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 )

People with Down syndrome (DS) (trisomy 21) have impaired immune function making them susceptible to infections and autoimmune disease. The molecular cause for this impairment is undetermined. Using mice we have found that an excess of RCAN1, a protein expressed at higher than normal levels in DS, adversely affects key immune functions, and that an excess of RCAN1 leads to suppression of the immune system. Our findings are of clinical relevance to DS and may also find application in situations in the non-DS population where suppression of the immune system is desirable; for example, in autoimmune disease or graft versus host responses. (By Dr. Melanie Pritchard, http://jmg.bmj.com/content/early/2013/05/02/jmedgenet-2013-101522 )

Intellectual disability (ID) is one of the most common disabilities worldwide, affecting nearly 2% of the global population. Here we examined patients from eight families suffering from a form of ID that is coupled with squint of the eye, and in each case found the same DNA mutation, in a gene called ADAT3. This gene is part of a sub-machinery vital for correctly converting DNA into protein within the cell, and excitingly this is the first time that a human mutation has been uncovered in this particular sub-machinery. Although mutations in a large number of genes lead to general ID, focusing on ID that contains a second defining feature (in this case, squint) appears to result in more focused genetic findings. (By Dr. Fowzan S Alkuraya, http://jmg.bmj.com/content/early/2013/04/24/jmedgenet-2012-101378 )

Intellectual disability (ID) is a common disability in humans and comprises both isolated forms as well as forms that are associated with a constellation of other clinical problems i.e. syndromic ID.  In this study, we describe an apparently novel syndromic ID in which patients have decreased sweating and brittle teeth.  Using positional cloning techniques in combination with next-generation sequencing, we identified a mutation in COG6 as the likely cause.  Interestingly, a previous report described a mutation in COG6 in a patient with congenital disorder of glycosylation, something we did not observe in the patients in this study.  Additional COG6 mutations are needed to establish the exact phenotype associated with COG6 deficiency in humans. (By Dr Fowzan S Alkuraya, http://jmg.bmj.com/content/early/2013/04/19/jmedgenet-2013-101527 )

Pulmonary arterial hypertension (PAH) in children is a progressive and often fatal disease of the lung vessels, for which no curative therapy exists. PAH may be heritable: mutations in the BMPR2-gene have been found in about 15% of children with the disease. In a national cohort of Dutch children with unexplained PAH, we identified mutations of the TBX4-gene in 30% of the cases. TBX4-mutations have previously been shown to cause Small Patella Syndrome (SPS) and, interestingly, the pediatric PAH-patients with TBX4 mutations, also appeared to have SPS. This is the first time that TBX4-mutations are reported in PAH. (By Dr. Wilhelmina S Kerstjens-Frederikse, http://jmg.bmj.com/content/early/2013/04/15/jmedgenet-2012-101152 )

Nemaline myopathy (NM) is the most common non-dystrophic congenital myopathy and is most frequently caused by mutations in the nebulin gene. The sarcomeric protein nebulin plays a crucial role in skeletal muscle performance. NM patients with nebulin mutations have muscle weakness through mechanisms including a lower responsiveness to calcium. No therapy exists to treat muscle weakness in NM. Here, we show that the novel fast skeletal muscle troponin activator, CK-2066260, augments force generation at submaximal calcium levels – levels that are typically used for daily life activities. Thus, fast troponin activation is a therapeutic mechanism to augment muscle strength in NM patients with nebulin mutations. (By Dr. Josine de Winter, http://jmg.bmj.com/content/early/2013/04/08/jmedgenet-2012-101470 )

Rhizomelic Chondrodysplasia Punctata (RCDP) is a rare genetic disorder associated with symmetrical shortening of the upper arms and legs, contractures, cataracts and developmenatal delay. The levels of plasmalogens (major constituents of cellular membranes) are low. Although high levels of plasmalogens are normally found in the heart, heart abnormalities have not previously been strongly associated with RCDP.  We found cardiac defects in 12/18(52%) RCDP patients, which is much higher than among the normal population. All 12 had type 1 RCDP, 11(92%) had the PEX 7:c.875T>A mutation and their plasmalogen levels were very low. The cardiac lesions included holes in the heart, persistent ductus arteriosus, underdeveloped lung arteries, Tetrology of Fallot and valve abnormalities. Routine cardiac evaluation in the management of RCDP patients is thus advisable.  (By Drs. Sally-Ann Clur and Irene Huffnagel, http://jmg.bmj.com/content/early/2013/04/08/jmedgenet-2013-101536 )