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Mosaic Variegated Aneuploidy Syndrome

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Mosaic Variegated Aneuploidy Syndrome. Core disease mechanisms, molecular...

2026-05-11
Asta MONDO:0000141 Model: Asta Scientific Corpus Retrieval 19 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Mosaic Variegated Aneuploidy Syndrome. Core disease mechanisms, molecular...

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

  • Papers retrieved: 19
  • Snippets retrieved: 20

Relevant Papers

[1] Prenatal diagnosis of mosaic chromosomal aneuploidy and uniparental disomy and clinical outcomes evaluation of four fetuses

  • Authors: Shengfang Qin, Xueyan Wang, Jin Wang, Na Xi, Mengjia Yan et al.
  • Year: 2023
  • Venue: Molecular Cytogenetics
  • URL: https://www.semanticscholar.org/paper/a66093d2bab75ff7942c5f7b22f8f815300af7cf
  • DOI: 10.1186/s13039-023-00667-9
  • PMID: 38057902
  • PMCID: 10701935
  • Citations: 3
  • Summary: Fetal clinical outcomes were related to the affected chromosomes aneuploidy and UPD, mosaic levels and tissues, methylation status, and homozygous variation of recessive genes on the UPD chromosome.
  • Evidence snippets:
  • Snippet 1 (score: 0.398) > The effects of mosaic chromosomal aneuploidy and UPD on fetuses are related to different chromosomes, mosaic levels, and mosaic tissues, which affect the intrauterine phenotype and clinical outcome. The four fetuses in this study had low-level mosaic chromosomes of T2, T15, monosomy X, and T20, respectively. The clinical influence of UPD is directly related to the gene content and size of the affected chromosomal region. If imprinted genes were involved, UPD could cause imprinted diseases, such as Beckwith-Wiedemann syndrome (BWS, patUPD11), Kagami-ogata syndrome (KOS, patUPD14), Angelman syndrome (AS, patUPD15)/PWS (PWS, matUPD15), pseudohypoparathyroidism (patUPD20) /Mulchandani-Bhoj-Conlin syndrome (MBCS, matUPD20) [15]. In addition, UPD events also increase the risk of recessive genetic disorders. The UPD of this study involved chr2, chr15, chr20, and the whole genome. In utero, fetuses usually have less visible phenotypes. However, when the prenatal imaging of the fetus is consistent with typical UPD manifestations of the KOS and BWS, chromosomal or genetic abnormalities should be validated by laboratory methods [16]. > In our four cases, we found more than two adverse genetic events happened in succession during their meiosis and mitosis as in previous reports [17] and proposed a possible formation mechanism of mosaic chromosomal aneuploidy and UPD. See Fig. 4 for details. We speculate multiple events might occur continuously on chromosome 2, including homologous recombination in prophase I, no separation in meiosis II, and rescue of trisomy and monosomy during mitosis. The chr2 consisted of normal cells, trisomy, and maternal UPD cells.
  • Snippet 2 (score: 0.388) > Background Few co-occurrence cases of mosaic aneuploidy and uniparental disomy (UPD) chromosomes have been reported in prenatal periods. It is a big challenge for us to predict fetal clinical outcomes with these chromosome abnormalities because of their highly heterogeneous clinical manifestations and limited phenotype attainable by ultrasound. Methods Amniotic fluid samples were collected from four cases. Karyotype, chromosome microarray analysis, short tandem repeats, and whole exome sequencing were adopted to analyze fetal chromosomal aneuploidy, UPD, and gene variation. Meanwhile, CNVseq analysis proceeded for cultured and uncultured amniocytes in case 2 and case 4 and MS-MLPA for chr11 and chr15 in case 3. Results All four fetuses showed mosaic chromosomal aneuploidy and UPD simultaneously. The results were: Case 1: T2(7%) and UPD(2)mat(12%). Case 2: T15(60%) and UPD(15)mat(40%). Case 3: 45,X(13%) and genome-wide paternal UPD(20%). Case 4: <10% of T20 and > 90% UPD(20)mat in uncultured amniocyte. By analyzing their formation mechanism of mosaic chromosomal aneuploidy and UPD, at least two adverse genetic events happened during their meiosis and mitosis. The fetus of case 1 presented a benign with a normal intrauterine phenotype, consistent with a low proportion of trisomy cells. However, the other three fetuses had adverse pregnancy outcomes, resulting from the UPD chromosomes with imprinted regions involved or a higher level of mosaic aneuploidy. Conclusion UPD is often present with mosaic aneuploidy. It is necessary to analyze them simultaneously using a whole battery of analyses for these cases when their chromosomes with imprinted regions are involved or known carriers of a recessive allele. Fetal clinical outcomes were related to the affected chromosomes aneuploidy and UPD, mosaic levels and tissues, methylation status, and homozygous variation of recessive genes on the UPD chromosome. Genetic counseling for pregnant

