerns of time and expense given the prominent and continuing ethical debates surrounding genetics and genomics research. The substantial number of researchers who did not consider returning research results suggests that researchers and institutional review boards need to devote more attention to a topic about which research participants are interested.
TL;DR: Patients with NS and a PTPN11 mutation presented significantly higher prevalence of short stature and pulmonary valve stenosis, and lower prevalence of hypertrophic cardiomyopathy, while no statistically significant difference was observed among the frequency of clinical findings regarding the studied polymorphisms.
Abstract: Noonan and Noonan-like syndromes are disorders of dysregulation of the rat sarcoma viral oncogene homolog (RAS)–mitogen-activated protein kinase signaling pathway. In Noonan syndrome (NS), four genes of this pathway (PTPN11, SOS1, RAF1, and KRAS) are responsible for roughly 70% of the cases. We analyzed PTPN11 and KRAS genes by bidirectional sequencing in 95 probands with NS and 29 with Noonan-like syndromes, including previously reported patients already screened for PTPN11 gene mutations. In the new patients with NS, 20/46 (43%) showed a PTPN11 gene mutation, two of them novel. In our total cohort, patients with NS and a PTPN11 mutation presented significantly higher prevalence of short stature (p = 0.03) and pulmonary valve stenosis (p = 0.01), and lower prevalence of hypertrophic cardiomyopathy (p = 0.01). Only a single gene alteration, of uncertain role, was found in the KRAS gene in an NS patient also presenting a PTPN11 gene mutation. We further analyzed the influence in clinical variability of thr...
TL;DR: It is indicated that the risk of MI was notably high in 4G and -844A carriers with elevated plasma PAI-1 and were associated with reduced tPA levels.
Abstract: Background: Myocardial infarction (MI) is induced by acquired and inherited risk factors, including the plasminogen activator inhibitor-1 (PAI-1) -844G/A and -675G/A (4G/5G) gene variants. Objective: The aim of this study was to investigate the association between PAI-1-844G/A and 4G/5G polymorphisms and changes in PAI-1 and tissue plasminogen activator (tPA) levels in MI in a Tunisian population. Methods: This was a case–control study involving 305 patients with MI and 328 unrelated healthy controls. PAI-1 genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (RFLP) (-844G/A) or by polymerase chain reaction-allele specific amplification. PAI-1 and tPA levels were assayed by serological assays. Results: In contrast to tPA levels, mean plasma PAI-1 antigen levels were higher in cases than in control subjects. The elevation in PAI-1 levels was more pronounced in -844A and 4G allele carriers. Significantly higher frequencies of (mutant) 4G and -844A alleles and 4G/4G and -...
TL;DR: The analysis led to the conclusion that CHEK2, STK11, and PALB2 mutations or large genomic rearrangements of either STK 11 or PALB 2 are rare, and do not contribute to a substantial fraction of breast cancer susceptibility in high-risk French Canadian breast cancer families.
Abstract: Inactivating mutations of the CHEK2 and STK11 genes are responsible for Li–Fraumeni and Peutz–Jeghers syndrome, respectively, both autosomal dominant syndromes associated with an increased risk of breast cancer. The PALB2/FANCN gene encodes a nuclear partner of BRCA2 and acts as a linker between BRCA1 and BRCA2. Monoallelic PALB2 truncating mutations were shown to confer higher risk of breast cancer. To evaluate the proportion of French Canadian non-BRCA1/BRCA2 families with high risk of breast cancer potentially harboring alterations in these three breast cancer susceptibility genes, the whole coding and flanking intronic sequences were analyzed in a series of 96 high-risk breast cancer individuals. Despite no PALB2 deleterious truncating mutations being identified, the c.1100delC breast-cancer-associated CHEK2 mutation and a STK11 mutation reported to be the causative mutation in a Peutz–Jeghers family were identified. This extensive analysis also led to the identification of several variants in these g...
TL;DR: It is found that there is no evidence suggesting that the CLCN2 gene is involved in MLC, and mice lacking this protein develop white matter abnormalities, which are characterized by vacuole formation in the myelin sheaths, strikingly similar to the intramyelinic vacuoles in M LC.
