Children (Basel). 2021 Feb 22;8(2):163. doi: 10.3390/children8020163.

ABSTRACT

The coincidence of two rare diseases such as congenital diaphragmatic hernia (CDH) and neuroblastoma is exceptional. With an incidence of around 2-3:10,000 and 1:8000 for either disease occurring on its own, the chance of simultaneous presentation of both pathologies at birth is extremely low. Unfortunately, the underlying processes leading to congenital malformation and neonatal tumors are not yet thoroughly understood. There are several hypotheses revolving around the formation of CDH and neuroblastoma. The aim of our study was to put the respective hypotheses of disease formation as well as known factors in this process into perspective regarding their similarities and possible overlaps of congenital disease formation. We present the joint occurrence of these two rare diseases based on a patient presentation and immunochemical prognostic marker evaluation. The aim of this manuscript is to elucidate possible similarities in the pathogeneses of both disease entities. Discussed are the role of toxins, cell differentiation, the influence of retinoic acid and NMYC as well as of hypoxia. The detailed discussion reveals that some of the proposed pathophysiological mechanisms of both malformations have common aspects. Especially disturbances of the retinoic acid pathway and NMYC expression can influence and disrupt cell differentiation in either disease. Due to the rarity of both diseases, interdisciplinary efforts and multi-center studies are needed to investigate the reasons for congenital malformations and their interlinkage with neonatal tumor disease.

PMID:33671521 | DOI:10.3390/children8020163

Nat Genet. 2021 Mar;53(3):313-321. doi: 10.1038/s41588-021-00800-7. Epub 2021 Mar 4.

ABSTRACT

Induced pluripotent stem cells (iPSCs) are an established cellular system to study the impact of genetic variants in derived cell types and developmental contexts. However, in their pluripotent state, the disease impact of genetic variants is less well known. Here, we integrate data from 1,367 human iPSC lines to comprehensively map common and rare regulatory variants in human pluripotent cells. Using this population-scale resource, we report hundreds of new colocalization events for human traits specific to iPSCs, and find increased power to identify rare regulatory variants compared with somatic tissues. Finally, we demonstrate how iPSCs enable the identification of causal genes for rare diseases.

PMID:33664507 | PMC:PMC7944648 | DOI:10.1038/s41588-021-00800-7

Genet Med. 2021 Mar 3. doi: 10.1038/s41436-021-01114-z. Online ahead of print.

ABSTRACT

PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis.

METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes.

RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes.

CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

PMID:33658631 | DOI:10.1038/s41436-021-01114-z

Medicine (Baltimore). 2021 Mar 5;100(9):e24978. doi: 10.1097/MD.0000000000024978.

ABSTRACT

RATIONALE: Severe hypofibrinogenemia after intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) is rare and easily overlooked, but hypofibrinogenemia increases the risk of major bleeding. However, it is unclear when hypofibrinogenemia reaches the peak and when hypofibrinogenemia is resolved.

PATIENT CONCERNS: Case 1 was of a 66-year-old man who was hospitalized due to sudden onset of vague speech and right hemiplegia for 4 hours. Case 2 was of an 84-year-old woman who was hospitalized for sudden onset of left hemiplegia and vague speech for 4 hours. In case 1, fibrinogen levels decreased from normal values to <0.25 g/L within 4.5 hours after commencing IVT and returned to normal at 35 hours later. In case 2, fibrinogen levels decreased from 1.1 to <0.25 g/L within 2 hours after commencing IVT and normalized 36.5 hours later.

DIAGNOSES: Both patients were diagnosed with rt-PA-related hypofibrinogenemia.

INTERVENTIONS: No antiplatelet or symptomatic treatment was administered during the period of hypofibrinogenemia.

OUTCOMES: Fibrinogen levels gradually recovered. In case 1, the patient did not experience cerebral hemorrhage during hypofibrinogenemia. His symptoms improved significantly within 1 week. In case 2, repeat computed tomography revealed minor cerebral hemorrhage, but no deterioration in her condition was noted until she was discharged.

