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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic AIREvariants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic AIREvariant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of AIRE-expressing primary patient monocyte-derived dendric cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109–base pair frame-shifting pseudoexon. We also found low-level AIREexpression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic AIRE–expressing cell lines. Through protein modeling and transcriptomic analyses of AIRE-transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal AIREtranscript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing AIREvariant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.

AbstractBackground:Monoclonal antibody (mAb) treatment for coronavirus disease 2019 (COVID-19) has been underutilized due to logistical challenges, lack of access, and variable treatment awareness among patients and health-care professionals. The use of telehealth during the pandemic provides an opportunity to increase access to COVID-19 care.Methods:This is a single-center descriptive study of telehealth-based patient self-referral for mAb therapy between March 1, 2021, and October 31, 2021, at Baltimore Convention Center Field Hospital (BCCFH).Results:Among the 1001 self-referral patients, the mean age was 47, and most were female (57%). White (66%), and had a primary care provider (PCP) (62%). During the study period, self-referrals increased from 14/mo in March to 427 in October resulting in a 30-fold increase. Approximately 57% of self-referred patients received a telehealth visit, and of those 82% of patients received mAb infusion therapy. The median time from self-referral to onsite infusion was 2 d (1-3 IQR).Discussion:Our study shows the integration of telehealth with a self-referral process improved access to mAb infusion. A high proportion of self-referrals were appropriate and led to timely treatment. This approach helped those without traditional avenues for care and avoided potential delay for patients seeking referral from their PCPs.