Abstract: Mutations in the gene MLC1 are found in approximately 80% of the patients with the inherited childhood white matter disorder megalencephalic leukoencephalopathy with subcortical cysts (MLC). Genetic linkage studies have not led to the identification of another disease gene. We questioned whether mutations in CLCN2, coding for the chloride channel protein 2 (ClC-2), are involved in MLC. Mice lacking this protein develop white matter abnormalities, which are characterized by vacuole formation in the myelin sheaths, strikingly similar to the intramyelinic vacuoles in MLC. Sequence analysis of CLCN2 at genomic DNA and cDNA levels in 18 MLC patients without MLC1 mutations revealed some nucleotide changes, but they were predicted to be nonpathogenic. Further, in electrophysiological experiments, one of the observed amino acid changes was shown to have no effect on the ClC-2-mediated currents. In conclusion, we found no evidence suggesting that the CLCN2 gene is involved in MLC.
TL;DR: In this article, the authors identify new candidate genes and molecular pathways involved in the pathogenesis and progression of colorectal cancer, as compared with sporadic CRC, and propose that similar genetic polymorphisms and mutations among regulatory genes of the actin-cytoskeleton pathway may also be associated with increased dysplasia, carcinogenesis, and susceptibility for invasion and metastasis in IBD-associated CRC.
Abstract: Introduction To improve our understanding of the various clinical phenotypes in inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) and provide potential targets for early diagnosis and future therapy, we sought to identify new candidate genes and molecular pathways involved in the pathogenesis and progression of this disorder. Recent evidence has implicated the actin-cytoskeleton pathway in the development of metastatic sporadic CRC through cytoskeletal proteins such as fascin-1. We hereby propose that similar genetic polymorphisms and mutations among regulatory genes of the actin-cytoskeleton pathway may also be associated with increased dysplasia, carcinogenesis, and susceptibility for invasion and metastasis in IBD-associated CRC, as compared with sporadic CRC. Materials and methods To test this hypothesis, we identified three patients with IBD-associated CRC. We subsequently retrieved normal, dysplastic, and cancerous tissue from within the same surgical colonic specimen. Messenger RNA was subsequently isolated from fresh frozen tissue, and oligonucleotide arrays were carried out to identify genes that were differentially expressed between the three various tissue types (normal, dysplasia, and cancer). By utilizing the same specimen to obtain each of the three various tissue types, we excluded intersubject variability during the analysis. Finally, we performed bioinformatic interaction pathway analysis using the "Ingenuity Pathway Analysis" software. Results Computerized pathway analysis revealed that the actin-cytoskeleton pathway was significantly dysregulated in the progression of normal cells, via dysplasia, to IBD-associated CRC (p Conclusion Via the dysregulation of these five genes within the actin-cytoskeleton pathway, we propose that this molecular pathway provides a potential mechanism for the malignant transformation and progression of normal tissue, via dysplasia, to IBD-associated CRC.
TL;DR: The mutation spectrum in the patients with Azeri Turkish ethnic origin differed from that observed in patients from other Mediterranean countries and further defined the molecular heterogeneity of this disease.
Abstract: Aim: Phenylalanine hydroxylase (PAH) deficiency is caused by mutations in the PAH gene resulting in a primary deficiency of the PAH enzyme activity, intolerance to the dietary intake of phenylalanine (Phe), and production of the phenylketonuria disease. To date there have been no reports on the molecular analysis of phenylketonuria in the Iranian Azeri Turkish population. In this study, a total of 88 independent alleles from this ethnic group were investigated. Results: Thirteen different mutations have been detected, which account for 75% of the total mutant alleles. Two mutations were found at high frequencies: IVS10-11G>A (19.3%) and P281L (19.3%), possibly due to consanguinity and genetic drift, among other factors. The frequencies of the other mutations were c.590_612del (5.7%), R261Q (5.7%), R261X (4.5%), R243X (4.5%), IVS2+5G>C (3.4%), IVS4+1G>A (3.4%), R158Q (2.3%), E280K (2.3%), G247D (2.3%), IVS11+1G>C (1.1%), and R270K (1.1%). Conclusions: These intriguing preliminary findings confirm IVS10-11G...
