Home / Deep Research / Heterotaxy Syndrome

Heterotaxy Syndrome

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of heterotaxy syndrome. Core disease mechanisms, molecular and cellular pathw...

2026-04-13
Asta Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of heterotaxy syndrome. Core disease mechanisms, molecular and cellular pathw...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] A Rare Case of Recurrent Pneumonia in Heterotaxy Syndrome, Polysplenia/Left Isomerism

  • Authors: A. Anwar, Jacob Jubin, Shafi Raza, Zafar K. Mirza
  • Year: 2021
  • Venue: Cureus
  • URL: https://www.semanticscholar.org/paper/caf72d32fccf9b41902f5c38e2ecd9138260de26
  • DOI: 10.7759/cureus.19055
  • PMID: 34858743
  • PMCID: 8614211
  • Citations: 3
  • Summary: The case of a female patient who presented with symptoms of fever and cough and had a recurrence of pneumonia within a few months raises questions related to long-term antibiotic use and immunization in the case of polysplenia in this patient population.
  • Evidence snippets:
  • Snippet 1 (score: 0.474) > The etiology and pathophysiology in the development of HS remain ambiguous and unclear. Heterotaxy in individuals is found in isolation or in combination with other features as a part of genetic syndromes such as Kartagener syndrome. > The major cause entails the vast variety of rare genetic mutations associated with environmental factors affecting embryological development during pregnancy. These include: > 1. Genetic mutations involving ZIC3, NODAL, CFC1, ACVR2B, LEFTY2, CITED2, and GDF1 [11], with the mode of inheritance involving autosomal-dominant pattern with incomplete inheritance, autosomalrecessive, and, in rare cases, X-linked patterns. These are the genes that have been identified in encoding proteins of the transforming growth factor (TGF)-beta pathway. > 2. Environmental factors like maternal diabetes, family history, especially in male infants, retinoic acid use, and maternal cocaine use during the first trimester. They are responsible for sporadic cases [12]. > The pathophysiology of heterotaxy is explained by the molecular and cellular mechanisms involved in normal left-right asymmetry. Despite extensive research, a comprehensive understanding of the exact mechanism remains unclear. > Studies on animals such as mice have demonstrated that the left-right axis is determined by ciliary movement located in the primitive node. Monocilia in nodes consists of motile and non-motile cilia. Motile cilia, composed of left-right dynein in mice and DNAH5 in humans (responsible for Kartagener syndrome), is located in the center of the node compared to non-motile mechanosensory cilia, expressing calcium ion channel polycystin-2, Pkd2, found in the peripheral region of the node. The clockwise rotation of motile cilia generates a leftward nodal flow, which produces the initial break in the body symmetry [13].

[2] Human 45,X Fibroblast Transcriptome Reveals Distinct Differentially Expressed Genes Including Long Noncoding RNAs Potentially Associated with the Pathophysiology of Turner Syndrome

  • Authors: Shriram N. Rajpathak, S. Vellarikkal, A. Patowary, V. Scaria, S. Sivasubbu et al.
  • Year: 2014
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/5ae975136b3a4bb370421d9084dff7037ab4a740
  • DOI: 10.1371/journal.pone.0100076
  • PMID: 24932682
  • PMCID: 4059722
  • Citations: 48
  • Influential citations: 3
  • Summary: Analysis of transcriptome profiles of human untransformed 45,X and 46,XX fibroblast cells and identified differential expression of genes in these two karyotypes revealed that these differentially expressing genes are associated with bone differentiation, glucose metabolism and gonadal development pathways.
  • Evidence snippets:
  • Snippet 1 (score: 0.402) > Turner syndrome is a chromosomal abnormality characterized by the absence of whole or part of the X chromosome in females. This X aneuploidy condition is associated with a diverse set of clinical phenotypes such as gonadal dysfunction, short stature, osteoporosis and Type II diabetes mellitus, among others. These phenotypes differ in their severity and penetrance among the affected individuals. Haploinsufficiency for a few X linked genes has been associated with some of these disease phenotypes. RNA sequencing can provide valuable insights to understand molecular mechanism of disease process. In the current study, we have analysed the transcriptome profiles of human untransformed 45,X and 46,XX fibroblast cells and identified differential expression of genes in these two karyotypes. Functional analysis revealed that these differentially expressing genes are associated with bone differentiation, glucose metabolism and gonadal development pathways. We also report differential expression of lincRNAs in X monosomic cells. Our observations provide a basis for evaluation of cellular and molecular mechanism(s) in the establishment of Turner syndrome phenotypes.

