Autosomal Dominant Hypercholesterolemia (ADH) is a heterogeneous common disorder characterized by elevated levels of plasma low-density lipoprotein (LDL-C), total cholesterol, and increased risk of cardiovascular disease. Uncovering the molecular determinants that underlie ADH is a major focus of cardiovascular research, but despite rapid technical advances, efforts to identify novel ADH genes have yet not been very successful.
Commonly used noveI-gene-finding criteria are LDL-C levels above the 95th percentile and a disease penetrance of 0.9. However, by applying such criteria the phenotypic and genetic heterogeneity of ADH will be largely ignored.
Our findings clearly showed that adjusted and refined phenotypic definitions within ADH families are necessary to increase the change of identifying novel genes associated with the ADH phenotype, and using a cut-point at the 75th percentile seems to be justified. (By Dr. Sigrid Fouchier, http://jmg.bmj.com/content/early/2014/11/20/jmedgenet-2014-102653 )
The imprinted 11p15 IGF2/ICR1/H19 domain contains ten differentially methylated loci all methylated on the paternal allele. Hypomethylation at this domain causes Russell Silver Syndrome (RSS), a condition associating severe growth retardation, metabolic disturbances and characteristic dysmorphism. We have exhaustively documented the methylation pattern across the entire IGF2/ICR1/H19 domain in a large cohort of RSS patients carrying 11p15 ICR1 hypomethylation (n =104). For these patients, we found uneven levels of methylation across the domain allowing to distinguish two groups of loci unevenly hypomethylated. Interestingly, 9% of the RSS patients showed normal methylation at some loci of the 11p15 IGF2/ICR1/H19. Our results constitute an important step toward understanding the mechanisms of regulation of the imprinted IGF2/ICR1/H19 domain. These finding are of major diagnostic consequences to design a reliable molecular test for RSS. (By Dr. Salah Azzi, http://jmg.bmj.com/content/early/2014/11/13/jmedgenet-2014-102732 )
Atrial fibrillation (AF) is the most common arrhythmia and a hereditary disease. AF may be caused by the joint effect of many or several common genetic variations or variants. Genome-wide association studies (GWAS) have identified common genetic variants in several genes associated with AF. Recent studies also suggest that rare genetic variants or mutations may also cause AF. Such rare variants may have a large effect and therefore we hypothesized that these rare variants are enriched in patients with severe symptoms. Importantly, we also hypothesized that rare variants and GWAS-defined common variants might locate in the same gene. We used next-generation sequencing to in-depth sequence all the AF genes in which there are GWAS-identified common variants, in carefully selected patients with extremely symptomatic AF patients. We proved our hypothesis, and identified 6 novel mutations, one of which we proved significantly affected PITX2 gene (the most important AF gene) expression. (By Dr. Chia-Ti Tsai, http://jmg.bmj.com/content/early/2014/11/12/jmedgenet-2014-102618 )
During the long history of human genome evolution, some gene loci have lost the protein-coding abilities due to various kinds of mutations. These genes are termed pseudogenes that are previously regarded as functional inert. Studies in recent decades, however, have discovered many kinds of functions pseudogenes play both in health and in disease, especially in cancer. In this review, we introduce the origination, classification, identification of pseudogenes, and focus on their roles in cancer pathogenesis. These roles have been categorized into DNA level, RNA level and protein level to make them easier to be understood and remembered. Recent advances in pseudogenes as promising subtyping signature of cancer have also been discussed. We sincerely wish this review to provide a concise and reliable reference for researchers interested in this area. (By Dr. Lu Xiao-Jie, http://jmg.bmj.com/content/early/2014/11/12/jmedgenet-2014-102785 )
