BMC Neurol. 2023 Aug 29;23(1):312. doi: 10.1186/s12883-023-03360-x.

ABSTRACT

BACKGROUND: The standard of diagnosing primary lateral sclerosis, the Pringle criteria, requires three years of purely upper motor neuron symptom presentation before confirming diagnosis. This classic standard has been questioned on occasion due to its restrictive range of both time period and symptomatic exhibition.

CASE PRESENTATION: This case report will review a 57-year-old Caucasian female who presented with pyramidal and extrapyramidal features suggestive of the exceedingly rare disease primary lateral sclerosis plus parkinsonism. We will describe the mixture of upper motor neuron signs and striking parkinsonian symptoms experienced by the patient, as well as the full diagnostic workup leading to her preliminary diagnosis. The details of this case will then be utilized to explore the diagnostic criteria of primary lateral sclerosis, as well as to work through the differential of conditions resembling Parkinson's disease.

CONCLUSIONS: The current criteria to diagnose primary lateral sclerosis may be excluding patients with the disease and is an ongoing area of investigation. A thorough differential including other neurodegenerative conditions is necessary to consider and requires long-term follow-up.

PMID:37644413 | DOI:10.1186/s12883-023-03360-x

Minerva Gastroenterol (Torino). 2023 Sep;69(3):365-373. doi: 10.23736/S2724-5985.21.03002-3.

ABSTRACT

BACKGROUND: The association between sleep disorders and gastroesophageal reflux disease (GERD) has been the subject of several studies; however, quality of sleep has been under investigated in adult patients with eosinophilic esophagitis (EoE) and achalasia (Ach). This study aims to evaluate the prevalence of sleep disturbances in patients with EoE and Ach compared to GERD patients and their associations with esophageal symptoms.

METHODS: Thirty Ach patients and 20 EoE patients were consecutively enrolled and compared to a control group of 46 GERD patients. All patients underwent a standardized questionnaire investigating the intensity-frequency scores (from 0 to 6) of esophageal symptoms, Pittsburgh Sleep Quality Index (PSQI) questionnaire to assess sleep quality, a SF-36 survey to investigate health-related quality of life (both physical (PCS) and mental (MCS) component scales), Beck Depression Inventory-II (BDI-II) and State Trait Anxiety Inventory (STAI) to assess the presence of depression and anxiety.

RESULTS: The prevalence of sleep disturbances was 66.7% in Ach, 50% in EoE, and 60% in GERD patients (P=0.5). PCS and MCS significantly correlated with depression and anxiety levels. Ach patients showed significantly higher intensity-frequency scores of dysphagia for solids (Scheffè P<0.001) and liquids (Scheffè P<0.001) than EoE and GERD patients. No differences were found in the intensity-frequency scores of the esophageal symptoms among the three groups. There was a significant association between worst quality of sleep and higher intensity-frequency scores of regurgitation.

CONCLUSIONS: Sleep disturbances are common with Ach and EoE, similar to GERD patients. Moreover, there is a significant association between regurgitation, a typical GERD symptom, and poor quality of sleep, independent from diagnosis.

PMID:37642600 | DOI:10.23736/S2724-5985.21.03002-3

Nat Neurosci. 2023 Aug 29. doi: 10.1038/s41593-023-01437-x. Online ahead of print.

NO ABSTRACT

PMID:37644260 | DOI:10.1038/s41593-023-01437-x

ACS Chem Neurosci. 2023 Sep 20;14(18):3528-3539. doi: 10.1021/acschemneuro.3c00437. Epub 2023 Aug 28.

