Search

Report the prevalence of multiple genetic diseases in the Undiagnosed Diseases Network (UDN) cohort in the post-exome-sequencing era. UDN subjects underwent genome sequencing before inclusion in the cohort. Records of all UDN subjects until January 2024 were analyzed. The number of diagnoses, proportion of molecular versus nonmolecular (i.e., not attributable to a discretely identifiable genetic change) diagnoses, and the inheritance patterns of the genetic diagnoses were determined. Of 2799 subjects, 766 (27.4%) had diagnoses. Of these 766, 95.4% had one diagnosis, 4.0% had two diagnoses, and 0.5% had three diagnoses. Of the diagnosed subjects, 93.4% had a genetic disease, and 6.5% had a nonmolecular disease. Of subjects with two diagnoses, both diagnoses were molecular in 90.3%, while 9.7% had one molecular and one nonmolecular diagnosis. All four subjects with three diagnoses had three molecular diagnoses. 4.2% of diagnosed subjects in the UDN had more than one molecular diagnosis, with four individuals having three concurrent Mendelian diagnoses. Additionally, three subjects had concurrent molecular and nonmolecular diagnoses. Given that numerous UDN subjects had a negative genome sequence prior to UDN enrollment, multiple molecular diagnoses may contribute to diagnostic uncertainty even with genome sequencing, as may concurrent nonmolecular disease., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Purpose: Diagnostic delay in monogenic disease is reportedly common. We conducted a scoping review investigating variability in study design, results, and conclusions., Methods: We searched the academic literature on January 17, 2023, for original peer reviewed journals and conference articles that quantified diagnostic delay in monogenic disease. We abstracted the reported diagnostic delay, relevant study design features, and definitions., Results: Our search identified 259 articles quantifying diagnostic delay in 111 distinct monogenetic diseases. Median reported diagnostic delay for all studies collectively in monogenetic diseases was 5.0 years (IQR 2-10). There was major variation in the reported delay within individual monogenetic diseases. Shorter delay was associated with disorders of childhood metabolism, immunity, and development. The majority (67.6%) of articles that studied delay reported an improvement with calendar time. Study design and definitions of delay were highly heterogenous. Three gaps were identified: (1) no studies were conducted in the least developed countries, (2) delay has not been studied for the majority of known, or (3) most prevalent genetic diseases., Conclusion: Heterogenous study design and definitions of diagnostic delay inhibit comparison across studies. Future efforts should focus on standardizing delay measurements, while expanding the research to low-income countries., Competing Interests: Conflict of Interest Lisa Bastarache is a consultant for Galatea Bio. Josh Peterson is a consultant for Natera. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling with studies on stress-induced endocannabinoid dysregulation focusing on cerebral changes that are temporally proximal to stressors. Little is known about temporally distal and sex-specific effects, especially in cerebellum, which is vulnerable to early developmental stress and is dense with cannabinoid receptors. Following limited bedding at postnatal days 2-9, adult (postnatal day 70) cerebellar and hippocampal endocannabinoids, related lipids, and mRNA were assessed, and behavioral performance evaluated. Regional and sex-specific effects were present at baseline and following early-life stress. Limited bedding impaired peripherally-measured basal corticosterone in adult males only. In the CNS, early-life stress (1) decreased 2-arachidonoyl glycerol and arachidonic acid in the cerebellar interpositus nucleus in males only; (2) decreased 2-arachidonoyl glycerol in females only in cerebellar Crus I; and (3) increased dorsal hippocampus prostaglandins in males only. Cerebellar interpositus transcriptomics revealed substantial sex effects, with minimal stress effects. Stress did impair novel object recognition in both sexes and social preference in females. Accordingly, the cerebellar endocannabinoid system exhibits robust sex-specific differences, malleable through early-life stress, suggesting the role of endocannabinoids and stress to sexual differentiation of the brain and cerebellar-related dysfunctions.