LESSONS: Rapid, severe, and prolonged hypofibrinogenemia may occur after IVT with rt-PA, which may increase the risk of massive hemorrhage and affect the related therapy. Prompt diagnosis of hypofibrinogenemia is important for preventing complications. We recommend checking the fibrinogen levels routinely after IVT. Fibrinogen replacement therapy and platelet transfusion are the main management routes for rt-PA-related symptomatic intracranial hemorrhage.

PMID:33655967 | PMC:PMC7939149 | DOI:10.1097/MD.0000000000024978

Eur J Health Law. 2020 Apr 16;27(3):290-307. doi: 10.1163/15718093-BJA10005.

ABSTRACT

Although several European law instruments specifically promote the development of orphan medicines, rare disease patients still suffer from an excessive lack of access to orphan drugs. In order to base a claim for equity of access to research benefits, health vulnerability is introduced as a human rights-based public health concept. It represents a potentially valuable and powerful means in European law for rare disease patients to claim for an improved public action to develop innovative orphan drugs, including through the use of novel data-driven technologies such as computer modelling and simulation, as they have the potential to palliate some of the obstacles in the current development process of orphan medicines. The human rights-based approach would be all the more valuable, as it would simultaneously draw attention on privacy aspects of vulnerability for orphan disease patients, especially regarding increased risks stemming from the processing of highly sensitive health data.

PMID:33652405 | DOI:10.1163/15718093-BJA10005

Muscle Nerve. 2021 Mar 2. doi: 10.1002/mus.27216. Online ahead of print.

ABSTRACT

INTRODUCTION/AIMS: RNA binding proteins (RBPs) play an important role in skeletal muscle development and disease by regulating RNA splicing. In myotonic dystrophy type 1 (DM1), the RBP MBNL1 (Muscleblind-like) is sequestered by toxic CUG repeats, leading to mis-splicing of MBNL1 targets. Mounting evidence from the literature has implicated other factors in the pathogenesis of DM1. Here we sought to evaluate the functional role of hnRNP L in normal and DM1 muscle cells. We sought to test if modulation of hnRNP L expression affected DM1 splicing targets and myogenic outcomes.

METHODS: Co-immunoprecipitation assays using hnRNPL and MBNL1 expression constructs and expression profiling in normal and DM1 muscle cell lines were performed. Zebrafish morpholinos targeting hnrnpl and hnrnpl2 were injected into one-cell zebrafish for developmental and muscle analysis. Ascochlorin administration to DM1 myoblasts was performed and expression of the CUG repeats, DM1 splicing biomarkers, and hnRNP L expression levels were evaluated.

RESULTS: Using DM1 patient myoblast cell lines we observed the formation of abnormal hnRNP L nuclear foci within and outside the expanded CUG repeats, further suggesting a role for this factor in DM1 pathology. We showed that the antiviral and antitumorigenic isoprenoid compound ascochlorin increased MBNL1 and hnRNP L expression levels. Drug treatment of DM1 muscle cells with ascochlorin partially rescued mis-splicing of established early biomarkers of DM1 and improved the defective myotube formation displayed by DM1 muscle cells.

DISCUSSION: Together, these studies reveal that hnRNP L modulated DM1 pathologies, and is a potential therapeutic target. This article is protected by copyright. All rights reserved.

PMID:33651408 | DOI:10.1002/mus.27216

Value Health. 2021 Mar;24(3):431-442. doi: 10.1016/j.jval.2020.10.014. Epub 2020 Dec 5.

ABSTRACT

OBJECTIVES: To analyze whether the adoption of a societal perspective would alter the results and conclusions of economic evaluations for rare disease-related healthcare technologies.