[2] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 4
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[3] Turner’s syndrome mosaicism in girls with neurodevelopmental disorders: a cohort study and hypothesis

  • Authors: S. Vorsanova, A. D. Kolotii, O. S. Kurinnaia, V. Kravets, I. Demidova et al.
  • Year: 2021
  • Venue: Molecular Cytogenetics
  • URL: https://www.semanticscholar.org/paper/9769a11d85d603b4437db8112bfd3695202f1abf
  • DOI: 10.1186/s13039-021-00529-2
  • PMID: 33573679
  • PMCID: 7879607
  • Citations: 14
  • Influential citations: 1
  • Summary: It appears that molecular cytogenetic monitoring of TSM, which is a likely risk factor/biomarker for adult-onset multifactorial diseases, is required and may be an element of pathogenic cascades in brain diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > Turner's syndrome represents a common chromosomal (gonosomal) syndrome (newborn prevalence: 5.9/1000) [24]. So far, this is the sole syndrome associated with non-mosaic monosomy in human [5,6]. However, it is systematically hypothesized that liveborn children with non-mosaic 45,X karyotype are tissue-specific mosaics [6,25,26]. Recently, analyses of multiple tissues repeatedly supported this idea [27]. Since mosaicism is an important biomarker in Turner's syndrome, high attention is paid to mosaic cases. Moreover, studies of TSM in clinical cohorts are a broad area of medical genetic research. This may be explained by the fact that gonosomal mosaicism is a phenomenon with global relevance to biomedicine [28]. Mostly, these studies are performed for cohorts of patients with reproductive problems or for children without specific clinical features [8,[29][30][31]. Surprisingly, despite of the presence of neurobehavioral and psychiatric endophenotypes in the clinical picture of Turner's syndrome, analyses of TSM are exclusive in neurodevelopmental cohorts [32,33]. The present study fills this gap providing a comprehensive analysis of TSM among females with neurodevelopmental disorders. Thus, this mosaicism type is involved in 1.9% of cases among neurodevelopmental disorders, i.e. such a phenotypically variable group of patients. Somatic gonosomal mosaicism manifesting as aneuploidy is a contributor to the pathogenesis of numerous diseases [7,[34][35][36][37]. Here, we have shown that 1.2% of females with neurodevelopmental disorders are affected by mosaic X chromosome loss alone. Therefore, one can suggest that mosaicism for monosomy of chromosome X is a highly probable and relatively common mechanism of brain diseases in females. Supernumerary marker chromosomes derived from gonosomes have extremely variable phenotypic outcomes from asymptomatic carriage to irritant medical problems [38,39].

[4] Prenatal diagnosis and long‐term follow‐up of a Chinese patient with mosaic variegated aneuploidy and its molecular analysis

