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Orphanet Journal of Rare Diseases May 2024Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral painless subacute visual loss. Prevalence data are scarce. The aim of this study...
BACKGROUND
Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral painless subacute visual loss. Prevalence data are scarce. The aim of this study was to examine the validity of different ascertainment sources used in population-based rare diseases registries to detect cases, and to explore the impact of a capture-recapture method in the estimation of the prevalence of LHON in the Autonomous Community of Madrid (ACM) in 2022.
METHODS
Descriptive cross-sectional population-based study. Potential LHON cases were detected by automatic capture from the healthcare information sources usually explored for the Regional Registry for Rare Diseases (SIERMA). Ophthalmologists provided data from their clinical registry. Positive predictive values (PPV) and sensitivity with 95% confidence intervals (CI) were estimated. Global and by sex prevalences were calculated with confimed cases and with those estimated by the capture-recapture method.
RESULTS
A total of 102 potential LHON cases were captured from healthcare information sources, 25 of them (24.5%) finally were confirmed after revision, with an overall PPV of 24.5% (95%CI 17.2-33.7). By source, the electronic clinical records of primary care had the highest PPV (51.2, 95%CI 36.7-65.4). The ophthalmologists clinical registry provided 22 cases, 12 of them not detected in the automatic capture sources. The clinical registry reached a sensitivity of 59.5% (95%CI 43.5-73.6) and the combination of automatic capture sources reached a 67.6% (95%CI: 51.5-80.4). The total confirmed cases were 37, with a mean age of 48.9 years, and a men: women ratio of 2.4:1. Genetic information was recovered in 27 cases, with the m.3460 mutation being the most frequent (12 cases). The global prevalence was 0.55 cases/100,000 inhabitants (95%CI 0.40-0.75), and with the capture-recapture method reached 0.79 cases/100,000 (95%CI 0.60-1.03), a 43.6% higher, 1.15 cases/100,000 (95%CI 0.83-1.58) in men and 0.43 cases/100,000 (95%CI 0.26-0.70) in women.
CONCLUSIONS
The prevalence of LHON estimated in the ACM was lower than in other European countries. Population-based registries of rare diseases require the incorporation of confirmed cases provided by clinicians to asure the best completeness of data. The use of more specific coding for rare diseases in healthcare information systems would facilitate the detection of cases. Further epidemiologic studies are needed to assess potential factors that may influence the penetrance of LHON.
Topics: Humans; Optic Atrophy, Hereditary, Leber; Spain; Male; Female; Prevalence; Cross-Sectional Studies; Adult; Middle Aged; Young Adult; Adolescent; Registries; Child; Aged
PubMed: 38811977
DOI: 10.1186/s13023-024-03225-7 -
PLoS Biology May 2024Despite significant progress in understanding epigenetic reprogramming of cells, the mechanistic basis of "organ reprogramming" by (epi-)gene-environment interactions...
Despite significant progress in understanding epigenetic reprogramming of cells, the mechanistic basis of "organ reprogramming" by (epi-)gene-environment interactions remained largely obscure. Here, we use the ether-induced haltere-to-wing transformations in Drosophila as a model for epigenetic "reprogramming" at the whole organism level. Our findings support a mechanistic chain of events explaining why and how brief embryonic exposure to ether leads to haltere-to-wing transformations manifested at the larval stage and on. We show that ether interferes with protein integrity in the egg, leading to altered deployment of Hsp90 and widespread repression of Trithorax-mediated establishment of active H3K4me3 chromatin marks throughout the genome. Despite this global reduction, Ubx targets and wing development genes preferentially retain higher levels of H3K4me3 that predispose these genes for later up-regulation in the larval haltere disc, hence the wing-like outcome. Consistent with compromised protein integrity during the exposure, the penetrance of bithorax transformations increases by genetic or chemical reduction of Hsp90 function. Moreover, joint reduction in Hsp90 and trx gene dosage can cause bithorax transformations without exposure to ether, supporting an underlying epistasis between Hsp90 and trx loss-of-functions. These findings implicate environmental disruption of protein integrity at the onset of histone methylation with altered epigenetic regulation of developmental patterning genes. The emerging picture provides a unique example wherein the alleviation of the Hsp90 "capacitor function" by the environment drives a morphogenetic shift towards an ancestral-like body plan. The morphogenetic impact of chaperone response during a major setup of epigenetic patterns may be a general scheme for organ transformation by environmental cues.