METHODS: A search strategy involving all the active substances considered as orphan drugs by the European Medicines Agency plus a list of 76 rare diseases combined with economic-related terms was conducted on Medline and the Cost-Effectiveness Registry from the beginning of 2000 until November 2018. We included studies that considered quality-adjusted life years as an outcome, were published in a scientific journal, were written in English, included informal care costs or productivity losses, and separated the results according to the applied perspective.

RESULTS: We found 14 articles that fulfilled the inclusion criteria. Productivity losses were considered in 12 studies, the human capital approach being the method most frequently used. Exclusively, informal care was considered in 2 articles, being valued through the opportunity cost method. The 14 articles selected resulted in 26 economic evaluation estimations, from which incremental cost-utility ratio values changed from cost-effective to dominant in 3 estimates, but the consideration of societal costs only modified the authors' conclusion in 1 study.

CONCLUSIONS: The presence of societal costs in the economic evaluation of rare diseases did not affect the conclusions of the studies except in a single specific case. In those studies where the societal perspective was considered, we did not find significant changes in the economic evaluation results due to the higher costs of treatments and the low quality-adjusted life-years gained.

PMID:33641778 | DOI:10.1016/j.jval.2020.10.014

Am J Hum Genet. 2021 Mar 4;108(3):482-501. doi: 10.1016/j.ajhg.2021.02.008. Epub 2021 Feb 25.

ABSTRACT

Rare monogenic disorders of the primary cilium, termed ciliopathies, are characterized by extreme presentations of otherwise common diseases, such as diabetes, hepatic fibrosis, and kidney failure. However, despite a recent revolution in our understanding of the cilium's role in rare disease pathogenesis, the organelle's contribution to common disease remains largely unknown. Hypothesizing that common genetic variants within Mendelian ciliopathy genes might contribute to common complex diseases pathogenesis, we performed association studies of 16,874 common genetic variants across 122 ciliary genes with 12 quantitative laboratory traits characteristic of ciliopathy syndromes in 452,593 individuals in the UK Biobank. We incorporated tissue-specific gene expression analysis, expression quantitative trait loci, and Mendelian disease phenotype information into our analysis and replicated our findings in meta-analysis. 101 statistically significant associations were identified across 42 of the 122 examined ciliary genes (including eight novel replicating associations). These ciliary genes were widely expressed in tissues relevant to the phenotypes being studied, and eQTL analysis revealed strong evidence for correlation between ciliary gene expression levels and laboratory traits. Perhaps most interestingly, our analysis identified different ciliary subcompartments as being specifically associated with distinct sets of phenotypes. Taken together, our data demonstrate the utility of a Mendelian pathway-based approach to genomic association studies, challenge the widely held belief that the cilium is an organelle important mainly in development and in rare syndromic disease pathogenesis, and provide a framework for the continued integration of common and rare disease genetics to provide insight into the pathophysiology of human diseases of immense public health burden.

PMID:33636100 | DOI:10.1016/j.ajhg.2021.02.008

JAMA Netw Open. 2021 Feb 1;4(2):e2036220. doi: 10.1001/jamanetworkopen.2020.36220.

ABSTRACT

IMPORTANCE: The Undiagnosed Diseases Network (UDN) is a national network that evaluates individual patients whose signs and symptoms have been refractory to diagnosis. Providing reliable estimates of admission outcomes may assist clinical evaluators to distinguish, prioritize, and accelerate admission to the UDN for patients with undiagnosed diseases.

OBJECTIVE: To develop computational models that effectively predict admission outcomes for applicants seeking UDN evaluation and to rank the applications based on the likelihood of patient admission to the UDN.

DESIGN, SETTING, AND PARTICIPANTS: This prognostic study included all applications submitted to the UDN from July 2014 to June 2019, with 1209 applications accepted and 1212 applications not accepted. The main inclusion criterion was an undiagnosed condition despite thorough evaluation by a health care professional; the main exclusion criteria were a diagnosis that explained the objective findings or a review of the records that suggested a diagnosis. A classifier was trained using information extracted from application forms, referral letters from health care professionals, and semantic similarity between referral letters and textual description of known mendelian disorders. The admission labels were provided by the case review committee of the UDN. In addition to retrospective analysis, the classifier was prospectively tested on another 288 applications that were not evaluated at the time of classifier development.