  • Authors: S. Lin, H. Luk, I. Lo, Wai-Keung Tam, K. Y. Chan et al.
  • Year: 2020
  • Venue: Clinical Case Reports
  • URL: https://www.semanticscholar.org/paper/55c0cf44e588c85d20a72365efc433be7b3b4219
  • DOI: 10.1002/ccr3.2802
  • PMID: 32884756
  • PMCID: 7455400
  • Citations: 4
  • Summary: The prenatal diagnosis, molecular characterization, and clinical management of a long‐lived patient with BUB1B‐related MVA are described.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > Mosaic variegated aneuploidy (MVA, OMIM 257300) is a congenital autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies, and monosomies, involving multiple chromosomes and tissues. 1 Mutations in BUB1B, CEP57, and TRIP13 genes, which are involved in mitotic spindle and microtubule stabilization, are responsible for the molecular pathogenesis of MVA. The clinical features of MVA syndrome include severe pre/postnatal growth retardation, microcephaly, central nervous system anomalies, intellectual disability, minor congenital malformation, and predisposition to malignancy. There is some genotype-phenotype correlation (Table 1). Intellectual disability, microcephaly, brain malformations, epilepsy, and cancer predisposition are more common in BUB1B subtype. Rhizomelic shortening of the upper limbs, skull anomalies with conserved head circumference, and absence of malignancy are more common in CEP57 subtype. In addition, TRIP13 subtype has growth retardation with microcephaly and developmental delay, but there is no other structural abnormality and dysmorphic facial feature as in BUB1B subtype. > Several cases of MVA were diagnosed in prenatal period, 2 followed by the termination of pregnancy. Here we reported a Chinese patient with the longest survival in literature, with cytogenetic and antenatal findings together with her longterm postnatal course and molecular finding.

[5] The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.

  • Authors: S. Silva, G. Arno, A. Robson, A. Fakin, Nikolas Pontikos et al.
  • Year: 2020
  • Venue: Progress in retinal and eye research
  • URL: https://www.semanticscholar.org/paper/0002f4d18faa348181db81ac27fed490c9ddb569
  • DOI: 10.1016/j.preteyeres.2020.100898
  • PMID: 32860923
  • Citations: 127
  • Influential citations: 7
  • Summary: An algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy is presented, current experimental therapeutic approaches are summarised, and questions for future research are considered.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > Inherited retinal diseases are a frequent cause of blindness in paediatric and working age populations in many countries Rahman et al., 2020;Solebo and Rahi, 2014;Solebo et al., 2017). > The X-linked retinopathies represent an important, diverse subgroup, including both progressive and stationary conditions, and disorders with and without syndromic features. They display a number of different pathogenic mechanisms, thereby yielding important and wide-ranging insights into key aspects of retinal physiology and pathophysiology. A significant number are also the subject of novel therapeutic trials. > Pathogenic variants usually cause disease by loss of protein function; hence these conditions are particularly attractive for gene-replacement strategies. There is a carrier phenotype in several of these conditions, which can help clinicians narrow the differential diagnosis and thereby mode of inheritance, and which may also reveal valuable information regarding patterns of X inactivation, normal retinal cellular development and migration, and mechanisms of disease. Carrier females are often asymptomatic, but may infrequently be as severely affected as males, which may result in inheritance being incorrectly classified as autosomal dominant. Some of the disorders also illustrate ways in which variants in the same gene can generate a number of phenotypes, and potential limitations in current genetic sequencing methods; awareness of the latter is particularly relevant as we enter the era of widely available whole genome sequencing and gene therapy. > In this article, X-inactivation and patterns of X-linked inheritance will be reviewed briefly. We then explore the burden of disease attributable to X-linked genes in a large clinically and genetically characterised inherited retinal disease cohort, highlighting the most frequently implicated genes, and investigating correlation between gene transcript length and numbers of affected families. Subsequently, we provide a list of X-linked genes involved in a number of non-syndromic and syndromic retinopathies, together with key clinical features, and a schematic showing sites of expression or impairment in the retina. We then discuss several genes in more detail as specified in the abstract. For several conditions, disease mechanisms, clinical features, carrier phenotypes, electrophysiological findings, and novel experimental therapies, where applicable, are considered. A comprehensive, detailed discussion of

[6] Total Hemi-overgrowth in Pigmentary Mosaicism of the (Hypomelanosis of) Ito Type