TL;DR: This study provides important information about characteristics associated with lower levels of knowledge and specific areas related to HBOC where additional education may be warranted in the Hispanic community.
Abstract: Purpose: To examine knowledge about hereditary breast and ovarian cancer (HBOC) among Mexican, Puerto Rican, and Cuban women. Methods: Women (age range, 18–65 years) with a personal or family history of breast or ovarian cancer were recruited to a mixed methods study using community-based approaches. Fifty-three women participated in the study: 16 Mexicans, 20 Puerto Ricans, and 17 Cubans. The majority of women (64.2%) were born outside the United States. All questions were interviewer administered in Spanish or English. HBOC knowledge was measured using an 11-item instrument developed by the National Center for Human Genome Research. We evaluated whether differences in knowledge varied as a function of Hispanic subethnicity, demographic characteristics, and medical and acculturation characteristics using a series of one-way analysis of variances. Results: The percentage of correct responses on the knowledge instrument ranged from 9.4% to 73.6% (median number of correct responses = 45%). Knowledge did not...
TL;DR: Considering that hCLP46 has the capability of modifying the Notch pathway, this finding adds weight to the importance of Notch signaling in hematopoiesis and suggests that overexpression of hClP46 might be an early event in the pathogenesis of AML and T-ALL.
Abstract: Aims: We earlier identified a novel gene human CAP10-like protein 46 KD (hCLP46) from human acute myelogenous leukemia (AML) transformed from myelodysplastic syndrome CD34+ cells, but the function of this gene remains unclear. In this study, a real-time polymerase chain reaction-based assay was developed to quantify expression of hCLP46 in the peripheral blood of AML and T-acute lymphoblastic leukemia (T-ALL) primary samples and in six leukemic cell lines. Also, we investigated expression of CDKN2A/B and the apoptosis in U937 cells when hCLP46 is downregulated in vitro. Results: Our findings showed that hCLP46 was overexpressed in AML, T-ALL, and the leukemic cell lines. Suppressing hCLP46 overexpression had no effect on expression of CDKN2A/B and apoptosis of U937 cells. Conclusion: Considering that hCLP46 has the capability of modifying the Notch pathway, our finding adds weight to the importance of Notch signaling in hematopoiesis and suggests that overexpression of hCLP46 might be an early event in th...
TL;DR: Evidence is provided diagnosing that the Leu/Leu genotype of EXO1 showed an inverse association with CRC, which is a major role in mismatch repair, DNA replication, and recombination.
Abstract: Background and Aim: One candidate gene for colorectal cancer (CRC) susceptibility is exonuclease 1 (EXO1). It is a member of RAD2 nuclease family, which plays a major role in mismatch repair, DNA replication, and recombination. Single-nucleotide polymorphisms are shown to be related with cancer incidence. The aim of the present study was to examine the association between the L757P polymorphism at exon 13 of the EXO1 gene and the risk of CRC in Iranian patients. Methods: In this case–control study, 90 cases and 98 healthy control samples were analyzed genetically. The EXO1 polymorphism, P757L, was analyzed by polymerase chain reaction–restriction fragment length polymorphism. The obtained polymorphisms were examined for the relationship with CRC risk and also clinicopathological characteristics. Results: Our findings showed that patients with the Leu/Leu genotype have a reduced risk of CRC (adjusted odds ratio [OR] = 0.192, 95% confidence interval [CI]: 0.040–0.921) when the Pro/Leu and Pro/Pro genotypes ...
TL;DR: It is reported for the first time that differential methylation of imprinted regions can lead to preferential amplification of unmethylated alleles, providing an accurate genotyping in cases with methylation-related diseases.
Abstract: Introduction: We detected false homozygosity at the NESP55 differentially methylated region of the imprinted GNAS locus while analyzing the segregation of single-nucleotide polymorphisms (SNPs) in ...