MAIN OUTCOMES AND MEASURES: The primary outcomes were whether a patient was accepted or not accepted to the UDN and application order ranked based on likelihood of admission. The performance of the classifier was assessed by comparing its predictions against the UDN admission outcomes and by measuring improvement in the mean processing time for accepted applications.

RESULTS: The best classifier obtained sensitivity of 0.843, specificity of 0.738, and area under the receiver operating characteristic curve of 0.844 for predicting admission outcomes among 1212 accepted and 1210 not accepted applications. In addition, the classifier can decrease the current mean (SD) UDN processing time for accepted applications from 3.29 (3.17) months to 1.05 (3.82) months (68% improvement) by ordering applications based on their likelihood of acceptance.

CONCLUSIONS AND RELEVANCE: A classification system was developed that may assist clinical evaluators to distinguish, prioritize, and accelerate admission to the UDN for patients with undiagnosed diseases. Accelerating the admission process may improve the diagnostic journeys for these patients and serve as a model for partial automation of triaging or referral for other resource-constrained applications. Such classification models make explicit some of the considerations that currently inform the use of whole-genome sequencing for undiagnosed disease and thereby invite a broader discussion in the clinical genetics community.

PMID:33630084 | PMC:PMC7907957 | DOI:10.1001/jamanetworkopen.2020.36220

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2021/02/23

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

J Pediatr Gastroenterol Nutr. 2021 May 1;72(5):748-751. doi: 10.1097/MPG.0000000000003052.

ABSTRACT

Venous thromboembolism (VTE) is a known complication in children with inflammatory bowel disease (IBD). Despite awareness of the increased thrombosis risk in this population, prophylaxis is not standardly used and there is limited published guidance for thrombosis prevention. To better appreciate the impact of thrombosis in this population, we compared children with IBD who did or did not have a VTE, using the Pediatric Health Information System inpatient database from 2009 to 2017. In hospitalized children with IBD, VTE was associated with longer median hospital stays (11 vs 5 days), need for intensive care unit admission (30.2% vs 4.8%), higher median adjusted costs ($32.8k vs $12.3k) and hospital charges ($96.6k vs $36k), and in-hospital death (1.5% vs 0.2%) (P < 0.001 in all comparisons). These findings highlight the need to determine and implement appropriate strategies to reduce VTE rates in children with IBD, given its association with high morbidity, mortality, and cost.

PMID:33616374 | DOI:10.1097/MPG.0000000000003052

Ophthalmic Epidemiol. 2021 Feb 21:1-7. doi: 10.1080/09286586.2021.1883675. Online ahead of print.

ABSTRACT

Purpose: Stargardt disease (SD) is the most common juvenile macular degeneration and a leading cause of uncorrectable childhood blindness. The progressive and incurable nature of this chronic condition entails a long-term financial burden on affected individuals. The economic costs of SD have not been characterized in detail, so we aimed to estimate the direct healthcare cost of SD. Methods: Outpatient administrative claims data (2010-2014) for patients with SD were analyzed from the IBM® MarketScan® Commercial Claims and Encounters Database. Two comparison groups were selected: nonexudative age-related macular degeneration (AMD) and bilateral sensorineural hearing loss (SHL). Gross median payments per year of insurance coverage were calculated. Results: A total of 472,428 patients were analyzed (5,015 SD, 369,750 SHL and 97,663 AMD patients respectively). The payment per year of insurance coverage for SD (median: 105.58 USD, IQR: 50.53 USD-218.71 USD) was higher than that of SHL (median: 51.01 USD, IQR: 25.66 USD-121.66 USD, p < .001) and AMD (median: 76.20 USD, IQR: 38.00 USD-164.86 USD, p < .001). When adjusted for age, sex, year of first service, and type of benefit plan, the annual payment for SD was 47.83 USD higher than SHL (p < .001) and 17.34 USD higher than AMD (p < .001). Conclusions: There is a significant direct healthcare cost associated with SD. The annual per-patient cost of SD was higher than SHL, another condition that causes sensory impairment in people of all ages, and nonexudative AMD which causes a similar pattern of visual loss that typically begins later in life. The total lifetime per-patient cost of SD may exceed that of nonexudative AMD.