[3] Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development

  • Authors: Huifang Peng, Wenyuan Peng, Jiali Chen, Keyan Hu, Yingyu Zhang et al.
  • Year: 2025
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/ff11ed0f8a3776fc0ef16b1d0673cc0735fc84a2
  • DOI: 10.3389/fendo.2025.1507749
  • PMID: 40026690
  • PMCID: 11867910
  • Citations: 1
  • Summary: Although the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear, ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways may be affected.
  • Evidence snippets:
  • Snippet 1 (score: 0.399) > The RNA helicase DHX37 gene is involved in ribosomal biological processes, and linked to human genetic diseases associated with 46,XY disorders of sex development (46,XY DSD) or neurodevelopment. Recently, relevant reports have primarily focused on 46,XY DSD. However, there is still a lack of overall understanding of the genetic characteristics, phenotype, etc. of the DHX37 gene in human genetic diseases, and its molecular mechanism is not fully understood. We searched literature databases and summarized and analyzed all the literature related to DHX37 to date, including case reports, cohort studies, and molecular mechanism studies, to comprehensively demonstrate the role of DHX37 in human genetic diseases. Sixty patients were reported to have DHX37-related 46,XY DSD, with p.R308Q, p.R674W variants being the two most common mutation hotspots, accounting for 36.67% and 11.67% of cases respectively. In DSD cohorts, DHX37 gene mutations have different detection frequencies (0.77%–45.45%), whereas in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts, they have a high detection rate. The gonadal development and fertility of female (46,XX) carriers with DHX37 gene mutations are not affected; however, incomplete penetrance may be observed in males (46,XY). The treatments are primarily surgical intervention and hormone replacement therapy administered at appropriate times; however, the long-term prognosis remains unknown. Although the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear, ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways may be affected. This review summarizes the profile of DHX37 defects in human genetic diseases.

[4] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.383) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[5] Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

  • Authors: Claudia Fuchs, P. A. ‛. ’t Hoen, A. Müller, Friederike Ehrhart, C. V. van Karnebeek
  • Year: 2024
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/b00d0859458647edeebf3cf53f9b39c79311d5ed
  • DOI: 10.3389/fmed.2024.1425038
  • PMID: 39135718
  • PMCID: 11317438
  • Citations: 1
  • Summary: The potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored and Leveraging existing drugs for new therapeutic purposes presents an attractive strategy.
  • Evidence snippets:
  • Snippet 1 (score: 0.382) > Rigorous preclinical and clinical studies are also crucial for better understanding the complex pathophysiology of these syndromes. To date, the precise molecular mechanisms underlying these complex disorders are still not fully understood; hindering the identification and validation of potential drug targets. This specifically applies to CDD and FOXG1-syndrome: both conditions were identified as distinct clinical entities only recently and it is understandable that research efforts initially focused primarily on "classical" RTT. This discrepancy is reflected also in the very different numbers of repurposing studies highlighted in Figure 1. Continued efforts in pre-clinical (identification of valuable cell and animal models etc.) and clinical research (better understanding of the natural history, clinical manifestations, disease progression, biomarkers etc.) will be essential for advancing our understanding and improving outcomes for individuals affected by these syndromes. In particular, better characterizing the shared symptoms and pathways across these entities, will provide valuable insights into the underlying biology and potentially uncover new common mechanisms and targeted therapies. If the disorders demonstrate convergence in their underlying molecular pathways, this provides an opportunity for designing joint DR 10.3389/fmed.2024.1425038 strategies across RTT and RTT-like disorders. This could reduce the time needed for the development of DR and increase the number of patients benefiting from the treatments, resulting in more attractive business models. > Despite promising DR results in preclinical or early-phase clinical trials for RTT and related disorders in our opinion DR is still underrated and underutilized in this kind of disorders. DR holds immense potential for addressing the unmet medical needs and therapeutic challenges posed by such complex NDDs, and recent advancements screening and computational techniques, offer the unique opportunity to predict drug-disease interactions and prioritize candidate compounds for further investigation. By leveraging existing drugs and repurposing them for new indications, this approach offers a pragmatic and efficient strategy to accelerate the development of treatments for individuals affected by these debilitating conditions.

