Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling.

Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.

In a Genomic Era, Placental Pathology Still Holds the Key in the Nondysmorphic Stillbirth.

Objective To explore the relative utility of genetic testing in contrast to placental pathology in explaining causation of death in the structurally normal stillborn population. Methods A retrospective review of a structurally normal stillborn infant cohort in South East Scotland between 2011 and 2015, defined by death at or after 24 weeks of gestation. We reviewed pathology reports and collected demographic data on cases. This information was collated with genetic test results (quantitative fluorescent polymerase chain reaction and microarray analysis) and placental pathology to create a database for analysis. Primary Results Within the structurally normal population (n = 131), there were 125 genetic tests performed and 11 abnormal results. Sixty-six microarray analyses were performed, and 2 (3%) of the results were thought likely to reflect cause of stillbirth (1 case of incomplete trisomy 4 and 1 case of deletion of chromosome Xp in a female). Analysis was significantly limited in 2 cases as parental samples were not available. The placental pathology was available in a total of 129 cases; significant findings were identified in 100 cases; 79 (61%) showed changes that were considered to have caused death (including cord "accidents"), and a further 21 (16%) showed findings likely to influence the management of subsequent pregnancies. Conclusions We reaffirm the utility of placental examination in the investigation of stillbirth. In cases of nondysmorphic stillbirth where placental pathology does not explain the cause of stillbirth, microarray analysis of fetal DNA can add further diagnostic information in 3% of cases but can add further diagnostic confusion, and it is important that parental bloods are taken to minimize this risk.

Ten years of neonatal autopsies in tertiary referral centre: retrospective study.

OBJECTIVES: To measure the neonatal autopsy rate at a tertiary referral centre and identify trends over the past decade. To identify factors that may influence the likelihood of consent being given for autopsy. To examine any discordance between diagnoses before death and at autopsy. DESIGN: Retrospective review of patients' records. SETTING: Tertiary neonatal referral centre affiliated to university. OUTCOME MEASURES: Sex, gestational age, birth weight, type of delivery, and length of stay in neonatal unit for baby. Maternal age, marital status, history of previous pregnancies, and details of who requested permission for autopsy. Concordance between diagnoses before death and at autopsy. RESULTS: An autopsy was performed in 209/314 (67%) cases. New information was obtained in 50 (26%) autopsies. In six (3%) cases this information was crucial for future counselling. In 145 (74%) there was complete concordance between the clinical cause of death and the findings at autopsy. From 1994 onwards the autopsy rate in the neonatal unit fell. The only significant factor associated with consent for autopsy was increased gestational age. CONCLUSIONS: Important extra information can be gained at neonatal autopsies. This should help parents to make an informed decision when they are asked to give permission for their baby to have an autopsy. These findings are of particular relevance in view of the recent negative publicity surrounding neonatal autopsies and the general decline in the neonatal autopsy rate over the decade studied.