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Archive for March, 2012

Correlation of tumor BRAF mutations and MLH1 methylation with germline MMR gene mutation status: a literature review assessing utility of tumor features for MMR variant classification

5 Mar, 12 | by hqqu

Lynch Syndrome is a heritable disorder characterized by increased risk of colorectal, endometrial and other cancers. It is caused by mutations in the DNA mismatch repair (MMR) genes. We conducted a literature review of published studies that investigated MMR gene mutation status and two tumor characteristics commonly used to exclude individuals with colorectal cancer from MMR gene mutation testing: BRAF V600E mutation status and MLH1 promoter methylation status. We showed that BRAF mutation status and MLH1 methylation are strong negative predictors of MMR mutation status, but are not definitive. These tumor characteristics should be used in conjunction with other data points in statistical models that predict likely mutation status. (By Dr Amanda B Spurdle, http://jmg.bmj.com/content/49/3/151)

Fabry International Prognostic Index: a predictive severity score for Anderson-Fabry disease

5 Mar, 12 | by hqqu

Anderson Fabry disease is a progressive and debilitating lysosomal storage disorder resulting from a deficiency of a lysosomal enzyme and progressive accumulation of storage material. It affects both males and females and can result in significant pain, bowel symptoms, hearing loss, rash and reduced life expectancy from renal failure, heart disease and stroke. A treatment is available with enzyme replacement therapy however it has previously not been possible to predict which patients may have most problems in the long term. This study has used a large database of Fabry patients to examine the factors which might be able to determine which patients will have cardiac, renal, neurological events. We have developed a simple scoring system based on routinely acquired clinical parameters. These scores have been used to divide patients into different groups with significantly different clinical outcomes. We hope that this will be useful for counselling of patients with respect to their condition, initiation of treatment and stratifying patients for the development of new treatments. (By Dr Derralynn A Hughes, http://jmg.bmj.com/content/early/2012/02/06/jmedgenet-2011-100407 )

CDKN2A is the main susceptibility gene in Italian pancreatic cancer families

5 Mar, 12 | by hqqu

Pancreatic adenocarcinoma (PC) is the deadliest among common cancers. Because PC progresses rapidly, identifying individuals with a high genetic risk of developing PC is critical to better define emerging strategies for the detection of  early lesions. PC is familial in roughly 10% of patients. Germline mutations in CDKN2A, the major melanoma susceptibility gene, are detected in 30-40% of patients with the melanoma-PC and the familial atypical multiple mole melanoma-PC syndromes, but are considered to play a minor role in familial PC (FPC). Our study identified CDKN2A mutations in 31% of patients with FPC, suggesting that CDKN2A is the main susceptibility gene in Italian FPC families, although melanoma is not a feature of FPC and was not recorded in these patients or their families. The mutation frequency ranged from 20% in FPC families with two affected members to 50% in families with three. Our findings  may be of  value to the purposes of identifying the best candidates for  future PC screening trials in Italy. (By Dr Paola Ghiorzo, http://jmg.bmj.com/content/49/3/164 )

Genotype–phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures

5 Mar, 12 | by hqqu

Ciliopathies are a group of disorders caused by primary cilium dysfunction and characterized by substantial genetic and phenotypic heterogeneity. Establishing genotype-phenotype correlations is critical for directing clinical genetic testing, informing medical management, and interpreting variants identified by genome-wide sequencing technologies. This study reports the spectrum of CC2D2A mutations in CC2D2A-related Joubert syndrome and identifies an enrichment for brain imaging abnormalities (particularlry ventriculomegaly) and seizures in these patients compared to Joubert syndrome as a whole. (By Ruxandra Bachmann-Gagescu, http://jmg.bmj.com/content/49/2/126 )

The phenotypic spectrum of the SMAD3-related Aneurysms-Osteoarthritis Syndrome (AOS)

5 Mar, 12 | by hqqu

Arterial aneurysms are associated with a high morbidity and mortality. Some arterial aneurysms are inherited and due to mutations in different genes in the TGFB signal transduction pathway. We recently identified a new genetic syndrome with arterial aneurysms associated with early-onset osteoarthritis (Aneurysms-Osteoarthritis Syndrome). This new syndrome is caused by mutations in the SMAD3 gene, a gene in the TGFB pathway. In the present study, we describe 8 families with Aneurysms-Osteoarthritis Syndrome caused by different SMAD3 mutations. In the majority of patients early-onset joint abnormalities including osteoarthritis were the initial symptom to seek medical advice. Cardiovascular abnormalities were present in almost 90% of patients, and involved mainly aortic aneurysms and dissections. (By Ingrid van de Laar, MD, http://jmg.bmj.com/content/49/1/47 )