Topics: Animals; Drosophila Proteins; Epigenesis, Genetic; Histones; HSP90 Heat-Shock Proteins; Wings, Animal; Drosophila melanogaster; Larva; Gene Expression Regulation, Developmental; Gene-Environment Interaction; Chromosomal Proteins, Non-Histone; Chromatin; Homeodomain Proteins; Epigenetic Memory; Transcription Factors
PubMed: 38805504
DOI: 10.1371/journal.pbio.3002629 -
Brain : a Journal of Neurology Jun 2024The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and...
The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.
Topics: Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Parkinson Disease; Female; Male; Middle Aged; Aged; Longitudinal Studies; Genetic Predisposition to Disease; Adult; Prospective Studies; Heterozygote; Penetrance; Aged, 80 and over; REM Sleep Behavior Disorder; Mutation
PubMed: 38804604
DOI: 10.1093/brain/awae073 -
Frontiers in Genetics 2024Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease caused by a combination of genetic and environmental factors. Rare variants with low predicted...
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease caused by a combination of genetic and environmental factors. Rare variants with low predicted effects in genes participating in the same biological function might be involved in developing complex diseases such as RA. From whole-exome sequencing (WES) data, we identified genes containing rare non-neutral variants with complete penetrance and no phenocopy in at least one of nine French multiplex families. Further enrichment analysis highlighted focal adhesion as the most significant pathway. We then tested if interactions between the genes participating in this function would increase or decrease the risk of developing RA disease. The model-based multifactor dimensionality reduction (MB-MDR) approach was used to detect epistasis in a discovery sample (19 RA cases and 11 healthy individuals from 9 families and 98 unrelated CEU controls from the International Genome Sample Resource). We identified 9 significant interactions involving 11 genes (, , , , , , , , , , and ). One interaction (* increasing RA risk and one interaction decreasing (*) were confirmed in a replication sample (200 unrelated RA cases and 91 GBR unrelated controls). Functional and genomic data in RA samples or relevant cell types argue the key role of these genes in RA.
PubMed: 38803542
DOI: 10.3389/fgene.2024.1375036 -
The Application of Clinical Genetics 2024Breast Cancer (BC) is the main female cancer diagnosed worldwide, and it has been described that few genes, such as , have a high penetrance for this type of cancer. In...
PURPOSE
Breast Cancer (BC) is the main female cancer diagnosed worldwide, and it has been described that few genes, such as , have a high penetrance for this type of cancer. In this manuscript, we were interested in evaluating the effect of 3'UTR variants on BRCA1 expression.
PATIENTS AND METHODS
To accomplish this objective, Whole Exome Sequencing (WES) data of 400 patients with unselected BC was used to filter variants located in the region of interest of gene, finding two of them (c.*36C>G and c.*369_373del). miRGate and miRanda in silico tools were used to predict microRNA (miRNA) interaction.
RESULTS
The two variants (c.*36C>G, c.*369_373del) were predicted to affect miRNA interaction. After cloning of 3'UTR into pMIR-Report vector, the construct was transfected into two BC cell lines (MDA-MB-231 and MCF-7), and the variant c.*36C>G evidenced overexpression of reporter gene luciferase, showing that the transcript was not being degraded by the miRNA in MDA-MB-231 cells.
CONCLUSION
The variant seems to protect against Triple Negative BC probably due to the expression level of miRNA in this particular cell line (MDA-MB-231). This is consistent with the clinical history of the patients who harbor BC Hormone Receptors positive (HR+).
