In this research, we describe 5 patients with a specific condition that we are referring to as Chitayat syndrome as the first patient with this condition was described in 1993 by Prof David Chitayat. Almost 15 years later, Dr Meena Balasubramanian saw a 5-month old baby with what appeared to be the exact same features as the patient described in 1993 including the similarities in facial appearance, hands and feet. Due to advances in genetic screening, we were able to identify a change in a gene usually known to cause premature fusion of the skull bones. This was puzzling as none of the patients presented with this. On further genetic testing, we were able to show the exact same gene change in the original patient described and in patients identified in Stanford (father and son) and Utah, demonstrating the power of studying human diseases to provide insights into development. Studies are ongoing to understand the function of this variant and whether there are possible therapies. (By Dr. Meena Balasubramanian, http://jmg.bmj.com/content/early/2016/10/13/jmedgenet-2016-104143 )
Photo showing David Chitayat and Meena Balasubramanian at the David Smith meeting, Lake Arrowhead, CA, USA this year where they presented this study.
It is more and more frequent the detection of CFTR mutations for which it lacks a clear and univocal interpretation. This is particularly true for complex alleles (i.e., more mutations on the same allele). We describe genotype-phenotype correlations in a large number of Cystic Fibrosis patients, carrying different CFTR complex alleles and suggest a poorly invasive tool that may help to predict the clinical severity of the disease. (By Dr. Vito Terlizzi, http://jmg.bmj.com/content/early/2016/10/13/jmedgenet-2016-103985 )
Dr. Vito Terlizzi
Prof Castaldo and his group
Mutations in the TRAPPC11 gene have been linked to a diverse range of phenotypes including intellectual deficit, muscular dystrophy and movement disorders. Here we report on individuals from two unrelated Turkish families who presented with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima. Although several of these symptoms are in common with Triple A syndrome, the remaining symptoms are not. We therefore performed whole exome sequence analysis on these patients and discovered a mutation in TRAPPC11. The gene product TRAPPC11 is involved in the movement of material within the cell and functional analyses revealed a delay in transport along the secretory pathway in patient fibroblast cells. This report expands the clinical phenotype of TRAPPC11 mutations. (By Dr. Katrin Köhler, http://jmg.bmj.com/content/early/2016/10/05/jmedgenet-2016-104108 )
Usher syndrome is a genetic disorder featured by combined visual impairment and hearing loss. Currently, the genetic basis remains unknown in 20-30% of patients. In this article, we described the identification of CEP78 as a new gene that leads to a mild Usher syndrome featured by juvenile or adult-onset cone-rod dystrophy and sensorineural hearing loss when mutated. Our results add additional link between ciliopathy and Usher protein network in photoreceptor cells and inner ear hair cells. (By Dr. Rui Chen, http://jmg.bmj.com/content/early/2016/09/21/jmedgenet-2016-104166 )
Cancer is a genetic disease. People are anxious to know their cancer risks, if several relatives have been diagnosed with cancer. However, due to lack population level data, their questions have no scientific answers. In our study, Swedish Family-Cancer Database was used to estimate common cancer risks for individuals with many relatives affected with cancer. We found that cancer family history, regardless of tumor type, increased individual’s cancer risk. Our data could provide tools for cancer genetic counseling. Furthermore, the mechanism of the general susceptibility is a novel challenge to cancer research. (By Dr. Hongyao Yu, http://jmg.bmj.com/content/early/2016/09/20/jmedgenet-2016-103932 )
Contrarily to initial expectations about the psychological impact of Direct to Consumer genetic testing, people are substantially resilient to long-term consequences of results to genetic testing. Previous literature raised concerns on DTC focusing on anxiety levels it might cause. We claim that there are three substantial limits to be considered: non-clinical anxiety is not a negative outcome; anxiety is limitedly predictive of health related behaviors and decisions; a number of previous studies are affected by methodological errors. We promote the exploration of complex cognitive and emotional mechanisms to capture the subtle and multifaceted nature of a living-at-risk situation. (By Dr. Serena Oliveri, http://jmg.bmj.com/content/early/2016/09/19/jmedgenet-2016-104184 )
Genetic variants (SNPs) in the vascular endothelial growth factor A (VEGFA) gene are associated with TSH levels. To characterize this association, we searched for SNPs in more than 8000 Danes. We identified rs881858 (in regulatory enhancer region of VEGFA), highly associated with human circulating TSH, which had alleles (A/G) with differential binding to CHOP (C/EBP homology protein) and C/EBPβ (ccaat enhancer binding protein β) proteins.
VEGF is an important angiogenic signal required for tissue expansion and is highly expressed in thyroid tissue. CHOP is a protein induced by cellular stress and these findings suggest a (genetically determined) stress-dependent response in normal or pathophysiological TSH stimulation of the thyroid. (By Dr. Louise Torp Dalgaard, http://jmg.bmj.com/content/early/2016/09/14/jmedgenet-2016-104084 )
Usher syndrome is a genetic disorder featured by combined visual impairment and hearing loss. Currently, the genetic basis remains unknown in 20-30% of patients. In this article, we described the identification of CEP78 as a new gene that leads to a mild Usher syndrome featured by juvenile or adult-onset cone-rod dystrophy and sensorineural hearing loss when mutated. Our results add additional link between ciliopathy and Usher protein network in photoreceptor cells and inner ear hair cells. (By Dr. Rui Chen, http://jmg.bmj.com/content/early/2016/09/14/jmedgenet-2016-104166 )
Establishment of a comprehensive diagnostic system for patients with inherited myopathies is challenging because of their genetic heterogeneity. In this paper, we introduced our genetic diagnostic system using four target gene panels, each covering all exonic and flanking regions of genes associated with 1) muscular dystrophy, 2) congenital myopathy/congenital myasthenic syndrome, 3) metabolic myopathy, and 4) myopathy with protein aggregations/rimmed vacuoles, combined with comprehensive muscle histological, mRNA, and protein analyses. Our study indicates that targeted gene panels are cost- and time- effective and useful for screening pathogenic variants and for giving molecular diagnosis to the patients with inherited myopathies. (By Dr. Satomi Mitsuhashi, http://jmg.bmj.com/content/early/2016/09/06/jmedgenet-2016-104073 )
The human cell functions are highly dependent on the regulated movement of ions across the cell membrane, which is carried out by proteins called ion channels. One subset of ion channels regulates the movement of potassium, especially in excitable tissues like that of the brain. In this report, we describe a genetic change in the DNA code of a potassium channel (known as KCNA4) that led to a novel disease affecting the brain and likely to involve in natural eye lens. All four affected patients had this change, which was absent in their non-affected family members as well as healthy control samples. Examination of clawed frog eggs that over-expressed the same genetic change revealed that potassium movement across the cell membrane was reduced compared to eggs with the normal genetic makeup. Such findings implicate the involvement of this genetic change in the disease process. (By Dr. Namik Kaya, http://jmg.bmj.com/content/early/2016/08/31/jmedgenet-2015-103637 )