ABSTRACT

Primary supranuclear palsy (PSP) is a rare neurodegenerative disease that perturbs body movement, eye movement, and walking balance. Similar to Alzheimer's disease (AD), the abnormal aggregation of tau fibrils in the central neuronal and glial cells is a major hallmark of PSP disease. In this study, we use multiple approaches, including docking, molecular dynamics, and metadynamics simulations, to investigate the binding mechanism of 10 first- and second-generations of PET tracers for PSP tau and compare their binding in cortical basal degeneration (CBD) and AD tauopathies. Structure-activity relationships, binding preferences, the nature of ligand binding in terms of basic intermolecular interactions, the role of polar/charged residues, induced-fit mechanisms, grove closures, and folding patterns for the binding of these tracers in PSP, CBD, and AD tau fibrils are evaluated and discussed in detail in order to build a holistic picture of what is essential for the binding and also to rank the potency of the different tracers. For example, we found that the same tracer shows different binding preferences for the surface sites of tau fibrils that are intrinsically distinct in the folding patterns. Results from the metadynamics simulations predict that PMPBB3 and PBB3 exhibit the strongest binding free energies onto the Q276[I277]I278, Q351[S352]K353, and N368[K369]K370 sites of PSP than the other explored tracers, indicating a solid preference for vdW and cation-π interactions. Our results also reproduced known preferences of tracers, namely, that MK6240 binds better to AD tau than CBD tau and PSP tau and that CBD2115, PI2620, and PMPBB3 are 4R tau binders. These findings fill in the well-sought-after knowledge gap in terms of these tracers' potential binding mechanisms and will be important for the design of highly selective novel PET tracers for tauopathies.

PMID:37639522 | DOI:10.1021/acschemneuro.3c00437

Vaccine. 2023 Sep 22;41(41):5940-5945. doi: 10.1016/j.vaccine.2023.08.020. Epub 2023 Aug 25.

ABSTRACT

Atypical hemolytic uremic syndrome is a rare, life-threatening disorder which can be triggered by COVID 19 infection and COVID 19 vaccination then induce multiple organ failure. Our study is the first to evaluate immune responses to COVID-19 vaccination and safety in a cohort of patients in a local single-center study in Taiwan.. Results indicate that vaccines effectively shield aHUS patients from severe COVID-19 complications without significant safety concerns. A double booster dose for the third vaccine is essential for optimal efficacy. Anti-complement therapy did not influence vaccination effectiveness. Transplant aHUS patients had the lowest immune response titers, indicating a need for additional vaccine doses. Compared to healthcare workers, aHUS patients had poor T-cell responses. We noted a superior trend with mixed-type COVID-19 vaccinations in aHUS patients, while fixed-type mRNA demonstrated better results in healthcare workers. Our findings endorse COVID-19 vaccination as a potent strategy to safeguard aHUS patients from severe complications, emphasizing the importance of vigilant monitoring pre- and post-vaccination.

PMID:37635000 | DOI:10.1016/j.vaccine.2023.08.020

Orv Hetil. 2023 Aug 27;164(34):1342-1349. doi: 10.1556/650.2023.32845. Print 2023 Aug 27.

ABSTRACT

INTRODUCTION: Aniridia is a rare congenital panocular disease associated with varying degrees of visual acuity impairment.

OBJECTIVE: To assess the experiences of congenital aniridia patients in Hungary, with visual impairment using a questionnaire developed by the ANIRIDIA-NET.

PATIENTS AND METHOD: Patients completed the Hungarian version of the 20-item ANIRIDIA-NET questionnaire with our assistance. The questionnaire covered demographic data, the most common complaints caused by the disease, the difficulties caused by low vision in different life situations and the frequency of low vision aids used in daily life.

RESULTS: 33 subjects (17 female [51.51%] and 16 male [48.48%]), 16 (48.5%) children and 17 (51.5%) adults completed the questionnaire, with an age of 25.69 ± 17.49 years (5-59 years). Daily photosensitivity was reported by 27 (81.8%), dry eyes by 5 (15.2%), tearing by 4 (12.1%), fluctuating vision by 3 (9.1%), and eye pain by 2 (6.1%) subjects. The majority of respondents said that personal communication with schoolmates (16 [48.5%]) or colleagues at work (11 [33.3%]) never caused difficulties because of their visual impairment. 29 people (87.9%) never needed help with daily routines at home, 24 (72.7%) with getting to school/work and 17 (51.5%) with various activities. 29 people (87.8%) never used low vision aids for communication, 23 (69.7%) for travelling, 20 (60.6%) for participating in social activities, 18 (54.5%) for studying/work.

CONCLUSION: Although aniridia is associated with reduced visual acuity, the majority of people with congenital aniridia, especially in childhood, manage to cope with personal communication and various life situations without difficulty, despite their eye complaints. Low vision aids can be an important aid for them as they grow into adulthood and as they age. Orv Hetil. 2023; 164(34): 1342-1349.

