Keywords Disease name and synonyms Background-definition Prevalence and epidemiology Etiology and... more Keywords Disease name and synonyms Background-definition Prevalence and epidemiology Etiology and biological significance of antisynthetase antibodies Clinical picture Differential diagnosis Laboratory evaluation Prognosis and treatment References Abstract X-linked dominant chondrodysplasia punctata, (CDPX2 - MIM 302960) also known as Conradi- Hünermann-Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton producing short stature, asymmetric shortening of the limbs
Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2)... more Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. To identify mutation-specific cancer risks for carriers of BRCA1/2. Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Mutations of BRCA1 or BRCA2. Breast and ovarian cancer risks. Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian c...
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme, 2014
This study analyses new information on gene mutations in paragangliomas and puts them into a clin... more This study analyses new information on gene mutations in paragangliomas and puts them into a clinical context. A suspicion of malignancy is critical to determine the workup and surgical approach in adrenal (A-PGL) and extra-adrenal (E-PGL) paragangliomas (PGLs). Malignancy rates vary with location, family history, and gene tests results. Currently there is no algorithm incorporating the above information for clinical use. A sum of 1,821 articles were retrieved from PubMed using the search terms "paraganglioma genetics". Thirty-seven articles were selected of which 9 were analyzed. It was found that 599/2,487 (24%) patients affected with paragangliomas had a germline mutation. Of these 30.2% were mutations in SDHB, 25% VHL, 19.4% RET, 18.4% SDHD, 5.0% NF1, and 2.0% SDHC genes. A family history was positive in 18.1-64.3% of patients. Adrenal PGLs accounted for 55.1% in mutation (+) and 81.0% in mutation (-) patients (RR 1.2, p < 0.0001). Bilateral A-PGLs accounted for 56....
ABSTRACT Direct nucleotide sequencing is the reference standard critical to all molecular biology... more ABSTRACT Direct nucleotide sequencing is the reference standard critical to all molecular biology whether it is used for the elucidation of an entire genome or the characterization of a specific mutation. Sequencing protocols were initially developed using either dideoxy nucleotides (1) or chemicals (2), although the latter became less attractive because of the toxic nature of the chemicals used. It is obvious that if sequencing was less expensive, then there would be no need for mutation-scanning techniques. However, although fluorescent technology is improving and capillary electrophoresis is replacing polyacrylamide gel electrophoresis, the cost of consumables is rising and laboratories are, therefore, forced to use other techniques to detect mutations. Mutation-scanning techniques need to detect new mutations within the entire coding region of a gene and there are several methods available to scan for sequence changes in either cellular RNA or genomic DNA. These include denaturing gradient gel electrophoresis (DGGE) (3) (see Chapter 8), chemical cleavage of mismatch (CCM) (4), enzyme mismatch cleavage (EMC) (5,6), single-stranded conformation polymorphism (SSCP) (see Chapter 7) (CR7), heteroduplex analysis (HA) (8), conformation-sensitive gel electrophoresis (CSGE) (9), the protein truncation test (PTT) (10); and, more recently, denaturing high-performance liquid chromatography (DHPLC) (11,CR12) (see Chapter24). The most critical factor that determines the success of any gene screening protocol is the sensitivity of the detection technique. The sensitivities of these methods vary greatly depending on the size of DNA/RNA template screened. For example, SSCP has a sensitivity of &gt;95‰ for fragments of 155 bp, but this is reduced to only 3‰ for 600 bp (13). Once optimised, DGGE has a sensitivity of approx 99‰ for fragments of up to 500 bp (14), and CSGE has a sensitivity of 90–100‰ for fragments of up to 450 bp (15). CCM and EMC, on the other hand, have sensitivities of 95–100‰ for fragments &gt;1.5 kb in size ( 16,17) and are ideal for screening compact genes where more than one exon can be amplified together using genomic DNA as the template. All of these techniques detect sequence changes such as nonsense, frame shift, splice site, and missense mutations, as well as polymorphisms, however, the PTT screens only for truncating mutations and is predicted to have a sensitivity of &gt;95‰ and can be used for RNA or DNA fragments in excess of 3 kb.
BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and o... more BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
It is frequent for news items to lead to a short lived temporary increase in interest in a partic... more It is frequent for news items to lead to a short lived temporary increase in interest in a particular health related service, however it is rare for this to have a long lasting effect. In 2013, in the UK in particular, there has been unprecedented publicity in hereditary breast cancer, with Angelina Jolie's decision to have genetic testing for the BRCA1 gene and subsequently undergo risk reducing mastectomy (RRM), and a pre-release of the NICE guidelines on familial breast cancer in January and their final release on 26th June. The release of NICE guidelines created a lot of publicity over the potential for use of chemoprevention using tamoxifen or raloxifene. However, the longest lasting news story was the release of details of film actress Angelina Jolie's genetic test and surgery. To assess the potential effects of the 'Angelina Jolie' effect, referral data specific to breast cancer family history was obtained from around the UK for the years 2012 and 2013. A cons...
X-linked dominant chondrodysplasia punctata, (CDPX2-MIM302960) also known as Conradi-Hünermann-Ha... more X-linked dominant chondrodysplasia punctata, (CDPX2-MIM302960) also known as Conradi-Hünermann-Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton, skin, hair, and eyes. The disorder is caused by mutations within the emopamil binding protein (Ebp) that functions as a delta(8), delta(7) sterol isomerase in the cholesterol biosynthesis pathway. To date, over 40 separate mutations have been reported in the Ebp gene, EBP, with no obvious correlation between the molecular defects and the severity of the clinical phenotype. We have studied a 30-year-old woman who presented in adulthood with skin, hair, and mild skeletal defects but no ocular abnormalities and have identified a heterozygous missense mutation within the third transmembrane domain of the protein. In addition, we have performed molecular prenatal testing on her unborn fetus. The results demonstrate inter-familial variability for missense mutations within the emopamil binding protein and add to the molecular data for CDPX2.
Copyright Public Library of Science. This is an open-access article distributed under the terms o... more Copyright Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. The... more Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. They report three loci newly associated with colorectal cancer, bringing the total number of common susceptibility loci to 20.
Keywords Disease name and synonyms Background-definition Prevalence and epidemiology Etiology and... more Keywords Disease name and synonyms Background-definition Prevalence and epidemiology Etiology and biological significance of antisynthetase antibodies Clinical picture Differential diagnosis Laboratory evaluation Prognosis and treatment References Abstract X-linked dominant chondrodysplasia punctata, (CDPX2 - MIM 302960) also known as Conradi- Hünermann-Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton producing short stature, asymmetric shortening of the limbs
Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2)... more Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. To identify mutation-specific cancer risks for carriers of BRCA1/2. Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Mutations of BRCA1 or BRCA2. Breast and ovarian cancer risks. Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian c...
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme, 2014
This study analyses new information on gene mutations in paragangliomas and puts them into a clin... more This study analyses new information on gene mutations in paragangliomas and puts them into a clinical context. A suspicion of malignancy is critical to determine the workup and surgical approach in adrenal (A-PGL) and extra-adrenal (E-PGL) paragangliomas (PGLs). Malignancy rates vary with location, family history, and gene tests results. Currently there is no algorithm incorporating the above information for clinical use. A sum of 1,821 articles were retrieved from PubMed using the search terms "paraganglioma genetics". Thirty-seven articles were selected of which 9 were analyzed. It was found that 599/2,487 (24%) patients affected with paragangliomas had a germline mutation. Of these 30.2% were mutations in SDHB, 25% VHL, 19.4% RET, 18.4% SDHD, 5.0% NF1, and 2.0% SDHC genes. A family history was positive in 18.1-64.3% of patients. Adrenal PGLs accounted for 55.1% in mutation (+) and 81.0% in mutation (-) patients (RR 1.2, p < 0.0001). Bilateral A-PGLs accounted for 56....