TL;DR: The data indicate that the FMF carrier rate and E148Q mutation frequency are high in the Iranian Azeri Turkish population.
Abstract: Familial Mediterranean fever (FMF) is an autosomal recessive disorder primarily affecting the Mediterranean populations. It is characterized by recurrent attacks of fever and inflammation of serosal membranes and gradual development of nephropathic amyloidosis. More than 70 disease-associated mutations have been identified in the Mediterranean fever gene (MEFV) responsible for FMF. The aim of this study was to determine the mutation carrier rate in the Iranian Azeri Turkish population. A cohort of 200 unrelated healthy individuals was screened for the five most common MEFV mutations (M694V, V726A, M680I, M694I, and E148Q) using the amplification refractory mutation system for the first four and by polymerase chain reaction–restriction-digestion testing for E148Q. Genotyping revealed that the carrier rate in the Azeri Turkish population was 25.5%, with E148Q being the most common mutation (11.5%) followed by V726A (1.75%). The remaining common mutations were not found in this cohort. Our data indicate that...
TL;DR: ACE DD genotype associated with higher serum ACE activity is increased in the studied population and might be clinically useful as markers to assess risk for AMI.
Abstract: Introduction: The role of the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) on acute myocardial infarction (AMI) is controversial. Objectives: To assess the effect of the ACE I/D polymorphism on AMI compared with the healthy controls and its relationship with serum ACE activity in a Tunisian population. Design and Methods: A total of 119 patients with AMI were compared with 238 healthy controls from the same geographical area. ACE genotyping was determined by polymerase chain reaction, and serum ACE activity was measured with N-[3-(2-furylacryloyl]-L-phenylalanyl-L-glycyl-L-glycine as substrate. Results: The ACE I/D polymorphism was significantly different between patients and controls (p < 0.0001). The frequencies of the DD genotype and the D allele were statistically higher in patients with AMI as compared with the controls and were associated with increased risk of AMI (DD vs. ID and II: odds ratio = 4.27, p < 0.0001, 95% confidence interval = 2.65–6.86; D vs. I:...
TL;DR: The assessment of time perspective in individuals at increased risk of cancer can provide valuable clinical insights and further investigation of the psychometric properties of the short form of this scale is warranted, as it did not meet the currently accepted criteria for psychometric validation studies.
Abstract: Aims: We aimed to assess the psychometric properties of a 25-item short form of the Zimbardo Time Perspective Inventory in a community sample (N = 276) and in individuals with a strong family history of cancer, considering genetic testing for cancer risk (N = 338). Results: In the community sample, individuals with high past-negative or present-fatalistic scores had higher levels of distress, as measured by depression, anxiety, and aggression. Similarly, in the patient sample, past-negative time perspective was positively correlated with distress, uncertainty, and postdecision regret when making a decision about genetic testing. Past-negative–oriented individuals were also more likely to be undecided about, or against, genetic testing. Hedonism was associated with being less likely to read the educational materials they received at their clinic, and fatalism was associated with having lower knowledge levels about genetic testing. Conclusions: The assessment of time perspective in individuals at increased ...
TL;DR: Familiarity of individual mutations showed some differences from those in other Mediterranean populations, and a wide spectrum of MEFV mutations in Egyptian patients in whom FMF was diagnosed was identified.
Abstract: Background: Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever and serositis. The disease affects mainly Mediterranean populations and is caused by mutations in the MEFV gene. Aim: This work was carried out to identify and determine the frequencies of MEFV gene mutations in Egyptian patients in whom FMF was diagnosed. Methods: We investigated 316 patients with a clinical diagnosis of FMF for 12 MEFV mutations including the 5 most common known mutations M694V, V726A, M694I, M680I, and E148Q by allele-specific hybridization. Results: Mutations were detected in 182 (57.6%) patients: 20 were homozygous, 80 were compound heterozygous, and 82 had only one identifiable mutant allele. In patients with clinically definite FMF (n = 112), no mutations were detected in 28 patients; whereas in patients with clinically unlikely FMF (n = 48), genetic analysis established the diagnosis in 6 patients. Overall, 10 mutations were detected in our patients. The mo...