PubMed: 38803352
DOI: 10.2147/TACG.S444546 -
BMC Medical Genomics May 2024Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disease that arises from TSC1 or TSC2 genetic mutations. These genetic mutations can induce the... (Review)
Review
BACKGROUND
Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disease that arises from TSC1 or TSC2 genetic mutations. These genetic mutations can induce the development of benign tumors in any organ system with significant clinical implications in morbidity and mortality. In rare instances, patients with TSC can have malignant tumors, including renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor (PNET). It is considered a hereditary renal cancer syndrome despite the low incidence of RCC in TSC patients. TSC is typically diagnosed in prenatal and pediatric patients and frequently associated with neurocognitive disorders and seizures, which are often experienced early in life. However, penetrance and expressivity of TSC mutations are highly variable. Herein, we present a case report, with associated literature, to highlight that there exist undiagnosed adult patients with less penetrant features, whose clinical presentation may contain non-classical signs and symptoms, who have pathogenic TSC mutations.
CASE PRESENTATION
A 31-year-old female with past medical history of leiomyomas status post myomectomy presented to the emergency department for a hemorrhagic adnexal cyst. Imaging incidentally identified a renal mass suspicious for RCC. Out of concern for hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, the mass was surgically removed and confirmed as RCC. Discussion with medical genetics ascertained a family history of kidney cancer and nephrectomy procedures and a patient history of ungual fibromas on the toes. Genetic testing for hereditary kidney cancer revealed a 5'UTR deletion in the TSC1 gene, leading to a diagnosis of TSC. Following the diagnosis, dermatology found benign skin findings consistent with TSC. About six months after the incidental finding of RCC, a PNET in the pancreatic body/tail was incidentally found on chest CT imaging, which was removed and determined to be a well-differentiated PNET. Later, a brain MRI revealed two small cortical tubers, one in each frontal lobe, that were asymptomatic; the patient's history and family history did not contain seizures or learning delays. The patient presently shows no evidence of recurrence or metastatic disease, and no additional malignant tumors have been identified.
CONCLUSIONS
To our knowledge, this is the first report in the literature of a TSC patient without a history of neurocognitive disorders with RCC and PNET, both independently rare occurrences in TSC. The patient had a strong family history of renal disease, including RCC, and had several other clinical manifestations of TSC, including skin and brain findings. The incidental finding and surgical removal of RCC prompted the genetic evaluation and diagnosis of TSC, leading to a comparably late diagnosis for this patient. Reporting the broad spectrum of disease for TSC, including more malignant phenotypes such as the one seen in our patient, can help healthcare providers better identify patients who need genetic evaluation and additional medical care.
Topics: Humans; Tuberous Sclerosis; Female; Adult; Kidney Neoplasms; Carcinoma, Renal Cell; Tuberous Sclerosis Complex 2 Protein; Tuberous Sclerosis Complex 1 Protein; Mutation
PubMed: 38802873
DOI: 10.1186/s12920-024-01913-8 -
Neuro-oncology Advances 2024Genomic ascertainment is the inversion of the traditional phenotype-first approach; with a "genome-first" approach, a cohort linked to electronic health records (EHR)... (Review)
Review
Genomic ascertainment is the inversion of the traditional phenotype-first approach; with a "genome-first" approach, a cohort linked to electronic health records (EHR) undergoes germline sequencing (array, panel, exome, and genome) and deleterious variation of interest in a gene (or set of genes) are identified. Phenotype is then queried from the linked EHR and from call-back investigation and estimates of variant prevalence, disease penetrance, and phenotype can be determined. This should permit a better estimate of the full phenotypic spectrum, severity, and penetrance linked to a deleterious variant. For now, given the modest size, limited EHR, and age of participants in sequenced cohorts, genomic ascertainment approaches to investigate cancer in children and young adults will likely be restricted to descriptive studies and complement traditional phenotype-first work. Another issue is the ascertainment of the cohort itself: Participants need to survive long enough to enroll. Not accounting for this may lead to bias and incorrect estimates of variant prevalence. Adult-focused cohorts with EHR extending back into childhood, linked to cancer registries, and/or studies that permit recontact with participants may facilitate genomic ascertainment in pediatric cancer research. In summary, genomic ascertainment in pediatric primary brain cancer research remains largely untapped and merits further investigation.
PubMed: 38800695
DOI: 10.1093/noajnl/vdae048 -
Frontiers in Cell and Developmental... 2024Neurofibromin, coded by the tumor suppressor gene, is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with...