[6] Mapping research trends of insulin resistance in polycystic ovary syndrome from 2017 to 2021: A bibliometric analysis

  • Authors: Yong Chen, Qian Zhang, Jinhui Ma, Yuexin Yu
  • Year: 2022
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/ba142a3e424e059139e25d776c774376f2a62d32
  • DOI: 10.3389/fendo.2022.963213
  • PMID: 36589816
  • PMCID: 9797656
  • Citations: 11
  • Summary: The six key words extracted can provide an in-depth perspective for the study of IR in PCOS, and provide valuable information to help researchers identify potential research directions, collaborators and cooperative institutions.
  • Evidence snippets:
  • Snippet 1 (score: 0.378) > Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women, affecting 5% to 20% of women of childbearing age (1,2). PCOS is one of the most complex and difficult diseases in the field of gynecologic endocrinology, which is characterized by uncertain and complex etiology, highly heterogeneous clinical manifestations, and nonspecific clinical treatment methods (3). Insulin resistance (IR), as the main metabolic characteristic of PCOS, is considered an important pathophysiological basis involved in the pathogenesis of PCOS. Many studies had focused on possible relationships between IR and PCOS (4). Available data on the molecular defects of IR, such as extracellular signal-regulated kinase (ERK) and AMP-activated protein kinase (AMPK) signal pathways involved in IR are inconsistent in PCOS women, suggesting heterogeneity mechanisms of IR involve in PCOS (5)(6)(7). The lack of accurate measures for IR and the heterogeneity of PCOS disease has blurred the relationship between IR and PCOS (8). Several family studies show that PCOS typical endocrine and metabolic characteristics are frequent in PCOS women relatives, which refer to the genetic and epigenetic mechanisms of PCOS (9). Putting all the puzzle together, it is unable for us to conclude the definitive association between IR and PCOS. > Furthermore, IR and hyperandrogenism, abnormal lipid metabolism, oxidative stress, nonalcoholic fatty liver disease (NAFLD) are intricate interactions that further promote the development and development of PCOS. Defining the molecular mechanism of IR may provide new perspectives and strategies for the treatment of PCOS. > In recent decades, numerous research papers related to IR in PCOS have been published in academic journals. This study uses bibliometric methods and mapping knowledge domains (MKD) methods to explore the current status of IR-related research in PCOS. Bibliometric analysis is a method of analyzing relevant documents using mathematical methods. It can make statistical data on the distribution, correlation and clustering of relevant documents to quantitatively measure relevant documents (10).

[7] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

  • Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
  • Year: 2020
  • Venue: Current Neuropharmacology
  • URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
  • DOI: 10.2174/1570159X17666191021141057
  • PMID: 31631822
  • PMCID: 7327943
  • Citations: 12
  • Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
  • Evidence snippets:
  • Snippet 1 (score: 0.375) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[8] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

  • Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
  • Year: 2025
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
  • DOI: 10.3389/fendo.2025.1501305
  • PMID: 40070584
  • PMCID: 11893406
  • Citations: 11
  • Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
  • Evidence snippets:
  • Snippet 1 (score: 0.375) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