PMID:33615979 | DOI:10.1080/09286586.2021.1883675

26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2021/02/20

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Autoimmun Rev. 2021 Apr;20(4):102774. doi: 10.1016/j.autrev.2021.102774. Epub 2021 Feb 17.

ABSTRACT

Systemic autoinflammatory disorders comprise an expanding group of rare conditions. They are mediated by dysfunction of the innate immune system and share a core of phenotypic manifestations including recurrent attacks of fever, cutaneous signs, chest or abdominal pain, lymphadenopathy, vasculopathy, and musculoskeletal symptoms. Diagnosis is often established in childhood, but a growing number of adult patients are being recognized with systemic autoinflammatory disorders, including adult-onset disease. In this review, we provide a concise update on the pathophysiology, clinical presentation, and diagnostic approach of systemic autoinflammatory disorders with an emphasis on the adult patient population. Despite the recent advances in genetic testing, the diagnosis of autoinflammatory disease in adult patients is often based on a thorough knowledge of the clinical phenotype. Becoming acquainted with the clinical features of these rare disorders may assist in developing a high index of suspicion for autoinflammatory disease in patients presenting with unexplained episodes of fever or inflammation.

PMID:33609798 | DOI:10.1016/j.autrev.2021.102774

BMC Med Inform Decis Mak. 2021 Feb 18;21(1):65. doi: 10.1186/s12911-021-01435-8.

ABSTRACT

BACKGROUND: Rare Diseases (RDs) are difficult to diagnose. Clinical Decision Support Systems (CDSS) could support the diagnosis for RDs. The Medical Informatics in Research and Medicine (MIRACUM) consortium developed a CDSS for RDs based on distributed clinical data from eight German university hospitals. To support the diagnosis for difficult patient cases, the CDSS uses data from the different hospitals to perform a patient similarity analysis to obtain an indication of a diagnosis. To optimize our CDSS, we conducted a qualitative study to investigate usability and functionality of our designed CDSS.

METHODS: We performed a Thinking Aloud Test (TA-Test) with RDs experts working in Rare Diseases Centers (RDCs) at MIRACUM locations which are specialized in diagnosis and treatment of RDs. An instruction sheet with tasks was prepared that the participants should perform with the CDSS during the study. The TA-Test was recorded on audio and video, whereas the resulting transcripts were analysed with a qualitative content analysis, as a ruled-guided fixed procedure to analyse text-based data. Furthermore, a questionnaire was handed out at the end of the study including the System Usability Scale (SUS).

RESULTS: A total of eight experts from eight MIRACUM locations with an established RDC were included in the study. Results indicate that more detailed information about patients, such as descriptive attributes or findings, can help the system perform better. The system was rated positively in terms of functionality, such as functions that enable the user to obtain an overview of similar patients or medical history of a patient. However, there is a lack of transparency in the results of the CDSS patient similarity analysis. The study participants often stated that the system should present the user with an overview of exact symptoms, diagnosis, and other characteristics that define two patients as similar. In the usability section, the CDSS received a score of 73.21 points, which is ranked as good usability.

CONCLUSIONS: This qualitative study investigated the usability and functionality of a CDSS of RDs. Despite positive feedback about functionality of system, the CDSS still requires some revisions and improvement in transparency of the patient similarity analysis.

PMID:33602191 | PMC:PMC7890997 | DOI:10.1186/s12911-021-01435-8

A novel proline substitution (Arg201Pro) in alpha helix 8 of TMEM98 causes autosomal dominant nanophthalmos-4, closed angle glaucoma and attenuated visual acuity.