The rs12975333 variant in the miR-125a and breast cancer risk in Germany, Italy, Australia and Spain

5 Mar, 12 | by hqqu

We all have the same genes; however, DNA mutations within genes, inherited from parents and transmitted to children, together with environmental factors, make us all different. Some mutations increase the risk of developing diseases with respect to general population. Recently, the mutation rs12975333 has been “associated with increased breast cancer risk” in the population of Antwerp, Belgium. We studied several thousands of persons from Germany, Italy, Australia and Spain and did not find anyone with the mutation. So, while rs12975333 may be responsible for breast cancer of some of the persons in Antwerp, it is absent in the other studied populations. (By Paolo Peterlongo, IFOM, http://jmg.bmj.com/content/48/10/703 )

Mutations in the Mitochondrial Complex I Assembly Factor NDUFAF1 Cause Fatal Infantile Hypertrophic Cardiomyopathy

5 Mar, 12 | by hqqu

Hypertrophic cardiomyopathy (HCM) describes abnormal thickening and dysfunction of heart muscle. It is a severe disorder and affected children frequently die of heart failure in infancy. Mitochondria are ‘batteries’ responsible for energy production inside most human cells. Mitochondrial disease can cause infantile-onset HCM by impairing energy production inside heart muscle cells. It is very difficult to identify the responsible gene in mitochondrial HCM, because so many genes can cause mitochondrial disease. However, identification of the precise genetic basis has important implications for prognosis, genetic counselling and prenatal diagnosis. We now show that two new mutations in a gene called NDUFAF1 caused HCM in a baby girl who died at 7 months. The NDUFAF1 gene encodes a protein needed to assemble the 45 protein components of mitochondrial complex I in a coordinated way in the inner mitochondrial membrane. This is only the second patient reported with NDUFAF1 mutations and the first to present with fatal infantile HCM. (By Elisa Fassone, http://jmg.bmj.com/content/48/10/691 )

Setleis Syndrome in Mexican-Nahua Sibs Due to a Homozygous TWIST2 Frameshift Mutation and Partial Expression in Heterozygotes: Review of the Focal Facial Dermal Dysplasias and Subtype Reclassification

5 Mar, 12 | by hqqu

Setleis syndrome, a type of focal facial derma dysplasia (FFDD), is a genetic abnormality involving fetal development of the face.  Setleis syndrome may have several genetic causes, but two mutations in the TWIST2 gene have been identified previously.  Patients are born with scar-like, “forcep” marks in their temporal regions along with other syndromic features.   Two Mexican siblings with the typical Setleis features were found to have a third TWIST2 mutation, further confirming the recessive inheritance of the disorder.   Of note, relatives who are only carriers for the mutation also have subtle syndromic features.  A review of all previously reported FFDD cases resulted in a re-classification of the subtypes. (By Amy Yang, MD, http://jmg.bmj.com/content/48/10/716 )

AKAP9-rs6964587 and breast cancer risk: an extended case-control study by the Breast Cancer Association Consortium

5 Mar, 12 | by hqqu

We have combined data from 23 studies in order to assess a previously reported association between a common genetic variant in the AKAP9 gene and breast cancer risk. Based on an analysis of 24,154 women with breast cancer and 33,376 without breast cancer, we observed that white European women with two copies of the variant appear to have small (approximately 8%) increased risk of breast cancer. The risk may be slightly higher for younger women. The results for Asian women were consistent, but inconclusive. Further studies are required to confirm this association and clarify the underlying biological processes. (Dr Roger L Milne, http://jmg.bmj.com/content/48/10/698 )

A role for XRCC2 gene polymorphisms in breast cancer risk and survival

5 Mar, 12 | by hqqu

Breast cancer can be caused by inherited changes in two major genes, BRCA1 and BRCA2, which can have devastating consequences, causing several cases of breast cancer in the same family. BRCA1 and BRCA2 code for proteins that are important for the repair of damaged DNA. In this study we have examined the effects of another gene, XRCC2, which is also involved in this same process. Whilst inherited variation in XRCC2 does not dramatically increase a woman’s risk of breast cancer, we have some evidence that it may play a minor role in breast cancer risk and survival, and is worthy of further investigation. Understanding these genes with smaller effects, like XRCC2, may help us design better targetted treatments. (By Dr Angela Cox, http://jmg.bmj.com/content/48/7/477 )

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