[9] Lateralized and Segmental Overgrowth in Children

  • Authors: A. Mussa, D. Carli, S. Cardaropoli, G. Ferrero, N. Resta
  • Year: 2021
  • Venue: Cancers
  • URL: https://www.semanticscholar.org/paper/1bf068188ceb52b6d570aedc7fc2b9bdfd8c7ca9
  • DOI: 10.3390/cancers13246166
  • PMID: 34944785
  • PMCID: 8699773
  • Citations: 19
  • Summary: Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.
  • Evidence snippets:
  • Snippet 1 (score: 0.373) > Simple Summary Congenital lateralized or segmental overgrowth (LO) disorders are conditions characterized by excessive tissue growth of a body region often associated with a predisposition to cancer. LOs are caused by mosaic DNA anomalies, that is, they are present only in a part of the cells making up the body. LOs have an extremely heterogeneous clinical presentation: they widely overlap in presentation, are difficult to frame from a clinical point of view and have a diagnostic complexity representing a challenge for the clinician who approaches them. Here we review the key features of the various LOs, expose their molecular causes, and detail the implications for each of them, such as the need for specific cancer screening or the possibility of treatment. The latter represents a recent scientific achievement in medicine, allowed by the development of precision drugs finely tuning cellular pathways involved in growth and tumorigenesis deranged in LO. Abstract Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue growth and related relevant complications. Recently, next-generation sequencing approaches have increased the knowledge on the molecular defects in LO, allowing classifying them based on the deranged cellular signaling pathway. LO is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Most LOs are classifiable in the Beckwith–Wiedemann spectrum (BWSp), PI3KCA/AKT-related overgrowth spectrum (PROS/AROS), mosaic RASopathies, PTEN Hamartoma Tumor Syndrome, mosaic activating variants in angiogenesis pathways, and isolated LO (ILO). These disorders overlap over common phenotypes, making their appraisal and distinction challenging. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.

[10] The genetics of monogenic intestinal epithelial disorders

  • Authors: Stephen J. Babcock, David Flores-Marin, Jay R. Thiagarajah
  • Year: 2022
  • Venue: Human Genetics
  • URL: https://www.semanticscholar.org/paper/9b0676b2e9805c377256b2b9e7f52547baf99670
  • DOI: 10.1007/s00439-022-02501-5
  • PMID: 36422736
  • PMCID: 10182130
  • Citations: 35
  • Influential citations: 3
  • Summary: The genetics, clinical presentation, and known pathophysiology for specific disorders, including a historical perspective of the field and relationship to other monogenic disorders of the intestine, are described.
  • Evidence snippets:
  • Snippet 1 (score: 0.370) > Although they are commonly linked and defined by altered intestinal epithelial function, CoDE disorders exhibit a wide variety of cell and tissue level pathophysiological mechanisms. Despite this heterogeneity some broad categories have emerged to classify specific genes. As the specific causative genes for many cases of non-acquired severe infantile-onset chronic diarrhea can now be established, it has become important to shift away from syndromic or clinically defined naming of disorders to more specific designation by affected gene (e.g., SPINT2 deficiency vs syndromic congenital sodium diarrhea). This is particularly relevant for current and future studies that aim to correlate specific mutations with phenotype, prognosis, and treatment. As with any attempt to classify such a heterogenous group of disorders there are specific genes/disorders that do not fit well in any one category. In some cases, such as the recently discovered WNT2B deficiency, this has allowed expansion or development of new categories. As new causative genes (e.g., PERCC1, UNC45A, AGR2) and new information on disease mechanisms continue to emerge, these categories will need ongoing revision and refinement. Disease can also be classified by other methods such as protein ontology (e.g., functional annotation) or clinical outcome (e.g., parenteral nutrition dependence). > Broadly, monogenic epithelial disorders can be classified into five major categories that comprise core modules of epithelial function. These are listed below (see also Fig. 1) and detailed descriptions of several disorders in each category follow: > • Epithelial transport

[11] Genetic evaluation using next-generation sequencing of children with short stature: a single tertiary-center experience