PMID:37634154 | DOI:10.1556/650.2023.32845

Medicina (Kaunas). 2023 Aug 17;59(8):1477. doi: 10.3390/medicina59081477.

ABSTRACT

Background and Objectives: Type I dentin dysplasia (DD-I) is a rare genetic disorder with autosomal dominant or recessive inheritance at risk of late or long-misunderstood diagnosis because the teeth, compared to other degenerative dentin diseases, do not have coronal defects and/or alterations but only at the root level (absent, conical, pointed roots, and obliterated pulp canals). The first radiographic suspicion often occurs only in case of sudden mobility and/or abscesses of the permanent teeth. Genetic tests confirm the diagnosis. Case Presentation: This case report describes the oral and radiographic characteristics of two siblings, 12 and 10 years old, a male and a female, at an early age affected by DD-I, whose diagnosis was made for a first orthodontic visit. The father and the older child had already undergone dental and orthodontic treatments, respectively, without the disease being suspected by the dentist. Results: Genetic tests support the diagnosis of DD-I. Following the diagnosis, the patients began a process of close periodic checks every 3-4 months to monitor their situation. The male child lost upper lateral incisors, which were then replaced with a light nylon removable prosthesis. Conclusions: The ability to recognize the radiographic features characteristic of DD-I is very important to avoid prejudicial diagnostic delays and to be able to plan the long-term treatment of these patients better, especially when the pathology was primarily misrecognized in the family.

PMID:37629767 | PMC:PMC10456812 | DOI:10.3390/medicina59081477

Int J Mol Sci. 2023 Aug 13;24(16):12744. doi: 10.3390/ijms241612744.

ABSTRACT

Stroke remains a major cause of death and disability worldwide. Identifying new circulating biomarkers able to distinguish and monitor common and rare cerebrovascular diseases that lead to stroke is of great importance. Biomarkers provide complementary information that may improve diagnosis, prognosis and prediction of progression as well. Furthermore, biomarkers can contribute to filling the gap in knowledge concerning the underlying disease mechanisms by pointing out novel potential therapeutic targets for personalized medicine. If many "conventional" lipid biomarkers are already known to exert a relevant role in cerebrovascular diseases, the aim of our study is to review novel "unconventional" lipid biomarkers that have been recently identified in common and rare cerebrovascular disorders using novel, cutting-edge lipidomic approaches.

PMID:37628924 | PMC:PMC10454673 | DOI:10.3390/ijms241612744

Genes (Basel). 2023 Aug 20;14(8):1656. doi: 10.3390/genes14081656.

ABSTRACT

CASK-related disorders are a form of rare X-linked neurological diseases and most of the patients are females. They are characterized by several symptoms, including microcephaly with pontine and cerebellar hypoplasia (MICPCH), epilepsy, congenital nystagmus, and neurodevelopmental disorders. Whole-genome sequencing has identified various mutations, including nonsense and missense mutations, from patients with CASK-related disorders, revealing correlations between specific mutations and clinical phenotypes. Notably, missense mutations associated with epilepsy and intellectual disability were found throughout the whole region of the CASK protein, while missense mutations related to microcephaly and MICPCH were restricted in certain domains. To investigate the pathophysiology of CASK-related disorders, research groups have employed diverse methods, including the generation of CASK knockout mice and the supplementation of CASK to rescue the phenotypes. These approaches have yielded valuable insights into the identification of functional domains of the CASK protein associated with a specific phenotype. Additionally, recent advancements in the AI-based prediction of protein structure, such as AlphaFold2, and the application of genome-editing techniques to generate CASK mutant mice carrying missense mutations from patients with CASK-related disorders, allow us to understand the pathophysiology of CASK-related disorders in more depth and to develop novel therapeutic methods for the fundamental treatment of CASK-related disorders.

PMID:37628707 | PMC:PMC10454856 | DOI:10.3390/genes14081656

Viruses. 2023 Aug 21;15(8):1778. doi: 10.3390/v15081778.

