Prevalence of osteoarthritis (OA), a disabling disease of the joints, increases with age which is expected to become a major problem in health care given the growing elderly population and the poor treatment options. Research to apply potential biomarkers such as serum COMP or urinary CTX-II to monitor OA is promising. However, adequate discrimination between patients and controls is still limited which may be due to innate differences in biomarker levels hampering the association to OA disease status.
By combining data from 7 European cohorts from the TreatOA consortium we identified genetic markers near CSDM1 and near MRC1 and the COMP gene itself, affecting respectively uCTX-II and sCOMP levels.
We advocate that increased biomarker performance for OA may be accomplished by taking such genetic variation into account. (By Dr. Yolande Ramos, http://jmg.bmj.com/content/early/2014/07/23/jmedgenet-2014-102478 )
The risks of breast cancer associated with gene faults in BRCA1 and BRCA2 have been reported to vary from as little as 30% (especially BRCA2) to as high as 90% by age 70 years. However, most studies that assessed risk look backwards at what has happened in families rather than forwards. These studies make adjustments for biases, but include women born before 1930 when breast cancer incidence rates were much lower. We assessed breast cancer risk prospectively in 254 unaffected women with BRCA1 and 238 with BRCA2 mutations.Nineteen breast cancers occurred in BRCA1 and 23 in BRCA2. Estimates of risk to 70 years of were 55.1% for BRCA1 and 71.5% for BRCA2. Breast cancers were associated with stronger family histories especially for BRCA2. (By Prof. D Gareth Evans, http://jmg.bmj.com/content/early/2014/07/22/jmedgenet-2014-102336 )
In this study we have investigated cancer risks in members of Swedish melanoma-prone families with an inherited mutation in the tumor suppressor gene CDKN2A. We find significantly increased risks among carriers not only for melanoma but also for non-melanoma cancers, in particular pancreatic, lung, head and neck and gastro-esophageal cancers. We show a positive association between tobacco smoking and these non-melanoma cancers among mutation carriers. It appears as smoking potentiates the effect of the mutation and greatly enhances the cancer risks in carriers. This is the first study to show an association between smoking and cancer in CDKN2A mutation carriers. Our study has important implications for counseling and monitoring of members of melanoma-prone families with inherited CDKN2A mutations. Carriers of CDKN2A mutations should be informed about the importance of abstinence from tobacco smoking to decrease their risk for non-melanoma cancers. (By Dr Hildur Helgadottir, http://jmg.bmj.com/content/early/2014/06/15/jmedgenet-2014-102320 )
Prostate specific antigen (PSA) is a useful marker for screening of prostate cancer (PCa), one of the leading causes of death in the world. Here, we showed that two genetic variants in SLC45A3 and KLK3 genes are significantly associated with PSA levels in the Japanese population. The association of SLC45A3 was not known in Japanese. We showed that the more variants of these two regions subjects carry, the lower accuracy of PCa a screening with the use of PSA levels provide. Our results suggest that classifying subjects based on number of these variants may lead better screening performance for PCa. (By Chikashi Terao, http://jmg.bmj.com/content/early/2014/06/11/jmedgenet-2014-102423 )
The most common spinocerebellar ataxias (SCA), SCA1, SCA2, SCA3 and SCA6, are caused by a (CAG)n repeat expansion with a correlation between the number of repeats of the coding (CAG)n expansions and age at onset. We combined data from two major European cohorts of SCA1-3 and SCA6 carriers: affected individuals from the EUROSCA registry and pre-clinical individuals from the RISCA cohort. We calculated expected age at onset according to CAG repeat size from birth and from a given age to account for the age an individual has already attained. These estimations can be valuable in clinical, research and predictive-testing programs. (By Sophie Tézenas du Montcel, MD, PhD, http://jmg.bmj.com/content/early/2014/04/29/jmedgenet-2013-102200 )
Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly. We collected the largest sample to date of individuals with variants affecting GLI2 and characterized their phenotype. This included previously published cases as well as new unpublished individuals. We found that individuals with mutations resulting in loss of function rather (versus those with variants of unknown significance) typically had a narrow phenotype including polydactyly and pituitary anomalies as well as subtle facial features, as opposed to frank HPE. (By Kelly Bear, http://jmg.bmj.com/content/early/2014/04/17/jmedgenet-2013-102249 )
Retinitis pigmentosa is a group of genetically inherited eye diseases which represents the most frequent cause of inherited blindness worldwide. Persons with retinitis pigmentosa experience night blindness, which is followed by tunnel vision due to the progressive degeneration of the light sensing cells called rods and cones. Approximately 60 different genes can be defective in retinitis pigmentosa. By sequence analysis of all 20.000 human genes, we could identify defects in DHX38 in 4 retinitis pigmentosa patients of a consanguineous Pakistani family. DHX38 encodes a protein that is important for the processing of RNA molecules, which are crucial intermediates between DNA and protein molecules. This finding enables genetic counseling in this family and provides new insights into the disease mechanism. (By Prof. dr. Frans P.M. Cremers, http://jmg.bmj.com/content/early/2014/04/15/jmedgenet-2014-102316 )
Genomic imprinting is an epigenetic process leading to parent-of-origin specific DNA methylation and gene expression. There are several recognizable phenotypes caused by DNA-methylation changes at disease specific imprinted loci. In the recent years it became obvious that some patients exhibit changes of DNA-methylation at multiple imprinted loci. We report a family with three offspring who were all affected by a widespread disorder of DNA methylation not only of maternally and paternally imprinted genes but also of a considerable number of loci not known to be associated with parent-of-origin specific DNA-methylation. This family suggests the existence of a hitherto unrecognised disorder of genomic imprinting. (By Dr. med. Almuth Caliebe, http://jmg.bmj.com/content/early/2014/04/10/jmedgenet-2013-102149 )
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, affecting > 30 million children worldwide. Children usually develop AIS around the time of the adolescent growth spurt, and girls are at greater risk of severe deformity requiring treatment. Until recently the causes of AIS have remained unknown. In 2011 a genome-wide association study (GWAS) in Japanese patients identified genetic markers near the LBX1 gene as risk factors for AIS. In this new study coordinated through the International Consortium for Scoliosis Genetics (ICSG), we demonstrate that the LBX1 locus is strongly associated with AIS in multiple ethnic populations (Japanese, Chinese, and non-Hispanic white), and that it is probably relevant in boys as well as girls. LBX1 is a regulator of other genes and may participate in AIS by effects on muscle and nerve development. (By Dr. Carol Wise, http://jmg.bmj.com/content/early/2014/04/10/jmedgenet-2013-102067 )
The NF1 microdeletion syndrome is caused by the deletion of a chromosome 17 region encompassing the NF1 gene and flanking genes. We previously found that the patients with the syndrome display a significantly higher incidence of Cardiovascular Malformations (CVMs) than that observed in the NF1 patients with intragenic mutations, suggesting that genes present in the deleted segment are essential for normal heart development.
Here we showed that one of these genes, ADAP2, is expressed in heart during fundamental phases of cardiac development. The functional inactivation of ADAP2 in zebrafish demonstrated its important role in heart development and pointed to ADAP2 as the best candidate gene for the occurrence of CVMs in NF1-microdeleted patients. Our study constitutes a step towards a better comprehension of the complex phenotypic spectrum of the syndrome. (By Dr. Marco Venturin, http://jmg.bmj.com/content/early/2014/04/07/jmedgenet-2013-102240 )