The immune system relies on a finely tuned balance between immunity to pathogens and cancers, and tolerance to healthy self, our environment and commensals. This equilibrium is dramatically disrupted in the Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. This rare disorder is caused by mutations in the FOXP3 gene, a master transcriptional regulator for the development of CD4⁺ regulatory T (Treg) cells. IPEX usually presents in infancy, as multi-organ autoimmunity encompassing type-1-diabetes, anemia, chronic dermatitis and bowel inflammation, hepatitis and nephritis. In this review, we describe the genetic, immunological and clinical characteristics of IPEX syndrome and highlight the impact of heritable mutations on the function of Treg cells. (By Eva d’Hennezel, http://jmg.bmj.com/content/49/5/291 )

Prostate cancer is the most common cancer in men and family history of cancer and age are the strongest contributing factors. We followed about 600,000 men from the Swedish Family-Cancer Database (world’s largest of its kind) for 10 years to design the Prostate Cancer Risk Assessment Model (PCRAM) for the first time, which enables clinicians to assess a man’s risk of prostate cancer based on his personal and family history of prostate, oesophagus and breast cancers. PCRAM, which was successfully tested in another large sample, also contains a chart of equivalent ages by risk score that assists health care providers to estimate when to begin prostate cancer screening individually. (By Mahdi Fallah, MD, PhD, http://jmg.bmj.com/content/49/5/345 )

Fraser syndrome (FS) is a rare genetically heterogeneous recessive disorder. FS patients are born with severe malformations affecting their eyes (cryptophthalmos), skin covering the digits (cutaneous syndactyly), respiratory tract, kidneys and genitals. The molecular defect underlying the majority of FS patients is unknown. Thus far mutations in two genes (FRAS1 and FREM2) are known to cause Fraser Syndrome. We tested FS patients without a molecular diagnosis. In three patients we could pinpoint the genetic defect in the GRIP1 gene.  This study demonstrates the involvement of GRIP1 in Fraser syndrome in humans. The results expand the possibilities for diagnostic testing and early prenatal diagnosis for Fraser syndrome patients and their families. (By Dr. Maartje Vogel, http://jmg.bmj.com/content/early/2012/04/16/jmedgenet-2011-100590 )

Molar pregnancies are abnormal pregnancies in which the placenta develops excessively and there is no normal fetal development. They are important because molar tissue can easily develop into a placental tumour for which the patient would need chemotherapy. Molar pregnancies are usually chance (sporadic) occurrences but occasionally women have an inherited predisposition to these pregnancies because they have mutations in both copies of a gene called NLRP7. We have investigated this gene in women with sporadic molar pregnancies and shown that these women do not have mutations in the gene and that mutations in this gene are not responsible for most molar pregnancies. (By Dr Rosemary A Fisher, http://jmg.bmj.com/content/49/3/206 )

Coagulation factor VII (FVII) is a clotting protein which triggers thrombus formation in the arterial vessels and modulates coronary artery disease (CAD) risk. Plasma FVII concentrations are largely determined by genetic markers as the A2 allele causing lower FVIIa and reduced CAD risk, or the -402A allele that induces higher FVIIa. Other mechanisms such as DNA methylation regulate gene expression via epigenetic phenomena. The epigenetic regulation through methylation at F7 promoter as well as the inter-relationship of genetic and epigenetic modifications at F7 promoter site were both previously unexplored. F7 epigenetic regulation through methylation relates to CAD risk by affecting plasma FVIIa concentrations and its role prevails in those A1A1 subjects, i.e. not carriers of the functional A2 allele. The correlation between a polymorphism and its effect on DNA methylation and, consequently, on gene product regulation is a novel and very intriguing concept. The striking impact of the findings pertains also to the fact that, differently form genetic marks, epigenetic transcriptional regulation systems are potentially reversible, therefore opening up possible fascinating genetic-epigenetic approaches for future preventive strategies. (Dr Simonetta Friso, http://jmg.bmj.com/content/49/3/192 )

An omphalocele is a birth defect affecting about 1 in 5000 live births and characterized by the internal organs located outside the abdomen.  We conducted a genetic study using linkage analysis and microarray with quantitative microsphere hybridization techniques in a large family with multiple affected individuals and found a 710 kb duplication of chromosome band 1p31.3 involving seven genes (FOXD3, ALG6, ITGB3BP, KIAA1799, DLEU2L, PGM1 and ROR1).  This suggests that the omphalocele resulted from over expression of one or more of these genes.  Our observation is the first to elucidate the molecular cause of omphaloceles in the general population. (By Dr. Uppala Radhakrishna, http://jmg.bmj.com/content/49/4/270.abstract )

Polycystic ovary syndrome (PCOS), characterized by menstrual irregularity, hyperandrogenism and polycystic ovarian morphology, is the most common endocrinopathy in reproductive-aged women leading to anovulatory infertility. Its clinical manifestations and complications are well elaborated while the pathogenesis is obscure. In the current study, the authors took advantage of recently published genome-wide association study and proceeded replication for the gene Yeast Associated Protein 1 (YAP1) – an important transcriptional co-activator. Finally, they proved YAP1 is a novel susceptibility gene for PCOS. (By Dr. Zi-Jiang Chen, http://jmg.bmj.com/content/49/4/254.abstract )

Keratinocyte epidermal nevi (KEN) are benign congenital skin lesions that result from postzygotic mutations in mosaicism. Activating oncogenic mutations in FGFR3 and PIK3CA have been reported in approximately 40% of KEN and are absent from normal skin. However, the cause of the remaining cases is not known. Hafner et al. report that postzygotic mutations in RAS genes, the most common oncogenes involved in human cancer, are associated with a large fraction of KEN and the HRAS p.G13R substitution is a new hotspot mutation involved in this lesion. Therefore, KEN represent examples of “mosaic RASopathies”. (By Dr. Francisco X Real, http://jmg.bmj.com/content/49/4/249.abstract)

Lynch Syndrome is a heritable disorder characterized by increased risk of colorectal, endometrial and other cancers. It is caused by mutations in the DNA mismatch repair (MMR) genes. We conducted a literature review of published studies that investigated MMR gene mutation status and two tumor characteristics commonly used to exclude individuals with colorectal cancer from MMR gene mutation testing: BRAF V600E mutation status and MLH1 promoter methylation status. We showed that BRAF mutation status and MLH1 methylation are strong negative predictors of MMR mutation status, but are not definitive. These tumor characteristics should be used in conjunction with other data points in statistical models that predict likely mutation status. (By Dr Amanda B Spurdle, http://jmg.bmj.com/content/49/3/151)

Anderson Fabry disease is a progressive and debilitating lysosomal storage disorder resulting from a deficiency of a lysosomal enzyme and progressive accumulation of storage material. It affects both males and females and can result in significant pain, bowel symptoms, hearing loss, rash and reduced life expectancy from renal failure, heart disease and stroke. A treatment is available with enzyme replacement therapy however it has previously not been possible to predict which patients may have most problems in the long term. This study has used a large database of Fabry patients to examine the factors which might be able to determine which patients will have cardiac, renal, neurological events. We have developed a simple scoring system based on routinely acquired clinical parameters. These scores have been used to divide patients into different groups with significantly different clinical outcomes. We hope that this will be useful for counselling of patients with respect to their condition, initiation of treatment and stratifying patients for the development of new treatments. (By Dr Derralynn A Hughes, http://jmg.bmj.com/content/early/2012/02/06/jmedgenet-2011-100407 )