Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al., 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al., 2008). The markers lie about 340 kb apart in the gene. Here, we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the National Institute of Mental Health (NIMH) waves 1–4 (P=0.05; odds ratio (OR)=1.24) and German (P=0.0006; OR=1.34) samples. This association was replicated in an independent US sample known as NIMH wave 5 (466 cases, 212 controls; P=0.017; OR=1.38). A random-effects meta-analysis of all three samples was significant (P=3 × 10⁻⁶; OR=1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (P=0.0001; OR=1.70), and similar ORs in the NIMH 1–4 and NIMH 5 samples that were not significant at the P<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (P=1.7 × 10⁻⁵; OR=1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker × marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.

CARMIL2 deficiency is a rare combined immunodeficiency (CID) characterized by defective CD28-mediated T cell co-stimulation, altered cytoskeletal dynamics, and susceptibility to Epstein Barr Virus smooth muscle tumors (EBV-SMTs). Case reports associated with EBV-SMTs are limited. We describe herein a novel homozygous CARMIL2 variant (c.1364_1393del) in two Saudi Arabian male siblings born to consanguineous parents who developed EBV-SMTs. CARMIL2 protein expression was significantly reduced in CD4+ T cells and CD8+ T cells. T cell proliferation on stimulation with soluble (s) anti-CD3 or (s) anti-CD3 plus anti-CD28 antibodies was close to absent in the proband, confirming altered CD28-mediated co-signaling. CD28 expression was substantially reduced in the proband's T cells, and was diminished to a lesser degree in the T cells of the younger sibling, who has a milder clinical phenotype. Defects in both T and B cell compartments were observed, including absent central memory CD8+ T cells, and decreased frequencies of total and class-switched memory B cells. FOXP3+ regulatory T cells (Treg) were also quantitatively decreased, and furthermore CD25 expression within the Treg subset was substantially reduced. These data confirm the pathogenicity of this novel loss-of-function (LOF) variant in CARMIL2 and expand the genotypic and phenotypic spectrum of CIDs associated with EBV-SMTs.

The overall neurobiological mechanisms by which lithium and valproate stabilize mood in bipolar disorder patients have yet to be fully defined. The therapeutic efficacy and dissimilar chemical structures of these medications suggest that they perturb both shared and disparate cellular processes. To investigate key pathways and functional clusters involved in the global action of lithium and valproate, we generated interaction networks formed by well-supported drug targets. Striking functional similarities emerged. Intersecting nodes in lithium and valproate networks highlighted a strong enrichment of apoptosis clusters and neurotrophin signaling. Other enriched pathways included MAPK, ErbB, insulin, VEGF, Wnt and long-term potentiation indicating a widespread effect of both drugs on diverse signaling systems. MAPK1/3 and AKT1/2 were the most preponderant nodes across pathways suggesting a central role in mediating pathway interactions. The convergence of biological responses unveils a functional signature for lithium and valproate that could be key modulators of their therapeutic efficacy.

There is controversy regarding the patterns and prognostic significance of Her-2/neu and p-53 expression in osteosarcoma. Further, their combined expression has not been studied. Prechemotherapy biopsy specimens of 63 osteosarcoma patients from June 2004 to August 2006 were analyzed for Her-2/neu and p-53 using immunohistochemistry and compared with grade, stage, and morphologic subtype of tumor. There were 59 high-grade tumors; 32 of 63 had metastases. Histopathologic types included 36 of 63 osteoblastic and 18 of 63 chondroblastic subtypes. Male sex (P=0.045) and chondroblastic type (P=0.004) were associated with metastatic disease. Her-2/neu cytoplasmic staining was seen in 30 of 63 (47.1%) cases, 4 of 30 had additional membranous staining, 17 of 30 were metastatic, and 29 of 30 were high-grade tumors. Staining grade was 3+ in 10 of 30 samples whereas staining intensity 3+ was observed in 26 of 30 samples. Her-2/neu 3+ staining grade was significantly associated with chondroblastic subtype (6/18, P=0.026). P-53 staining was seen in 20 of 63 (31.74%) cases (all high grade), of which 11 were metastatic. Staining grades 3+ and 4+ were seen in 16 of 20 samples whereas staining intensity 3+ in 13 of 20 samples. P-53 expression was higher in chondroblastic (7/18, P value was not significant) and fibroblastic (3/3, P<0.05) subtypes. Coexpression of Her-2/neu and p-53 was seen in 10 cases (15.87%); 3 of 10 cases showed Her-2/neu membranous staining (P=0.01). Her-2/neu (47.1%), p-53 (31.74%), and their combined expression (15.87%) were not related to grade or stage of tumor. Chondroblastic subtype was associated with staining grade 3+ of Her-2/neu staining whereas coexpression of Her-2/neu and p-53 was significantly associated with membranous Her-2/neu staining.

Infantile fibrosarcoma (IFS) is nearly universally driven by gene fusions involving the NTRK family. ETV6-NTRK3 fusions account for ∼85% of alterations; the remainder are attributed to NTRK-variant fusions. Rarely, other genomic aberrations have been described in association with tumors identified as IFS or IFS-like. We describe the utility of genomic characterization of an IFS-like tumor. We also describe the successful treatment combination of VAC (vincristine, actinomycin, cyclophosphamide) with tyrosine kinase inhibitor (TKI) maintenance in this entity. This patient presented at birth with a right facial mass, enlarging at 1 mo to 4.9 × 4.5 × 6.3 cm. Biopsy demonstrated hypercellular fascicles of spindle cells with patchy positivity for smooth muscle actin (SMA) and negativity for S100, desmin, myogenin, and MyoD1. Targeted RNA sequencing identified a novel RBPMS-MET fusion with confirmed absence of ETV6-NTRK3, and the patient was diagnosed with an IFS-like tumor. A positron emission tomography (PET) scan was negative for metastatic disease. VAC was given for a duration of 10 mo. Resection at 13 mo of age demonstrated positive margins. Cabozantinib, a MET-targeting TKI, was initiated. The patient tolerated cabozantinib well and has no evidence of disease at 24 mo of age. We describe a novel RBPMS-MET driver fusion in association with a locally aggressive IFS-like tumor. MET functions as an oncogene and, when associated with the RNA binding protein RBPMS, forms an in-frame fusion product that retains the MET kinase domain. This fusion is associated with aberrant cell signaling pathway expression and subsequent malignancy. We describe treatment with cabozantinib in a patient with an IFS-like neoplasm.