ABSTRACT

Emerging omicron subtypes with immune escape lead to inadequate vaccine response with breakthrough infections in immunocompromised individuals such as Anti-neutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis (AAV) patients. As AAV is considered an orphan disease, there are still limited data on SARS-CoV-2 vaccination and prospective studies that have focused exclusively on AAV patients are lacking. In addition, there are safety concerns regarding the use of highly immunogenic mRNA vaccines in autoimmune diseases, and further studies investigating reactogenicity are urgently needed. In this prospective observational cohort study, we performed a detailed characterization of neutralizing antibody responses against omicron subtypes and provided a longitudinal assessment of vaccine reactogenicity and AAV disease activity. Different vaccine doses were generally well tolerated and no AAV relapses occurred during follow-up. AAV patients had significantly lower anti-S1 IgG and surrogate-neutralizing antibodies after first, second, and third vaccine doses as compared to healthy controls, respectively. Live-virus neutralization assays against omicron subtypes BA.1 and BA.5 revealed that previous SARS-CoV-2 vaccines result in an inadequate neutralizing immune response in immunocompromised AAV patients. These data demonstrate that new vaccination strategies including adapted mRNA vaccines against epitopes of emerging variants are needed to help protect highly vulnerable individuals such as AAV patients.

PMID:37632120 | DOI:10.3390/v15081778

Children (Basel). 2023 Jul 26;10(8):1282. doi: 10.3390/children10081282.

ABSTRACT

Erythromelalgia is a descriptive term for severe burning pain and erythema in the distal extremities relieved by cold and exacerbated by heat. Pediatric case series to date are relatively small. We extracted and analyzed medical record data for 42 pediatric patients to describe clinical characteristics, associated conditions, and responses to treatments. Informed consent was obtained according to an IRB-approved protocol that included gene discovery. Three patients had confirmed Nav1.7 sodium channelopathies, with six additional patients under investigation with novel gene candidates. There was a female predominance (2.5:1), and the median onset age was 12 years (IQR = 3-14). Patients saw a median of three specialists (IQR = 2-3) for a diagnosis. The majority (90%) reported bilateral symptoms. Cooling methods usually provided partial relief, while heat and exercise exacerbated pain. No medication appeared to be consistently effective; commonly prescribed medications included sodium channel blockers (n = 37), topical analgesics (n = 26), gabapentin (n = 22), and aspirin (n = 15). Based on the currently published literature, we believe this cohort is the largest pediatric study of erythromelalgia to date. Many findings are consistent with those of previously published case series. Work is in progress to establish a prospective cohort and multi-center registry.

PMID:37628281 | DOI:10.3390/children10081282

Hum Gene Ther. 2023 Sep;34(17-18):776-781. doi: 10.1089/hum.2023.127.

ABSTRACT

Rare and ultrarare diseases have been central to the field of gene therapy since its earliest stage, and we are now witnessing more and more effective treatments entering the clinical realm for patients in need. However, despite promising results across a range of rare diseases, transformative gene therapies may not be available and accessible to patients for nonmedical reasons. Traditional regulatory and commercialization pathways to licensed products seem to be prohibitive for ultrasmall patient populations. Here, we highlight some of the challenges of delivering gene therapies in rare diseases and discuss innovative solutions being proposed by the gene therapy community.

PMID:37624746 | DOI:10.1089/hum.2023.127

Ther Adv Rare Dis. 2023 Aug 22;4:26330040231181406. doi: 10.1177/26330040231181406. eCollection 2023 Jan-Dec.

ABSTRACT

BACKGROUND: Due to racial, cultural, and linguistic marginalization, some populations experience disproportionate barriers to genetic testing in both clinical and research settings. It is difficult to track such disparities due to non-inclusive self-reported race and ethnicity categories within the electronic health record (EHR). Inclusion and access for all populations is critical to achieve health equity and to capture the full spectrum of rare genetic disease.

OBJECTIVE: We aimed to create revised race and ethnicity categories. Additionally, we identified racial and ethnic under-representation amongst three cohorts: (1) the general Boston Children's Hospital patient population (general BCH), (2) the BCH patient population that underwent clinical genomic testing (clinical sequencing), and (3) Children's Rare Disease Cohort (CRDC) research initiative participants.