BACKGROUND
Neurofibromin, coded by the tumor suppressor gene, is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1)-a tumor predisposition syndrome caused by a germline mutation-have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by which mutations lead to breast cancer tumorigenesis is not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer.
APPROACH
To accurately model the germline monoallelic mutations in NF1 patients, we utilized an deficient rat model with accelerated mammary development before presenting with highly penetrant breast cancer.
RESULTS
We identified increased collagen content in -deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that -deficient mature adipocytes in the rat mammary gland have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with differentiation, however, flow cytometry analysis did not show a change in mammary adipose-derived mesenchymal stem cell abundance.
CONCLUSION
Collectively, this study uncovered the previously undescribed role of in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary glands will create a foundation for developing early detection strategies of breast cancer among NF1 patients.
PubMed: 38799507
DOI: 10.3389/fcell.2024.1375441 -
BioRxiv : the Preprint Server For... Apr 2024Organisms must sense temperature and modify their physiology to ensure survival during environmental stress. Elevated temperature leads to reduced fertility in most...
Organisms must sense temperature and modify their physiology to ensure survival during environmental stress. Elevated temperature leads to reduced fertility in most sexually reproducing organisms. Maternally supplied mRNAs are required for embryogenesis. They encode proteins that govern early events in embryonic patterning. RNA-binding proteins (RBPs) are major effectors of maternal mRNA regulation. MEX-3 is a conserved RBP essential for anterior patterning of embryos. We previously demonstrated that the 3' untranslated region (3'UTR) represses MEX-3 abundance in the germline yet is dispensable for fertility. Here, we show that the 3'UTR becomes essential during thermal stress. Deletion of the 3'UTR causes a highly penetrant temperature sensitive embryonic lethality phenotype distinct from a null. Loss of the 3'UTR decreases MEX-3 abundance specifically in maturing oocytes and early embryos experiencing temperature stress, suggesting a mechanism that regulates MEX-3 abundance at the oocyte-to-embryo transition is sensitive to temperature. We propose that a primary role of the 3'UTR is to buffer MEX-3 expression to ensure viability during fluctuating temperature. We hypothesize that a major role of maternally supplied mRNAs is to ensure robust expression of key cell fate determinants in uncertain conditions.
PubMed: 38798418
DOI: 10.1101/2024.04.01.587367 -
Research Square May 2024There is much interest in targeting the activity in the oxytocin system to regulate social bonding. However, studies with exogenous administration of oxytocin face the...
There is much interest in targeting the activity in the oxytocin system to regulate social bonding. However, studies with exogenous administration of oxytocin face the caveats of its low stability, poor brain permeability and insufficient receptor specificity. The use of a small-molecule oxytocin receptor-specific agonist could overcome these caveats. Prior to testing the potential effects of a brain-penetrant oxytocin receptor agonist in clinical settings, it is important to assess how such an agonist would affect social bonds in animal models. The facultatively monogamous prairie voles (), capable of forming long-term social attachments between adult individuals, are an ideal rodent model for such testing. Therefore, in a series of experiments we investigated the effects of the recently developed oxytocin receptor-specific agonist LIT-001 on the acquisition and expression of partner preference, a well-established model of pair bonding, in prairie voles. LIT-001 (10 mg/kg, intraperitoneal), as expected, facilitated the acquisition of partner preference when administered prior to a 4-hour cohabitation. In contrast, while animals injected with vehicle after the 4-hour cohabitation exhibited significant partner preference, animals that were injected with LIT-001 did not show such partner preference. This result suggests that OXTR activation during expression of pair bonding can inhibit partner preference. The difference in effects of LIT-001 on acquisition versus expression was not due to basal differences in partner preference between the experiments, as LIT-001 had no significant effects on expression of partner preference if administered following a shorter (2 hour-long) cohabitation. Instead, this difference agrees with the hypothesis that the activation of oxytocin receptors acts as a signal of presence of a social partner. Our results indicate that the effects of pharmacological activation of oxytocin receptors crucially depend on the phase of social attachments.
PubMed: 38798348
DOI: 10.21203/rs.3.rs-4351761/v1