  • Authors: Su Jin Kim, E. Joo, Jisun Park, Chang Ahn Seol, Ji-Eun Lee
  • Year: 2024
  • Venue: Annals of Pediatric Endocrinology & Metabolism
  • URL: https://www.semanticscholar.org/paper/311197f38687167cde5e936f15afd95f3ff9c192
  • DOI: 10.6065/apem.2346036.018
  • PMID: 38461804
  • PMCID: 10925784
  • Citations: 7
  • Summary: Genetic evaluation using NGS can be helpful in patients with suspected genetic short stature who have clinical and genetic heterogeneity, and further studies are needed to develop patient selection algorithms and panels containing growth-related genes.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > This classification contains a large number of genes, and the associated pathophysiologic mechanisms and clinical diseases are heterogeneous. In previous studies, this pathway accounted for the largest portion of genetic causes in patients with short stature. 6,8,10,11) The phenotypes of these patient groups were very diverse, but they were often syndromic short stature accompanied by clinical features other than those of ISS. 10) Among them, abnormalities in the Ras-MAPK pathway, including atypical Noonan syndrome, is an important determinant of genetic short stature, and 2 of the patients in this study belonged to that category. > Another important genetic cause of short stature is defects in cartilage ECM construction and maintenance. Five patients with that cause were included in this study, and most of them had skeletal deformity. The ACAN gene, which encodes the proteoglycan core protein aggrecan, is an important causative gene for short stature and has recently received attention. Aggrecan is mainly expressed in cartilage growth plates, and the pathogenic variant of ACAN can accelerate bone mutations and cause early growth cessation. 25) A heterozygous variant of the ACAN gene was found at a high frequency (2.5%) in both nonsyndromic and syndromic short stature 8,9,11) and was similar to the SHOX gene (2.4%), which is known to be the most common single gene defect in short stature. 26) These patients might have severe short stature with accelerated bone age, and other symptoms, such as early-onset osteoarthritis, should be noted. > Short children with SGA also form a clinically heterogeneous group, and various factors are known to be involved in the failure of catch-up growth. 27) As mentioned above, disorders of the GH-IGF axis, paracrine signaling, cartilage ECM, and fundamental cellular (intracellular) pathways can also be affected in children with SGA without catch-up growth.

[12] VEXAS Syndrome: Genetics, Gender Differences, Clinical Insights, Diagnostic Pitfalls, and Emerging Therapies

  • Authors: S. Corrao, Marta Moschetti, S. Scibetta, L. Calvo, Annarita Giardina et al.
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/a4a8629aace3ad297f6f1c4d45022fd3e2f64e79
  • DOI: 10.3390/ijms26167931
  • PMID: 40869252
  • PMCID: 12386336
  • Summary: This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > VEXAS syndrome, caused by somatic mutations in the UBA1 gene, leads to severe inflammatory conditions that manifest in adulthood. Its genetic origin, linked to the X chromosome, highlights a significant clinical impact even in female patients, who remain underrepresented in research due to a frequently milder disease course influenced by lyonization. The primary manifestations include systemic inflammation and hematologic abnormalities. However, the clinical phenotype is broad and complex, often resulting in misdiagnosis, diagnostic delays, and initially inappropriate treatments. A deeper understanding of the molecular mechanisms underlying this syndrome could pave the way for precision therapeutic strategies that target the disease at its core. One promising avenue is the longitudinal study of UBA1 mutations through genomic sequencing and functional assays, which will be essential for elucidating the impact of different variants on disease progression and treatment response. Another potential approach is to disrupt the inflammatory cascade associated with the disease by targeting the ubiquitination pathway. Additionally, restoring UBA1 function could represent a significant therapeutic breakthrough in re-establishing cellular homeostasis. With these strategies, we aim to provide clinicians with concrete tools to enhance the recognition and management of VEXAS syndrome, ensuring timely diagnosis and personalized care. The role of mosaicism and lyonization in female patients further underscores the complexity of the disease and the necessity for refined diagnostic approaches to detect milder cases. Future studies should concentrate on unraveling the impact of mosaicism in women, seeking to identify subtle clinical manifestations and optimize patient outcomes. A deeper understanding of these mechanisms could ultimately elevate quality of life and improve prognosis for individuals affected by this complex and potentially life-threatening condition. > This remains a significant challenge owing to the involvement of multiple organ systems, the variability in clinical manifestations, the common co-occurrence with hematologic malignancies, the reliance on glucocorticoids, and the limited response to standard immunosuppressive treatments.