Exp Eye Res. 2021 Feb 14;:108497

Authors: Koenighofer M, Parzefall T, Frohne A, Frei E, Waldstein SM, Mitulovic G, Schoefer C, Frei K, Lucas T

Abstract
Nanophthalmos-4 is a rare autosomal dominant disorder caused by two known variations in TMEM98. An Austrian Caucasian pedigree was identified suffering from nanophthalmos and late onset angle-closure glaucoma and premature loss of visual acuity. Whole exome sequencing identified segregation of a c.602G > C transversion in TMEM98 (p.Arg201Pro) as potentially causative. A protein homology model generated showed a TMEM98 structure comprising α4, α5/6, α7 and α8 antiparallel helix bundles and two predicted transmembrane domains in α1 and α7 that have been confirmed in vitro. Both p.Arg201Pro and the two missense variations representing proline insertions identified previously to cause nanophthalmos-4 (p.Ala193Pro and p.His196Pro) are located in the charge polarized helix α8 (p.183-p210). Stability of the C-terminal alpha helical structure of TMEM98 is therefore essential to prevent the development of human nanophthalmos-4. Precise molecular diagnosis could lead to the development of tailored therapies for patients with orphan ocular disease.

PMID: 33596443 [PubMed - as supplied by publisher]

New Drugs for Rare Disorders.

Am J Nurs. 2021 02 01;121(2):27

Authors: Aschenbrenner DS

Abstract
Several new drugs have been approved to treat rare genetic disorders: setmelanotide for certain conditions causing obesity; lumasiran for primary hyperoxaluria type 1, a kidney disorder; and lonafarnib for two diseases that cause premature aging.

PMID: 33497125 [PubMed - indexed for MEDLINE]

Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients-A Known Issue of Unknown Origin.

Int J Environ Res Public Health. 2020 12 30;18(1):

Authors: Keipert C, Drechsel-Bäuerle U, Oberle D, Müller-Olling M, Hilger A

Abstract
There is a broad range of factor products approved in Germany for haemophilia A treatment. Since the introduction of recombinant coagulation factor VIII (FVIII) products in the 1990s, there has been substantial debate whether there is a difference in inhibitor incidence between single FVIII products or product classes. Neither haemophilia registries nor clinical studies, including a randomised controlled clinical trial, provided a consistent and definite answer. The reasons were mainly related to methodological challenges in conducting controlled studies in a rare disease. In this analysis, the most relevant epidemiological challenges and main problems were examined, including study bias, potential overlap of individual studies and advanced development of therapy and methods in the course of time. Meta-analyses on two levels showed that therapies using recombinant products resulted in different event rates when compared to plasma-derived products. These results are accompanied by substantial study heterogeneity evidenced by Cochran's Q tests. Only three studies have been identified that meet the standards of current clinical guidance. To finally resolve this ongoing and disputable safety issue of replacement therapy, collaboration among registry owners, academia and regulators must be fostered.

PMID: 33396748 [PubMed - indexed for MEDLINE]

Editorial of Special Issue "Rare Kidney Diseases: New Translational Research Approach to Improve Diagnosis and Therapy".

Int J Mol Sci. 2020 Jun 14;21(12):

Authors: Zaza G, Gambaro G

Abstract
In this Special Issue entitled "Rare Kidney Diseases: New Translational Research Approach to Improve Diagnosis and Therapy", of the International Journal of Molecular Sciences, that includes original articles and reviews, authors have underlined the role of biomedical research in providing new insights into the pathologies of complex kidney diseases [...].

PMID: 32545922 [PubMed - indexed for MEDLINE]

Mol Psychiatry. 2021 Feb 17. doi: 10.1038/s41380-021-01035-y. Online ahead of print.

ABSTRACT

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3'-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.

PMID:33597717 | DOI:10.1038/s41380-021-01035-y