Citations

Background: Potentially lethal cardiac channelopathies/cardiomyopathies may underlie a substantial portion of sudden unexplained death in the young (SUDY). The whole-exome molecular autopsy represents the latest approach to postmortem genetic testing for SUDY. However, proper variant adjudication in the setting of SUDY can be challenging. Methods: From January 2012 through December 2013, 25 consecutive cases of SUDY from 1 to 40 years of age (average age at death 27±5.7 years; 13 white, 12 black) from Cook County, Illinois, were referred after a negative (n=16) or equivocal (n=9) conventional autopsy. A whole-exome molecular autopsy with analysis of 99 sudden death-susceptibility genes was performed. The predicted pathogenicity of ultrarare, nonsynonymous variants was determined using the American College of Medical Genetics guidelines. Results: Overall, 27 ultrarare nonsynonymous variants were seen in 16/25 (64%) victims of SUDY. Among black individuals, 9/12 (75%) had an ultrarare nonsynonymous variant compared with 7/13 (54%) white individuals. Of the 27 variants, 10 were considered pathogenic or likely pathogenic in 7/25 (28%) individuals in accordance with the American College of Medical Genetics guidelines. Pathogenic/likely pathogenic variants were identified in 5/16 (31%) of autopsy-negative cases and in 2/6 (33%) victims of SUDY with equivocal findings of cardiomyopathy. Overall, 6 pathogenic/likely pathogenic variants in 4/25 (16%) cases were congruent with the phenotypic findings at autopsy and therefore considered clinically actionable. Conclusions: Whole-exome molecular autopsy with gene-specific surveillance is an effective approach for the detection of potential pathogenic variants in SUDY cases. However, systematic variant adjudication is crucial to ensure accurate and proper care for surviving family members.

AbstractBackgroundGastrointestinal sensorimotor dysfunction underlies a wide range of esophageal, gastric, and intestinal motility and functional disorders that collectively constitute nearly half of all referrals to gastroenterologists. As a result, substantial effort has been dedicated toward the development of prokinetic agents intended to augment or restore normal gastrointestinal motility. However, the use of several clinically efficacious gastroprokinetic agents, such as cisapride, domperidone, erythromycin, and tegaserod, is associated with unfavorable cardiovascular safety profiles, leading to restrictions in their use.PurposeThe purpose of this review is to detail the cellular and molecular mechanisms that lead commonly to drug‐induced cardiac arrhythmias, specifically drug‐induced longQTsyndrome, torsades de pointes, and ventricular fibrillation, to examine the cardiovascular safety profiles of several classes of prokinetic agents currently in clinical use, and to explore potential strategies by which the risk of drug‐induced cardiac arrhythmia associated with prokinetic agents and otherQTinterval prolonging medications can be mitigated successfully.

Background— WEMA (Whole-Exome Molecular Autopsy) and surveillance of cardiac channelopathy and cardiomyopathy genes represents the latest molecular autopsy for sudden death in the young (SDY). To date, the majority of WEMA has been performed on the SDY case only. Methods and Results— We performed whole-exome sequencing and nucleotide-level coverage analysis on 28 SDY cases (18.4±7.8 years) and their parents to determine the inheritance patterns of ultrarare, nonsynonymous variants in 99 sudden death–susceptibility genes. Nonsynonymous variants were adjudicated using the American College of Medical Genetics guidelines. Overall, 17 sudden death–susceptibility gene variants were identified in 12 of 28 (43%) SDY cases. On the basis of the American College of Medical Genetics guidelines, 6 of 28 (21%) cases had a pathogenic or likely pathogenic nonsynonymous variant with 3 (50%) being de novo. Two nonsynonymous variants would not have been elevated to likely pathogenic status without knowing their de novo status. Whole-exome sequencing reached a read depth of 10× across 90% of nucleotides within sudden death–susceptibility genes in 100% of parental exomes from fresh blood draw, compared with only 82% of autopsy-sourced SDY exomes. Conclusions— An SDY-parent, trio-based WEMA may be an effective way of elucidating a monogenic cause of death and bringing clarity to otherwise ambiguous variants. If other studies confirm this relatively high rate of SDY cases stemming from de novo mutations, then the WEMA should become even more cost-effective given that the decedent’s first-degree relatives should only need minimal cardiological evaluation. In addition, autopsy-sourced DNA demonstrated strikingly lower whole-exome sequencing coverage than DNA from fresh blood draw.

Abstract Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR.

AbstractObjectiveTo identify the underlying genetic cause for recurrent intrauterine fetal death (IUFD) of males.MethodsWhole genome sequencing was performed on DNA from five healthy obligatory carrier females and an unaffected male offspring of a multigenerational pedigree with recurrent second‐trimester IUFD of males (n = 19). When documented, all deaths occurred at ≤20 weeks of gestation. Hydrops fetalis was diagnosed at death in the most recent case.ResultsFollowing variant filtering based on a recessive X‐linked inheritance pattern, a rare FOXP3 frameshift mutation (p.D303fs*87) that results in a premature truncation of the protein was discovered. Sanger sequencing confirmed the mutation in the affected fetus. The FOXP3 gene encodes for a transcriptional regulator critical to the function of regulatory T cells. FOXP3 mutations are associated with immune dysregulation, polyendocrinopathy, enteropathy, and X‐linked (IPEX) syndrome which exclusively affects males and may present with a potentially life‐threatening complex autoimmune disorder in early childhood.ConclusionsHere, we demonstrate the utility of whole genome sequencing‐based pedigree analysis to identify the genetic cause for recurrent IUFD when chromosome studies, including microarray analysis, are normal. Further studies are needed to determine the prevalence of FOXP3‐mediated IUFD in males. © 2017 John Wiley & Sons, Ltd.