[13] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

  • Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
  • Year: 2015
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
  • DOI: 10.1186/s13023-015-0242-9
  • PMID: 25874378
  • PMCID: 4358699
  • Citations: 92
  • Influential citations: 5
  • Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

[14] Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome

  • Authors: K. Neier, T. Grant, Rebecca Palmer, D. Chappell, S. Hakam et al.
  • Year: 2021
  • Venue: Communications Biology
  • URL: https://www.semanticscholar.org/paper/537ffa8fa15fa5c0cff75c2ec481ad9aa1dbb49e
  • DOI: 10.1038/s42003-021-02915-3
  • PMID: 34916612
  • PMCID: 8677842
  • Citations: 16
  • Summary: Using a mouse model for Rett syndrome (RTT), Neier et al analyze gut microbiome and metabolome profiles during disease progression and suggest that changes in the microbiome and metabolism of the gastrointestinal tract influence disease progression.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > Rett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 deficient rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolites were altered in Mecp2e1 mutant females before onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males. These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp2 animal models. Using a mouse model for Rett syndrome (RTT), Neier et al analyze gut microbiome and metabolome profiles during disease progression. They show that pathophysiology and progression of RTT is different in females than in males and suggest that changes in the microbiome and metabolism of the gastrointestinal tract influence disease progression.

[15] Role of Transcriptomics in Precision Oncology

  • Authors: Ruby Srivastava
  • Year: 2024
  • Venue: Reports of Radiotherapy and Oncology
  • URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
  • DOI: 10.5812/rro-142195
  • Citations: 4
  • Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
  • Evidence snippets:
  • Snippet 1 (score: 0.364) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[16] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

  • Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
  • Year: 2026
  • Venue: Nucleus
  • URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
  • DOI: 10.1080/19491034.2025.2611484
  • PMID: 41489464
  • PMCID: 12773485
  • Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
  • Evidence snippets:
  • Snippet 1 (score: 0.364) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[17] Collagen Type IV Variants and Kidney Cysts: Decoding the COL4A Puzzle

  • Authors: Albert Jeltsch, L. Metzinger, Matteo Rigato, C. Caprara, J. Cabrera-Aguilar et al.
  • Year: 2025
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/f44f382b1a6000498c4fee4a7a6766c8739d8559
  • DOI: 10.3390/genes16060642
  • PMID: 40565535
  • PMCID: 12193310
  • Citations: 1
  • Summary: Evidence from murine models and human studies indicating defects in collagen IV and their contribution to cystogenesis is explored, underscoring the need for broader genetic screening strategies and further investigation into the molecular mechanisms underlying this emerging phenotype.
  • Evidence snippets:
  • Snippet 1 (score: 0.362) > The precise molecular and cellular mechanisms through which collagen IV variations lead to cyst formation require further elucidation. It is crucial to understand whether cystogenesis is a direct consequence of basement membrane structural fragility, leading to tubular dilation, or if more active mechanisms are involved, such as altered cell polarity, abnormal epithelial proliferation, or the activation of specific signaling pathways. Future studies should prioritize the investigation of cell-matrix interactions in renal cystogenesis, particularly focusing on collagen IV receptors such as integrins and discoidin domain receptors. Additionally, exploring the activation of the unfolded protein response in response to collagen IV deficiency may provide insights into the molecular mechanisms underlying cyst formation. Finally, it is crucial to define more precisely the prevalence and clinical significance of the cystic phenotype in patients with AS and to evaluate whether the presence of cysts can influence the progression of kidney disease and the response to therapies. > Considering the relatively high population frequency of variants in collagen genes (1:106), potential overlap between genetic and acquired renal phenotypes is plausible. As highlighted in the provided information, instances exist where individuals present clinical features suggestive of PKD alongside identified variants in COL4A3, COL4A4, or COL4A5 [13,32]. In such cases, it is not entirely possible to exclude the co-inheritance of pathogenic or likely pathogenic variants in genes typically associated with ADPKD, such as PKD1 and PKD2, or less common ADPKD-related genes like GANAB and DNAJB11 [31]. > The current diagnostic approach often involves targeted genetic testing based on the primary clinical suspicion. Consequently, when a variant is identified in a collagen gene in a patient with cystic kidney features, a comprehensive evaluation for concurrent variants in PKD1, PKD2, or other cystic kidney disease-associated genes might not be routinely performed [15,33].