DESIGN AND METHODS: Race and ethnicity data were collected from the EHRs of the general BCH, clinical sequencing, and CRDC cohorts. We constructed a single comprehensive set of race and ethnicity categories. EHR-based race and ethnicity variables were mapped within each cohort to the revised categories. Then, the numbers of patients within each revised race and ethnicity category were compared across cohorts.

RESULTS: There was a significantly lower percentage of Black or African American/African, non-Hispanic/non-Latine individuals in the CRDC cohort compared with the general BCH cohort, but there was no statistically significant difference between the CRDC and the clinical sequencing cohorts. There was a significantly lower percentage of multi-racial, Hispanic/Latine individuals in the CRDC cohort than the clinical sequencing cohort. White, non-Hispanic/non-Latine individuals were over-represented in the CRDC compared to the two other groups.

CONCLUSION: We highlight underrepresentation of certain racial and ethnic populations in sequencing cohorts compared to the general hospital population. We propose a range of measures to address these disparities, to strive for equitable future precision medicine-based clinical care and for the benefit of the whole rare disease community.

PMID:37621556 | PMC:PMC10445838 | DOI:10.1177/26330040231181406

Nature. 2023 Aug;620(7975):737-745. doi: 10.1038/s41586-023-06388-8. Epub 2023 Aug 23.

ABSTRACT

The substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs-for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly.

PMID:37612393 | DOI:10.1038/s41586-023-06388-8

BMC Health Serv Res. 2023 Aug 23;23(1):904. doi: 10.1186/s12913-023-09886-7.

ABSTRACT

BACKGROUND: Patients with rare diseases usually go through years of diagnostic odysseys. The large number of rare diseases and the associated lack of expertise pose a major challenge to physicians. There are few physicians dealing with patients with rare diseases and they usually work in a limited number of specialized centers. The aim of this study was to evaluate the diagnostic efficiency of an expert center.

METHODS: The diagnostic pathway of 78 patients of the outpatient clinic for rare inflammatory systemic diseases with renal involvement was analyzed retrospectively. For this purpose, each examination day was documented with the corresponding examinations performed from the onset of initial symptoms. Three time points were considered: The time when patients first visited a physician with symptoms, the time when patients consulted an expert, and the time when they received the correct diagnosis. In addition, it was documented whether the diagnosis could be made without the expert, or only with the help of the expert. The examinations that confirmed the diagnosis were also documented for each patient.

RESULTS: A correct diagnosis was made without the help of the expert in only 21% of cases. Each patient visited an average of 6 physicians before consulting the expert. Targeted diagnostics enabled the expert to make the correct diagnosis with an average of seven visits, or one inpatient stay. However, referral to the expert took an average of 4 years.

CONCLUSION: The data show that rapid and targeted diagnostics were possible in the expert center due to the available expertise and the interdisciplinary exchange. Early diagnosis is of great importance for many patients, as an early and correct therapy can be decisive for the course of the disease.

PMID:37612679 | DOI:10.1186/s12913-023-09886-7

Unfallchirurgie (Heidelb). 2023 Aug 22. doi: 10.1007/s00113-023-01360-7. Online ahead of print.

ABSTRACT

Traumatic and non traumatic spinal cord injury are rare and an orphan disease in comparison to common diseases. Those affected represent a very special patient population in the treatment even at the site of the accident and in emergency medicine and require a high level of professional expertise. The rehabilitation with the complexity of a spinal cord injury can only succeed with a multiprofessional team that is less focused on the often similar diagnoses according to the International Classification of Diseases (ICD) but on functional disorders and associated activity impairments. Only then the best possible integration and participation/inclusion in sociocultural and professional life can be achieved. In addition to the importance of classical physiotherapy and occupational therapy, this article highlights important but often missing team players, such as neurourology and electrical stimulation. In addition, the problems of frequent and some less recognized complications, such as autonomic dysfunction and the benefits of airway management are highlighted. For a comprehensive overview of rehabilitation in spinal cord injury, reference textbooks and guidelines are recommended that are cited in the text.

PMID:37608182 | DOI:10.1007/s00113-023-01360-7

Acta Biomed. 2023 Aug 22;94(S1):e2023232. doi: 10.23750/abm.v94iS1.14988.

