Paclitaxel is a microtubule-binding drug widely used to treat several solid tumors. The paclitaxel dose-limiting toxicity is peripheral neuropathy, which is dose-cumulative and occurs in about one third of the patients. It exhibits a large interindividual variability of unknown molecular basis. We have conducted a GWAS in patients uniformly treated with paclitaxel/carboplatin by which we independently support EPHA5-rs7349683 and XKR4-rs4737264 as markers of paclitaxel-induced neuropathy. In addition, other EPHA genes, also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualized paclitaxel chemotherapy. (By Luis Javier Leandro García, http://jmg.bmj.com/content/early/2013/06/16/jmedgenet-2012-101466 )

This paper finds very different variants in MEF2C are associated with forearm bone mineral density (BMD) compared to the MEF2C variants associated with femoral neck BMD. We conclude that these variants are likely independent signals that have different independent effects on the two BMD phenotypes. It is also possible that both associations arise from several rare causal variants on the same haplotype background. These results might suggest that the variants identified by GWAS are not causal, but the synthetic association created by rare variants with big effect size, however, this hypothesis will likely be tested as more sequencing studies emerge for BMD. (By Dr. Hou-Feng Zheng, http://jmg.bmj.com/content/50/7/473 )

Infantile neuroaxonal dystrophy (INAD) is a recessive disease that results in total neurologic degeneration and death in childhood. A family with two INAD sibs without mutation in PLA2G6, the known gene for INAD, was investigated. NALCN was identified as the gene responsible for the disease. The gene protein forms an ion channel that has a role in the regulation of neuronal excitability. The two patients are adults with a severe clinical phenotype. Testing infants with idiopathic severe growth retardation and neurodegeneration for NALCN mutations could benefit families. Our results add to the success of new generation genetic technologies that facilitate the identification of disease genes in even very small families. (By Prof. Asli Tolun, http://jmg.bmj.com/content/early/2013/06/06/jmedgenet-2013-101634 )

Non-progressive cerebellar hypoplasias are rare developmental disorders leading to movement incoordination and intellectual disability. In an affected eight year-old girl, we identified an exchange between chromosomes X and 8 (translocation X;8). The Protein Tyrosine Kinase 2 (PTK2) and THO complex 2 (THOC2) gene structure was altered and both proteins were reduced to at least half dose. We studied THOC2 reduction in cellular and an animal model (C. elegans), and propose that it can play key roles in neuron development, and possibly in combination with PTK2 decrease, may affect normal neural network formation, leading to cognitive impairment and cerebellar congenital hypoplasia. (By Dr. Alfredo Brusco, http://jmg.bmj.com/content/early/2013/06/06/jmedgenet-2013-101542 )

Comparing and identifying phenotypic differences between genetically close-related populations is interesting but challenging. Here we attempt to understand the difference between Han Chinese and Japanese via the analysis of gene expression data which we assume to be a proxy measure of phenotypic differences. We first identified expression showing significant differences between the two populations (about 4.4% of the transcriptome). Next we established association between variants on DNA level and the differential expression. Our analysis showed that genetic differences can explain 7 – 43% of the identified expression differences, many of which are associated with hematological and biochemical traits, or possibly height. (By Dr. Shuhua Xu, http://jmg.bmj.com/content/early/2013/06/03/jmedgenet-2012-101501 )

Mutations in CDH1 cause the Hereditary Diffuse Gastric Cancer Syndrome. We report the largest series to date of index cases with a germline CDH1 mutation, and propose a revision of the testing criteria as a substantial proportion of our cases did not fulfil them. More specifically, we show that patients with a personal or family history of multiple breast cancers of the lobular type, even in the absence of diffuse gastric cancer, often carry CDH1 mutations. We also highlight the importance of identifying carriers early in order to offer them prophylactic gastrectomy before they develop highly-lethal, symptomatic diffuse gastric cancer. Finally, we propose for consideration the name “Hereditary Diffuse Gastric and Lobular Breast Cancer”, instead of “Hereditary Diffuse Gastric Cancer” to define the syndrome associated with germline CDH1 mutations.  (By Dr Patrick BENUSIGLIO, http://jmg.bmj.com/content/early/2013/05/24/jmedgenet-2012-101472 )

Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair genes. Borràs and collaborators assessed the pathogenicity of variants of unknown significance detected in the mutational analysis of PMS2 gene using a comprehensive strategy. Pathogenic PMS2 mutations were detected in 9 of 13 (69%) candidate patients: seven alterations based on their molecular nature and two after demonstrating a functional defect. In all PMS2 mutations account for 6% of the LS cases. The comprehensive functional analysis performed has been useful in the classification of PMS2 VUS and contributes in refining the role of PMS2 in LS. (By Dr Gabriel Capellá and Dr Marta Pineda, http://jmg.bmj.com/content/early/2013/05/23/jmedgenet-2012-101511 )

Mutations in TSC1 or TSC2 cause Tuberous Sclerosis Complex (TSC) a multisystemic disorder with many features including intellectual disability (ID). TSC1, TSC2 and TBC1D7 form a complex that inhibits mTORC1 signaling and limits cell growth. Using homozygosity mapping and exome sequencing to study a consanguineous family with ID and megalencephaly, we identified, in the affected individuals, a homozygous truncating mutation in TBC1D7. This mutation (p.Y180fsX1) abolishes TBC1D7 expression and is associated with increased mTORC1 signaling in cells of the affected individuals. Our study shows that disruption of TBC1D7 causes ID but without the other typical features found in TSC. (By Fadi F. Hamdan, PhD, http://jmg.bmj.com/content/early/2013/05/16/jmedgenet-2013-101680 )

Kaufman oculocerebrofacial syndrome (KOS) is a rare disorder affecting development and growth originally recognized 40 years ago. KOS is characterised by microcephaly, mental retardation, ocular anomalies, distinctive facial features, generalised hypotonia, and reduced growth. In this paper, exome sequencing was employed to identify UBE3B, encoding an E3 ubiquitin-protein ligase, as the gene mutated in KOS. Molecular data demonstrate that this disorder is a clinically homogeneous, recessive trait caused by UBE3B loss of function. This finding further demonstrates the impact of misregulation of protein ubiquitination on development and growth. (By Marco Tartaglia, PhD, http://jmg.bmj.com/content/early/2013/05/16/jmedgenet-2012-101405 )

Graves’ disease is an autoimmune illness mostly seen in female. The contribution of the X chromosomes to its risk has long been appreciated. We re-examined the X chromosome data from our recent study using a technology named genome-wide association study (GWAS). A single nucleotide polymorphism (SNP) which changes an amino acid within the G protein-coupled receptor 174 gene (GPR174)  on Xq21.1, namely rs3827440, was associated with susceptibility to Graves’ disease and the odds ratio was next to that of the HLA SNPs, the previously established most significant locus related to this disease. Resequencing results revealed other rare variants of GPR174 also contributed to disease risk. GPR174 is widely expressed in immune-related tissues and might serve as a potential drug target in future studies. The finding of an X-linked risk locus for Graves’ disease expands our understanding of the role played by X chromosome in the pathogenesis of autoimmune diseases. (Professor Wei Huang, http://jmg.bmj.com/content/early/2013/05/09/jmedgenet-2013-101595 )