[18] A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

  • Authors: M. Formosa, D. Bergen, C. Gregson, A. Maurizi, A. Kämpe et al.
  • Year: 2021
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/be13ff3ea01dc5719f2c63b2cbf5d9f77bafd659
  • DOI: 10.3389/fendo.2021.709711
  • PMID: 34539568
  • PMCID: 8444146
  • Citations: 21
  • Summary: The monogenic forms of rare low and high rare bone Mass disorders known to date are described, a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders is provided, using proper phenotyping and genotyping methods are provided, and different genetic validation approaches paving the way for future treatments are described.
  • Evidence snippets:
  • Snippet 1 (score: 0.362) > Skeletal development is regulated by numerous genetic factors that guide the growth, modeling and remodeling of skeletal structures starting in early fetal development and continuing throughout life. These processes are crucial for attainment of normal height, skeletal patterning, bone shape, and mobility, but also for maintenance of normal bone mass and fracture resistance. Defects in the involved genes result in a large and heterogeneous group of disorders, collectively called skeletal dysplasias, in which the primary features are confined to the skeleton. More than 460 different forms of skeletal dysplasia, most of them monogenic, have been recognized (1). They are estimated to affect approximately 1/5,000 children (2,3), and can have distinct clinical manifestations and course. Clinical outcomes range in severity from neonatal lethality to only mild growth retardation, deformity or fracture risk. Diagnosis is based on growth pattern and other clinical characteristics, skeletal imaging, bone density testing, biochemical diagnostics, and genetic tests. Although the genetic basis has been described and mutations in the responsible genes identified in a significant proportion of these conditions, for several distinct skeletal dysplasia phenotypes the genetic cause is still not known (1). > Within this large group of genetic skeletal disorders, monogenic disorders affecting bone mass comprise an expanding subgroup (1,4). This includes disorders with low bone mass and skeletal fragility, and disorders leading to increased bone mass, both commonly associated with extraskeletal complications (5,6). Due to significant variability in severity, diagnosis can be challenging. Importantly, the underlying molecular genetic mechanisms for these disorders remain inadequately explored and, in several entities, the causative genetic defect, and underlying cellular and molecular pathophysiology are still uncharacterized. > The various skeletal dysplasia delineated to date have provided important information about the molecular pathways governing skeletal health both in these conditions and in the general population, underscoring the significance of new gene discoveries not only for the individuals affected by the monogenic rare bone mass disorder, but also more widely to the musculoskeletal research field (7). Indeed, the large wealth of data generated from monogenic and polygenic bone mass disorders, frailty and other musculoskeletal traits, have led

[19] Renal ciliopathies: promising drug targets and prospects for clinical trials