ABSTRACT

Basal cell carcinoma (BCC) of the prostate is a very rare histologic variant of prostate cancer, of difficult diagnosis and uncertain prognosis. In fact, despite the frequency of prostate cancer, only 100 cases have been described in the literature, and most of the data derived from case reports. Because of the rarity of this disease, therapeutic options for these patients are scarce and no randomized trials are available. Here, we report the case of a 63-year-old man treated for a prostatic BCC (pBCC) that was challenging in terms of both diagnosis and treatment. We also performed a review of the literature to provide an overview of the therapeutic options for this rare tumor type and to better understand the role of molecular characterization in rare prostate cancer histologies. Given the rarity of pBCC worldwide, further collection of real-world data is needed to better understand the optimal diagnostic and therapeutic strategies for this rare disease.

PMID:37606060 | DOI:10.23750/abm.v94iS1.14988

J Med Case Rep. 2023 Aug 22;17(1):360. doi: 10.1186/s13256-023-04094-7.

ABSTRACT

BACKGROUND: Gorham-Stout disease is a rare condition with fewer than 400 reported cases in the literature. The presentation of Gorham-Stout disease varies on the basis of location, extent, fracture, and accompanying symptoms. It lacks a specific histopathological appearance but is characterized by vascular changes and the absence of cellular atypia.

CASE PRESENTATION: This article presents a case study of a 16-year-old Persian boy with an entire femur with Gorham-Stout disease, highlighting the difficulties in managing this condition. The lack of a clear diagnosis resulted in prolonged procedures, delayed medical treatments, and ultimately required total femoral replacement with an endoprosthesis.

CONCLUSION: It is important to note that raising awareness of this disease and its potential complications can facilitate timely and appropriate treatment for patients presenting in the early stages of the disease.

PMID:37605280 | DOI:10.1186/s13256-023-04094-7

Front Endocrinol (Lausanne). 2023 Aug 1;14:1205977. doi: 10.3389/fendo.2023.1205977. eCollection 2023.

ABSTRACT

INTRODUCTION: Hypophosphatasia (HPP) is a rare genetic disease caused by inactivating variants of the ALPL gene. Few data are available on the clinical presentation in Italy and/or on Italian HPP surveys.

METHODS: There were 30 suspected HPP patients recruited from different Italian tertiary cares. Biological samples and related clinical, biochemical, and anamnestic data were collected and the ALPL gene sequenced. Search for large genomic deletions at the ALPL locus (1p36) was done. Phylogenetic conservation and modeling were applied to infer the effect of the variants on the protein structure.

RESULTS: There were 21 ALPL variants and one large genomic deletion found in 20 out of 30 patients. Unexpectedly, NGS-driven differential diagnosis allowed uncovering three hidden additional HPP cases, for a total of 33 HPP subjects. Eight out of 24 coding variants were novel and classified as "pathogenic", "likely pathogenic", and "variants of uncertain significance". Bioinformatic analysis confirmed that all the variants strongly destabilize the homodimer structure. There were 10 cases with low ALP and high VitB6 that resulted negative to genetic testing, whereas two positive cases have an unexpected normal ALP value. No association was evident with other biochemical/clinical parameters.

DISCUSSION: We present the survey of HPP Italian patients with the highest ALPL mutation rate so far reported and confirm the complexity of a prompt recognition of the syndrome, mostly for HPP in adults. Low ALP and high VitB6 values are mandatory for the genetic screening, this latter remaining the gold standard not only to confirm the clinical diagnosis but also to make differential diagnosis, to identify carriers, to avoid likely dangerous therapy in unrecognized cases.

PMID:37600704 | PMC:PMC10433156 | DOI:10.3389/fendo.2023.1205977

Cell Genom. 2023 Jul 6;3(8):100356. doi: 10.1016/j.xgen.2023.100356. eCollection 2023 Aug 9.

ABSTRACT

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)-present in some but not all cells-remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e-4), with recurrent somatic deletions of exons 1-5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5' deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.

PMID:37601975 | PMC:PMC10435376 | DOI:10.1016/j.xgen.2023.100356