ABSTRACT Direct nucleotide sequencing is the reference standard critical to all molecular biology... more ABSTRACT Direct nucleotide sequencing is the reference standard critical to all molecular biology whether it is used for the elucidation of an entire genome or the characterization of a specific mutation. Sequencing protocols were initially developed using either dideoxy nucleotides (1) or chemicals (2), although the latter became less attractive because of the toxic nature of the chemicals used. It is obvious that if sequencing was less expensive, then there would be no need for mutation-scanning techniques. However, although fluorescent technology is improving and capillary electrophoresis is replacing polyacrylamide gel electrophoresis, the cost of consumables is rising and laboratories are, therefore, forced to use other techniques to detect mutations. Mutation-scanning techniques need to detect new mutations within the entire coding region of a gene and there are several methods available to scan for sequence changes in either cellular RNA or genomic DNA. These include denaturing gradient gel electrophoresis (DGGE) (3) (see Chapter 8), chemical cleavage of mismatch (CCM) (4), enzyme mismatch cleavage (EMC) (5,6), single-stranded conformation polymorphism (SSCP) (see Chapter 7) (CR7), heteroduplex analysis (HA) (8), conformation-sensitive gel electrophoresis (CSGE) (9), the protein truncation test (PTT) (10); and, more recently, denaturing high-performance liquid chromatography (DHPLC) (11,CR12) (see Chapter24). The most critical factor that determines the success of any gene screening protocol is the sensitivity of the detection technique. The sensitivities of these methods vary greatly depending on the size of DNA/RNA template screened. For example, SSCP has a sensitivity of &gt;95‰ for fragments of 155 bp, but this is reduced to only 3‰ for 600 bp (13). Once optimised, DGGE has a sensitivity of approx 99‰ for fragments of up to 500 bp (14), and CSGE has a sensitivity of 90–100‰ for fragments of up to 450 bp (15). CCM and EMC, on the other hand, have sensitivities of 95–100‰ for fragments &gt;1.5 kb in size ( 16,17) and are ideal for screening compact genes where more than one exon can be amplified together using genomic DNA as the template. All of these techniques detect sequence changes such as nonsense, frame shift, splice site, and missense mutations, as well as polymorphisms, however, the PTT screens only for truncating mutations and is predicted to have a sensitivity of &gt;95‰ and can be used for RNA or DNA fragments in excess of 3 kb.
BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and o... more BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
It is frequent for news items to lead to a short lived temporary increase in interest in a partic... more It is frequent for news items to lead to a short lived temporary increase in interest in a particular health related service, however it is rare for this to have a long lasting effect. In 2013, in the UK in particular, there has been unprecedented publicity in hereditary breast cancer, with Angelina Jolie's decision to have genetic testing for the BRCA1 gene and subsequently undergo risk reducing mastectomy (RRM), and a pre-release of the NICE guidelines on familial breast cancer in January and their final release on 26th June. The release of NICE guidelines created a lot of publicity over the potential for use of chemoprevention using tamoxifen or raloxifene. However, the longest lasting news story was the release of details of film actress Angelina Jolie's genetic test and surgery. To assess the potential effects of the 'Angelina Jolie' effect, referral data specific to breast cancer family history was obtained from around the UK for the years 2012 and 2013. A cons...
X-linked dominant chondrodysplasia punctata, (CDPX2-MIM302960) also known as Conradi-Hünermann-Ha... more X-linked dominant chondrodysplasia punctata, (CDPX2-MIM302960) also known as Conradi-Hünermann-Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton, skin, hair, and eyes. The disorder is caused by mutations within the emopamil binding protein (Ebp) that functions as a delta(8), delta(7) sterol isomerase in the cholesterol biosynthesis pathway. To date, over 40 separate mutations have been reported in the Ebp gene, EBP, with no obvious correlation between the molecular defects and the severity of the clinical phenotype. We have studied a 30-year-old woman who presented in adulthood with skin, hair, and mild skeletal defects but no ocular abnormalities and have identified a heterozygous missense mutation within the third transmembrane domain of the protein. In addition, we have performed molecular prenatal testing on her unborn fetus. The results demonstrate inter-familial variability for missense mutations within the emopamil binding protein and add to the molecular data for CDPX2.
Copyright Public Library of Science. This is an open-access article distributed under the terms o... more Copyright Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. The... more Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. They report three loci newly associated with colorectal cancer, bringing the total number of common susceptibility loci to 20.
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