TL;DR: Empirically targeted genetic screening for GJB2 mutations could be a useful tool toward the management of NSHL in this area, reflecting the genetic heterogeneity of the western area of the Kingdom of Saudi Arabia.
Abstract: Nonsyndromic hearing loss (NSHL) affects a substantial proportion of newborns in the world every year. This proportion increases proportionally with the degree of consanguineous marriages in any society. In the Kingdom of Saudi Arabia, consanguineous marriages are common practice and this is associated with a noticeably high frequency of inherited conditions affecting the resulting progeny, including NSHL. Until now there is no published data on the genetic causes of NSHL in Saudi Arabia, which greatly hindered the ability of local genetic counseling and family planning centers to distinguish between hereditary and nonhereditary forms of NSHL and subsequently could not give information on the possible inheritance of deafness. In addition, the lack of validated genetic tests for NSHL delayed the detection of deafness in affected individuals and may have lowered the efficiency of later medical interventions. Further, the population covered in this study is likely to have a multiethnic background caused by decades of religious and economic migration to this region. To address such problems, we undertook the task of unraveling the genetic causes of hearing loss in Saudi Arabia, starting with identifying the GJB2/DFNB1 mutation spectrum in a cohort of unrelated individuals suffering from mild to profound NSHL. A total of 12 reported GJB2 mutations were identified in 17 out of 109 (15.59%) NSHL cases. Biallelic GJB2 mutations were identified in 11 out of the 109 NSHL cases (10.09%), with c.35delG being the most common (7/11, 63.63%). The remaining six patients were found to have monoallelic GJB2 mutations. Interestingly, biallelic GJB2 mutations were not detected in patients of Arab tribal origins, reflecting the genetic heterogeneity of the western area of the Kingdom of Saudi Arabia. Therefore, ethnically targeted genetic screening for GJB2 mutations could be a useful tool toward the management of NSHL in this area.
TL;DR: A developed sense of spirituality is identified as a personal resource associated with the perception of benefit from genetic testing for HD, which may be useful in genetic counseling and health care of people with prodromal HD.
Abstract: Aims: A family history of Huntington disease (HD) or receiving results of HD predictive genetic testing can influence individual well-being, family relationships, and social interactions in positive and negative ways. The aim of this study was to examine benefits reported by people with an HD family history or those who have undergone predictive HD testing, as well as the personal variables associated with perceived benefits. Methods: Seventy-four of 433 people completing the International Response of a Sample Population to HD risk (I-RESPOND-HD) survey reported benefits. Knowledge and understanding was perceived as the most common benefit from participants in both groups. The next most frequent perceived benefits from a family history were connecting with others and achieving life meaning and insights. The next most common perceived benefits from genetic testing were life planning and social support. The least common perceived benefit for both groups was renewed hope and optimism. Older age and spiritual...
TL;DR: ACGH analysis accurately identified all chromosomal abnormalities in CVS from pregnancy loss, suggesting that it is suitable in the clinical setting for prenatal diagnosis.
Abstract: Objective: The aim of this study was to evaluate the use of array comparative genomic hybridization (aCGH) for genetic analysis of chorionic villus sampling (CVS) from pregnancy loss. aCGH results were compared with results from karyotyping and multiplex ligation-dependent probe amplification (MLPA) analysis to assess the suitability of aCGH as a method for detecting a variety of known chromosomal abnormalities. It was determined which technique gave the most valuable information. Method: Twenty anonymised samples from CVS were analyzed by aCGH, MLPA, and karyotyping. Results: Ten cases were identified as normal by all three methods. Aneuploidy was detected in four cases by all three methods. Partial deletion and duplication was detected in two cases by aCGH and karyotyping but missed by MLPA. In addition, mosaicism was detected by aCGH in 3 of 20 cases missed by MLPA and karyotyping. Conclusion: aCGH is a rapid, automated, reliable, high-resolution technique to diagnose unbalanced chromosomal abnormaliti...