Ober, Carole

Anthracycline-induced cardiotoxicity (ACT) is a key limiting factor in setting optimal chemotherapy regimes, with almost half of patients expected to develop congestive heart failure given high doses. However, the genetic basis of sensitivity to anthracyclines remains unclear. We created a panel of iPSC-derived cardiomyocytes from 45 individuals and performed RNA-seq after 24 hr exposure to varying doxorubicin dosages. The transcriptomic response is substantial: the majority of genes are differentially expressed and over 6000 genes show evidence of differential splicing, the later driven by reduced splicing fidelity in the presence of doxorubicin. We show that inter-individual variation in transcriptional response is predictive of in vitro cell damage, which in turn is associated with in vivo ACT risk. We detect 447 response-expression quantitative trait loci (QTLs) and 42 response-splicing QTLs, which are enriched in lower ACT GWAS p -values, supporting the in vivo relevance of our map of genetic regulation of cellular response to anthracyclines.

ACTB encodes the β-actin, and pathogenic variations in this gene have typically been associated with Baraitser-Winter cerebrofrontofacial syndrome, a congenital malformation syndrome characterized by short stature, craniofacial anomalies, and cerebral anomalies. Here, we describe the third case with the p.Arg183Trp variant in ACTB causing juvenile-onset dystonia. Our patient has severe, intractable dystonia, developmental delay, and sensorineural hearing loss, besides hyperintensities in the caudate nuclei and putamen on the brain MRI, which is a distinct but overlapping phenotype with the previously reported case of identical twins with the same alteration in ACTB.

Abstract Juvenile dermatomyositis (JDM) is a multisystem autoimmune disease that at times resembles chronic graft-vs-host disease. This led us to suggest that nonself cells may play a role in the disease process. In this study we examined the relationship between HLA genotype and the presence of maternally derived chimeric cells in JDM patients and healthy controls, and assessed immunologic activity in the chimeric cells. We identified chimeric cells more often in children with JDM (60 of 72) than in their unaffected siblings (11 of 48) or in healthy controls (5 of 29). The presence of chimerism in the JDM patients, their healthy siblings, and unaffected control children was associated with a HLA-DQA1*0501 allele in the mother (p = 0.011). Further, we show that maternally transferred chimeric T cells are responsive to the host’s (JDM childs’) lymphocytes (33.75 ± 8.4 IFN-γ-producing cells from JDM cells vs 5.0 ± 1.25 from maternal cells), and that this is a memory response. These combined data indicate that chimeric cells play a direct role in the JDM disease process and that the mother’s HLA genotype facilitates the transfer and/or persistence of maternal cells in the fetal circulation.