RNA toxicity due to increased FMR1 mRNA levels observed in premutation carriers is the leading molecular mechanism proposed for FMR1 associated disorders. Our analysis comparing premutation carriers and control samples suggests that RNA toxicity may arise from increased expression levels of all FMR1 mRNA isoforms. In addition, Iso10 and Iso10b transcripts, which lack important functional sites for FMRP function encoded in the missing C-terminal, are the most differentially expressed in premutation carriers relative to controls, suggesting a potential functional relevance in the pathology of FMR1 associated premutation disorders. (By Dr. Dalyir Pretto, http://jmg.bmj.com/content/early/2014/10/30/jmedgenet-2014-102593 )
Inherited optic neuropathy can be isolated or syndromic and are associated with mutations in genes encoding proteins involved in various mitochondrial functions. We identified mutations in ACO2 encoding the mitochondrial aconitase, an enzyme of the tricarboxylic acid cycle, in five patients with optic atrophy isolated or associated with severe neurological signs. By using a yeast model we demonstrated that all these mutations were deleterious and observed a good correlation between severity of the clinical phenotype of patients and growth deficiency in yeast. These results illustrate the wide clinical expression associated with mutations in the same gene. (By Dr. Agnès Rötig, http://jmg.bmj.com/content/early/2014/10/28/jmedgenet-2014-102532 )
It is uncontroversial that, if any possible, biobank researcher should seek consent from the individuals whose biomaterials they use. However, a gold standard for consent procedures in Biobank research does not yet exist. Also research guidelines do not explicitly mention all potentially relevant issues for consent in biobank research. Based on a qualitative review of internationally-recognized research guidelines, we present a list of all 41 consent issues that are of potential relevance to biobank research. Furthermore, we explain similarities and differences between the analysed guidelines. Our findings can inform the balanced development and evaluation of consent forms, as well as the development and revision of corresponding research guidelines. (By Dr. Daniel Strech, http://jmg.bmj.com/content/early/2014/10/28/jmedgenet-2014-102692 )
This review presents the latest data on the relations between the genetic basis of primary ciliary dyskinesia (PCD) and improvement of its diagnosis. PCD is a rare disorder caused by mutations in one of many ciliary genes. The PCD diagnosis is challenging and requires a well described clinical phenotype combined with the identification of abnormalities in ciliary ultrastructure and beating pattern, as well as of the underlying genetic cause. New technologies available in the genetic studies have a great influence on the number of identified PCD-causative genes and mutations and this number is bound to rise. The current knowledge can already be used to create new genetic tests for PCD which can accelerate the correct diagnosis. (By Dr. Małgorzata Kurkowiak, http://jmg.bmj.com/content/early/2014/10/28/jmedgenet-2014-102755 )
Tubular aggregate myopathies (TAM) are progressive muscle disorders characterized by abnormal accumulations of densely packed membrane tubules on biopsies. The implicated gene STIM1 controls intracellular calcium balance and plays an important role in the regulation of muscle contraction. Here we describe patients with new STIM1 mutations clustering the calcium-binding domain and impairing normal protein function. Patient phenotypes ranged from childhood onset muscle weakness to adult-onset myalgia without muscle weakness, expanding the spectrum associated with this muscle disorder. Our study indicates a genotype/phenotype correlation for tubular aggregate myopathies, and has an important diagnostic relevance. (By Dr. Johann Böhm, http://jmg.bmj.com/content/early/2014/10/17/jmedgenet-2014-102623 )
Pattern dystrophy (PD) of the retinal pigment epithelium is a slowly progressive genetically heterogeneous autosomal dominant disorder. As the name suggests, the disease manifests as changes in the retina that display a certain ‘pattern’. We performed genetic analyses in two families with PD; different approaches that included linkage analysis and whole exome sequencing were used. We identified a novel missense variant (E79K) in OTX2 gene to underlie PD in both families. OTX2 has been previously associated with developmental eye and pituitary anomalies in humans. Our work is the first to associate OTX2 to cause PD and shows that mutations OTX2 can also lead to progressive retinal diseases. (By Dr. Ajoy Vincent, http://jmg.bmj.com/content/early/2014/10/07/jmedgenet-2014-102620 )