People born with a mutation in a gene called PTEN often develop cancer, but also show other symptoms including benign growths, an enlarged head and autism. To date it has been unclear whether the diversity seen in these patients is caused by differences in the way precise genetic changes alter the function of PTEN, or by other factors. By studying how different PTEN proteins function in cells in the laboratory, our work found that mutations with specific effects on the function of the PTEN protein were more commonly found in particular patient groups. The clinical prospects of these patient groups are very different. Therefore, information at initial diagnosis would be of great benefit if it could predict from the specific mutant PTEN protein inherited, what problems the patient is likely to develop. In the future this may be able to match patients with the best treatments. (By Dr Nicholas R Leslie, http://jmg.bmj.com/content/early/2014/12/19/jmedgenet-2014-102803 )
The practice of Genetics in areas of low human development index is not trivial. This manuscript tells a success story which combines training family health agents to pinpoint large consanguineous families with several individuals with deficiencies, conducting field medical evaluation in remote areas of Brazil and finalizing by state-of-art technology for linkage and high-throughput sequencing, performed in more developed centers of the country. This mix of barefoot medicine, good clinical skills and high yield molecular biology and bioinformatics allowed the identification of MED25 as another gene involved in autosomal recessive intellectual disability (ID). MED25 codes for one of the more than 30 subunits of Mediator Complex, who plays a critical role in controlling synthesis of messenger RNA; other members of the “club MED” have been already associated to ID.
There is a narrow window of opportunity for this type of study, since a large change in demography is already underway in Brazil. As families are becoming smaller and consanguineous unions less frequent, we should hurry and go back to the backlands! (By MSc Thalita Figueiredo, http://jmg.bmj.com/content/early/2014/12/19/jmedgenet-2014-102793 )
Pediatric hearing loss is a common disorder and universal newborn hearing screening is used to aid in the early identification of children with hearing impairment. However this screening has a significant failure rate in newborns, and hearing loss may have delayed onset and be missed by newborn screening. Genetic screening of newborns for variants that may predispose towards nonsyndromic hearing loss is being increasingly explored as a means to supplement standard audiologic examinations. Here we examined the association of mitochondrial mutations with non-syndromic hearing loss in previously published studies, including the effect of ethnicity, audiologic test methods and aminoglycoside exposure. This analysis identified several mitochondrial variants that were significantly associated with hearing loss susceptibility. Mutations that are significant when exposure to aminoglycoside is considered were also identified. (By Dr. Brian Z Ring, http://jmg.bmj.com/content/early/2014/12/16/jmedgenet-2014-102753 )
Observational epidemiology has implicated a wide range of biomarkers in the onset of human disease, however given that these methods are prone confounding it becomes difficult to identify causal biomarkers deserving of pharmaceutical intervention. Mendelian randomization (MR) is an emerging technique in human genetics which utilizes the power of random assignment of genetic information at meiosis to determine whether a biomarker is causal in human disease. It has been suggested that this technique can help guide drug development and inevitably improve the delivery of new drugs to clinical care. In this article we review examples of MR studies in cardiovascular disease and discuss limitations in the technique’s ability to predict therapeutic success in humans. (By Lauren E Mokry, http://jmg.bmj.com/content/early/2014/12/16/jmedgenet-2014-102438 )
Here, we identified recessive mutations in the PNPLA6 gene, encoding Neuropathy Target Esterase (NTE) protein, responsible for Oliver-McFarlane and Laurence-Moon syndromes in humans. Our finding expands the spectrum of PNPLA6-associated diseases to include hair abnormalities and pituitary atrophy, which can lead to intellectual disability and short stature. We further link the mechanisms among other PNPLA6-associated diseases, including Spastic Paraplegia Type 39, by surveying normal human embryonic expression in eye, pituitary and brain, and by analyzing the effects of PNPLA6 mutations on NTE function both in zebrafish and patient cells. Our results suggest that the common cause of these disorders is NTE loss-of-function, and that the extent of remaining NTE function may help define the course of disease. (By Drs. Robert Hufnagel and Zubair M. Ahmed, http://jmg.bmj.com/content/early/2014/12/05/jmedgenet-2014-102856 )
In a small subset of patients, apparently balanced structural chromosome rearrangements may associate with neurocognitive problems ranging from mild (ADHD, dyslexia) to severe (within the autism spectrum disorders and intellectual disability). Here, we use low coverage massive parallel whole genome sequencing and microarray analysis to identify hemizygous loss of CTNND2 in three individuals from two unrelated families who show borderline to moderate intellectual dysfunction and specific problems with reading. The gene was first identified by whole genome sequencing in a carrier of two balanced reciprocal chromosomal translocations, t(1;8)(p22;q24) and t(5;18)(p15;q11). We then demonstrate an effect of CTNND2 polymorphisms on normal reading ability and normal variability in white matter volume. Finally, we show that the loss of CTNND2 function in zebrafish results in ectopic neurons, indicative of abnormal neuronal migration. Our work indicates that isolated CTNND2 mutations lead to learning difficulties, in particular reading disability. (By Dr. Anna Lindstrand, http://jmg.bmj.com/content/early/2014/12/03/jmedgenet-2014-102757 )
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 )