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Genotype phenotype associations across the voltage-gated sodium channel family

27 Aug, 14 | by hqqu

Mutations in genes which code for sodium ion channel proteins have emerged as the most important genetic factors associated with epilepsy, cardiac rhythm disorders, skeletal muscle channelopathies and pain disorders. Geneticists in partnership with neurologists and cardiologists are often asked to comment on the clinical significance of specific mutations. Comparing over 1300 sodium ion channel mutations in diseases affecting the central and peripheral nervous system, heart and muscle, we have identified many similarities in genetic and clinical characteristics across this ion channel family. These findings should lead to a better understanding of the clinical significance of specific mutations, aiding geneticists and physicians in the interpretation of genetic variants and in counselling individuals and their families. (By Dr Andreas Brunklaus, http://jmg.bmj.com/content/early/2014/08/27/jmedgenet-2014-102608 )

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Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy

25 Aug, 14 | by hqqu

Our study investigated the relationship between rare gene variants, clinical features and natural history in arrhythmogenic right ventricular cardiomyopathy. In particular, we explored the phenotype and outcome of rare variant carriers of the giant gene titin and desmosomal genes in a cohort of families with a long-term follow-up, up to 22 years. We found that desmosomal gene rare variant carriers were characterized by a severe prognosis and specific clinical and electrocardiographic features, while titin gene carriers had an intermediate outcome, supraventricular arrhythmias and severe conduction defects, information that may be useful in the clinical practice. (Drs. Francesca Brun and Luisa Mestroni for the authors, http://jmg.bmj.com/content/early/2014/08/25/jmedgenet-2014-102591 )

 

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The two first authors, Francesca Brun , MD, and Carl Barnes, MD, presenting their work at the AHA meeting in Dallas, 2013.

The clinical significance of small copy number variants in neurodevelopmental disorders

8 Aug, 14 | by hqqu

The majority of neuro-developmental disorders (NDDs) such as intellectual disability are likely due to alterations in the genome. It has been shown that about 30% of these patients have losses or gains of large segments of the genome containing many genes or whole chromosomes as in trisomy 21. In this study, we evaluated the contribution of small gains and losses sizing less than 500 kb affecting only few or single genes. We showed that such smaller changes cause NDDs in 2% of patients. In addition, we discovered three novel genetic conditions associated with losses of the genes MED13L, CTNND2 or ACOT7. Our findings are useful for better diagnosis and management of patients with NDDs. (By Prof. Anita Rauch, http://jmg.bmj.com/content/early/2014/08/08/jmedgenet-2014-102588 )

Comprehensive genotype phenotype correlations between NLRP7 mutations and the balance between embryonic tissue differentiation and trophoblastic proliferation

5 Aug, 14 | by hqqu

Hydatidiform mole (HM) is a human pregnancy with no embryo, but excessive trophoblastic proliferation. Maternal recessive mutationsin NLRP7 are responsible for recurrent HMs, which are characterized by diploid biparental genomes, abnormal DNA methylation, and absence of p57Kip2 expression, the protein coded by the imprinted CDKN1C gene. In this study, we demonstrate a strong correlation between the nature of NLRP7 mutations in the patients and the phenotypical features of their HMs. Protein-truncating mutations repress p57KIP2 expression and are associated with the absence of embryonic tissues and excessive trophoblastic proliferation. However, some missense mutations do not completely repress p57KIP2 expression and are associated with the presence of embryonic tissues and mild trophoblastic proliferation. Our data suggest a novel role for NLRP7in regulating the balance between tissue differentiation and proliferation during early development. (By Ngoc Minh Phuong Nguyen, http://jmg.bmj.com/content/early/2014/08/05/jmedgenet-2014-102546 )

Genetic architectures of ADME genes in five Eurasian admixed populations and implications for drug safety and efficacy

29 Jul, 14 | by hqqu

The genetic heterogeneity can lead to heterogeneous drug responses among individuals, such as less efficacy or unwanted side effects of drug therapy. Moreover, the ethnic/genetic diversity also affects the effective prescription. Here, we investigated the genetic diversity of 282 ADME genes in five northwestern Chinese minority populations which are all admixed people with ancestry contributions from both Eastern and Western Eurasian populations. We revealed that substantial allelic and haplotype differences exist at drug related genes between those minority ethnic groups and Han Chinese, which is likely to violate a single, unified standard of medication in China. (By Dr. Shuhua Xu, http://jmg.bmj.com/content/early/2014/07/29/jmedgenet-2014-102530 )

A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia

25 Jul, 14 | by hqqu

Spinocerebellar ataxias (SCAs) are a group of genetically diverse neurodegenerative disorders causing cerebellar degeneration and progressive ataxia. We identified an autosomal dominant SCA family (SCA40) which displays typical cerebellar ataxia signs and pontocerebellar atrophy. By performing whole-exome sequencing on multiple members of this family, we found a novel missense mutation in the gene CCDC88C in all affected individuals. Our cell-based assays showed that the SCA40 mutation causes an up-regulation of the JNK stress kinase signaling cascade that subsequently triggers programmed cell death. A similar cellular dysregulation was also observed in patient primary fibroblasts. Our work implicates that targeting JNK signaling and/or caspase cascades would be of therapeutic potential for treating SCA40. (By Dr. Edwin Chan, http://jmg.bmj.com/content/early/2014/07/25/jmedgenet-2014-102333 )

Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research

25 Jul, 14 | by hqqu

This Position Paper draws together the emerging evidence that the early life experience of parents and/or ancestors can influence development and common disease risk in the current generation, with the aim of promoting human transgenerational research . The few human observational studies reported to date of the effects of ancestral exposures (such as nutrition or smoking) support transgenerational effects that cannot easily be attributed to cultural and/or genetic inheritance. This points to non-genetic biological inheritance in humans similar to that convincingly demonstrated in transgenerational animal experiments, particularly involving altered nutritional or stress exposures. The authors argue that transgenerational responses to specific exposures in previous generations should be factored into future studies with a public health focus. (By Dr Richard Saffery, http://jmg.bmj.com/content/early/2014/07/25/jmedgenet-2014-102577 )

Photo for Pembrey et al JMG blog July 2014

Harvest in northern Sweden a hundred years ago (© the Demographic Database, Umeå University)

Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance

23 Jul, 14 | by hqqu

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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 )

Long-term prospective clinical follow-up after BRCA1/2 presymptomatic testing: BRCA2 risks higher than in adjusted retrospective studies

23 Jul, 14 | by hqqu

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 )evanstonightPic

High Risk of Tobacco-Related Cancers in CDKN2A Mutation-Positive Melanoma Families

17 Jun, 14 | by hqqu

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 )

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