mTOR is a critical effector of cell signaling, playing a pivotal role in regulating physiology of the whole body, including the brain. Mutations in genes encoding GATOR1 complex, an inhibitor of mTOR activity, have been recently implicated in the pathogenesis of a wide spectrum of focal epilepsies (FEs), occasionally associated with malformations of cortical development. Loss of mTOR inhibitor activity is the hypothesized mechanism underlying epilepsy. In this review, the authors summarize the current knowledge about GATOR1 mutations in FEs, and discuss the future therapeutic opportunities for patients. (By Sara Baldassari, http://jmg.bmj.com/content/early/2016/05/19/jmedgenet-2016-103883 )
Many women diagnosed with epithelial ovarian cancer do not access genetic testing for BRCA1/2 mutations. The reasons for this are complex but may in part be due to lack of awareness or an over-complicated referral pathway. The Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study looked at a streamlined approach led by Oncology and coordinated by Genetic services. Women did not receive formal genetic counselling and were only seen by Genetics if a mutation or variant of unknown significance was identified. Results showed this model to be feasible, cost-effective and acceptable to participants. It therefore offers new approach to increase test uptake without requiring additional resources. (By Dr. Marc Tischkowitz, http://jmg.bmj.com/content/early/2016/05/12/jmedgenet-2016-103902 )
Inga Plaskocinska, Dr Marc Tischkowitz, and Hannah Shipman.
Ciliopathies are an extensive group of disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. Our study resulted in the identification of six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy. The CEP120-associated phenotype ranges from mild classical JS in four patients, to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies. Our findings broaden the spectrum of phenotypes caused by CEP120 mutations, that account for nearly 1% of JS patients as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies. (By Dr. Susanne Roosing, http://jmg.bmj.com/content/early/2016/05/06/jmedgenet-2016-103832 )
Floating-Harbor syndrome (FHS) is a rare human disease characterized by developmental defects, often associated with mental retardation. FHS was first described at Boston’s Floating Hospital in 1973, but the causative gene, called Srcap, was identified only recently. Srcap encodes a protein with a key role in control of gene expression, however, the underlying molecular bases of FHS still need elucidating. In this review article, the authors critically examine recent studies on FHS, proposing possible mechanisms for the molecular events leading to the onset of the disease. (By Professor Patrizio Dimitri, http://jmg.bmj.com/content/early/2016/04/26/jmedgenet-2016-103842 )
From left to right:
Maria Teresa Atterrato, Giovanni Messina, Emanuele Celauro, Patrizio Dimitri, Yuri Prozzillo.
Mitochondrial diseases occur when insufficient energy is produced, affect both adults and children and often require a muscle biopsy to help the investigation and diagnosis. We have identified the same genetic defect – a mutation within the NDUFB3 gene – in ten children from eight families with identical physical features; affected children are short, have prominent foreheads and were noted to be developing slowly during pregnancy. These children have recovered well whereas many other mitochondrial genetic defects have a fatal outcome. Early recognition of this combination of physical features could lead to other children being diagnosed without requiring an invasive muscle biopsy. (By Dr. Charlotte Alston, http://jmg.bmj.com/content/early/2016/04/18/jmedgenet-2015-103576 )
SHOX encodes a transcription factor involved in cell-cycle and growth regulation. Here, we report the association between microduplications at the SHOX locus and autism spectrum disorders (ASD) and related neurodevelopmental conditions (NDD). The study was triggered by observations in a discovery series of 90 ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation. A link between SHOX microduplications and ASD/NDD was subsequently supported by examination of a follow-up sample of 18,857 ASD/NDD cases, compared with 12,594 controls. Our findings suggest that SHOX microduplications are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, concomitant duplication of SHOX enhancers may be required to trigger NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment. (By Dr. Maria Tropeano, http://jmg.bmj.com/content/early/2016/04/12/jmedgenet-2015-103621 )
Dr. Maria Tropeano
The 7TM receptor for long chain fatty acids FFAR4 (GPR120) currently attracts great attention as a therapeutic target to treat metabolic diseases. A low-frequency missense variant (p.R270H, rs116454156) in FFAR4 has previously been reported to associate with obesity in European populations and to impair signaling of the receptor. Here we further examine the functional consequences of p.R270H on receptor properties, and expand the human association studies by investigating traits of relevance for obesity- and glucose metabolism. Despite impaired effects on receptor function, we found no statistically significant associations with any examined traits. (By Marie Aare Vestmar, http://jmg.bmj.com/content/early/2016/04/11/jmedgenet-2015-103728 )
Acromicric dysplasia and geleophysic dysplasia are both forms of acromelic dysplasia. Several causative genes have been identified for the acromelic dysplasias, all of which affect TGF-β signalling and/or interactions with fibrillin. Here, we have used massive parallel sequencing to identify a dominant mutation in latent TGF-β binding protein-3 (LTBP3) in a family with acromicric dysplasia, and de novo mutations in LTBP3 causing geleophysic dysplasia in two separate unrelated individuals. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum. (By Aideen McInerney-Leo, http://jmg.bmj.com/content/early/2016/04/11/jmedgenet-2015-103647 )
Genetic testing of BRCA1 and BRCA2 genes in cancer patients frequently reveals gene variations with unknown clinical effects. Some of these variations might affect mRNA splicing, an important step in gene expression. Aberrant splicing is typically determined by looking for novel mRNA molecules. We wanted to know if these molecules could also occur at random. We found there are 24 different splicing events in BRCA2 that appear in some, but not all mRNA samples examined, and may be random events. This work shows that novel mRNA molecules are not sufficient to conclude that a gene variation is a disease-causing mutation. (By Dr. James D. Fackenthal, http://jmg.bmj.com/content/early/2016/04/08/jmedgenet-2015-103570 )
Mutations in a variety of Ras-MAPK pathway genes are detected in 70-80% of patients with Noonan Syndrome (NS) and related disorders, collectively referred to as RASopathies. Certain patients with RASopathies are predisposed to developing juvenile myelomonocytic leukemia (JMML), a myeloproliferative disorder of early childhood. We recently identified somatic mutations in RRAS2 in JMML and hypothesized that germline RRAS2 mutations could be an additional cause of NS. We therefore screened a cohort of 116 NS patients for mutations in RRAS2 that had no identified lesions. No recurrent mutations were found, ruling out germline mutations in RRAS2 as a cause of Noonan syndrome. (By Dr. Elliot Stieglitz, http://jmg.bmj.com/content/early/2016/04/07/jmedgenet-2016-103889 )