  • Authors: L. Devlin, Praveen Dhondurao Sudhindar, J. Sayer
  • Year: 2023
  • Venue: Expert Opinion on Therapeutic Targets
  • URL: https://www.semanticscholar.org/paper/ab2155b6e12caba53d57ac0e8ce28860d69ec9fd
  • DOI: 10.1080/14728222.2023.2218616
  • PMID: 37243567
  • Citations: 10
  • Summary: The advances in basic science and clinical research into renal ciliopathies which have yielded promising small compounds and drug targets are reviewed, within both preclinical studies and clinical trials.
  • Evidence snippets:
  • Snippet 1 (score: 0.361) > Although renal ciliopathies can be classified into distinct syndromes, causative mutations in genes encoding proteins involved in the primary cilium or centrosome mean they may share overlapping mechanisms of disease, which may be amenable for therapeutic intervention (Figure 2). Abnormal functioning of proteins involved in ciliogenesis, such as CEP164, can prevent proper cilia formation, which will effect a myriad of downstream ciliary signaling pathways. Additionally, mutations in genes encoding for proteins involved in cargo trafficking or regulation, such as CEP290, will have implications for signal pathway transduction, as well as mutations in components of signaling pathways themselves, such as PKD1. In regard to renal ciliopathies, abnormalities in signaling pathways such as cAMP, Shh, Wnt, mTOR, and AMPK, likely cause misoriented cellular divisions, increased proliferation, increased fluid secretion and subsequent cystogenesis, consequently leading to further kidney damage. Ciliary and centriolar proteins which have roles in DDR and cell cycle regulation may also be driving a renal cystogenesis phenotype alongside increased fibrosis and apoptosis. Increased inflammation and dysfunctional mitochondria are also byproducts of dysregulated signaling pathways have been shown to contribute to the progression of renal ciliopathies. Extensive reviews of mechanisms of renal ciliopathy diseases have recently been performed [23,24]. Importantly, due to the wide range of cellular processes that primary cilia regulate, it is likely that in each syndrome there are multiple pathogenic drivers of disease. In some ways, this is advantageous as it offers many points for potential therapeutic targets. However, the cross talk between pathways and feedback loops introduces complications of changing one pathway without negatively affecting another. Further challenges arise with core biological pathways, such as Shh signaling, in which modification in vitro may be beneficial, but systemic treatment is unrealistic due to the expected severe side effects [18,24,116].

[20] Diagnostic and referral pathways in patients with rare lipodystrophy and insulin-resistance syndromes: key milestones assessed from a national reference center

  • Authors: B. Donadille, S. Janmaat, H. Mosbah, Inès Belalem, Sophie Lamothe et al.
  • Year: 2024
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/823da349ccd35ba745c9241586d2fa0cb443118a
  • DOI: 10.1186/s13023-024-03173-2
  • PMID: 38678257
  • PMCID: 11056061
  • Citations: 3
  • Summary: The national rare disease database provides an important tool for assessment of care pathways in patients with lipodystrophy and rare insulin-resistance syndromes in France and improving knowledge to reduce diagnostic delay is an important objective of the PRISIS reference center.
  • Evidence snippets:
  • Snippet 1 (score: 0.361) > Lipodystrophy syndromes are heterogeneous chronic rare diseases, characterized by anatomical and functional defects of adipose tissue resulting from genetic or acquired causes. Lipodystrophy syndromes present as systemic diseases with progressive metabolic alterations associated with insulin-resistance, such as diabetes, hypertriglyceridemia, non-alcoholic fatty liver disease, and ovarian dysfunction in women, with multi-tissue involvement depending on the underlying cause. Besides different clinical presentations with generalized or partial lipoatrophy, with or without fat overgrowth in body areas without lipoatrophy, these syndromes are highly heterogeneous diseases. The onset of lipodystrophy may be precocious, from birth or early infancy, or delayed in late childhood or adulthood. Some subtypes of lipodystrophy are associated with specific clinical signs and complications, such as cardiovascular and/or neurological involvement [1][2][3]. Acquired forms of lipodystrophies generally result from autoimmune mechanisms and/or iatrogenic therapies. The identification of causative pathogenic variants in more than 20 genes leading to monogenic forms of lipodystrophies has highlighted several determinants in adipose tissue pathophysiology. Molecular and cellular bases of monogenic lipodystrophy syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet and/ or premature cellular senescence. This field of research, still highly productive, indicates adipose tissue as a major actor to ensure proper whole-body insulin sensitivity [4]. Other rare conditions characterized by severe insulinresistance without primary adipose tissue dysfunction result from direct defects in insulin signaling pathways, due to specific genetic or dysimmune disorders [5]. The four main forms of Congenital Generalized Lipodystrophy, referred to as CGL1 to CGL4, are due to pathogenic variants in AGPAT2, BSCL2, CAV1, and CAVIN1/PTRF genes, respectively.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.