  • Authors: V. Pavone, S. Signorelli, A. Praticò, G. Corsello, S. Savasta et al.
  • Year: 2016
  • Venue: Medicine
  • URL: https://www.semanticscholar.org/paper/d3902c737bb463b877dc93ccf49c3a144415d82e
  • DOI: 10.1097/MD.0000000000002705
  • PMID: 26962770
  • PMCID: 4998851
  • Citations: 40
  • Summary: The present study, which includes children and adults with the longest follow-up so far recorded, confirms the association between pigmentary mosaicism of the Ito type and HOG lowering previous estimates (7% vs 16%) for HOG in the context of mosaic hypopigmentation.
  • Evidence snippets:
  • Snippet 1 (score: 0.389) > The systemic form of ND in its unilateral form may be difficult to differentiate from pigmentary mosaicism, but it is usually not associated with systemic manifestations. > Regarding the likely role of pigmentary genes in the occurrence of mosaic phenomena of hypopigmentation (along the lines of Blaschko) either as isolated traits or as syndromic patterns, Taibjee et al 19 reported several ranges of mosaic chromosomal abnormalities, including diploidy, triploidy, aneuploidy, chromosomal deletions, insertions, and translocations (of basically all chromosomes) in about 50% of affected individuals with hypopigmentation along the lines of Blaschko: cross-comparison of these cytogenetic abnormalities and one or more pigmentary genes showed significant (ie, >70%) overlaps. The claimed familial occurrence and the number of reported pedigrees inferring Mendelian inheritance in pigmentary mosaicism of the Ito type have not been proven at a clinical level. 20 It has been hypothesized that the pigmentary pattern that follows Blaschko's lines is the result of the migration of 2 different clones of cells during embryogenesis, and the clinical findings of pigmentary mosaicism (of the Ito type) is a nonspecific manifestation (ie, a phenotype) reflecting genetic mosaicism, which likely disrupts expression or function of pigmentary genes. 19,21 The pigmentary anomalies are the results of an interaction between 2 different cellular populations as it happens with the mosaicism. 7,9 The current term of pigmentary mosaicism along the lines of Blaschko (or of the Ito type) (or linear hypomelanosis in narrow bands, according to the system of archetypical patterns of cutaneous mosaicism) 9,10 thus reflects the anatomical distribution of the abnormal skin patterning over the body and the assumed pathogenesis of the disorder: that is, somatic mosaicism for a yet undiscovered gene or genes responsible for pigmentation in humans. 5,9

[7] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

  • Authors: M. M. Wong, L. Watson, Esther B. E. Becker
  • Year: 2017
  • Venue: Journal of neurology & neuromedicine
  • URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
  • DOI: 10.29245/2572.942X/2017/7.1134
  • PMID: 28825058
  • PMCID: 5558869
  • Citations: 10
  • Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
  • Evidence snippets:
  • Snippet 1 (score: 0.388) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[8] Consequences of aneuploidy in human fibroblasts with trisomy 21

  • Authors: Sunyoung Hwang, Paola Cavaliere, Rui Li, L. Zhu, Noah E. Dephoure et al.
  • Year: 2020
  • Venue: Proceedings of the National Academy of Sciences of the United States of America
  • URL: https://www.semanticscholar.org/paper/5ae9f7792cd2e4a8e2d6178f5a322da9f96ba3ac
  • DOI: 10.1101/2020.08.14.251082
  • PMID: 33526671
  • PMCID: 8017964
  • Citations: 57
  • Influential citations: 6
  • Summary: It is shown that several aneuploidy-associated phenotypes are present in trisomy 21 cells, including lower viability and increased dependency on serine-driven lipid synthesis, and the lack of evidence for widespread dosage compensation or dysregulation of chromosomal domains in human autosomes is supported.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Significance An abnormal number of chromosomes or aneuploidy accounts for most spontaneous abortions, as missegregation of a single chromosome during development is often lethal. Only individuals with trisomy 21, which causes Down syndrome, can live to adulthood but show cognitive disabilities, increased risk for leukemias, autoimmune disorders, and clinical symptoms associated with premature aging. The mechanisms by which aneuploidy affects cellular function to cause Down syndrome are not understood. Our studies revealed that aneuploidy causes several defects in cells from individuals with Down syndrome. These include increased gene and protein expression, lower viability, and increased dependency on serine to proliferate. Our studies establish a critical role of aneuploidy, independent of triplicated gene identity, in driving cellular defects associated with trisomy 21. An extra copy of chromosome 21 causes Down syndrome, the most common genetic disease in humans. The mechanisms contributing to aneuploidy-related pathologies in this syndrome, independent of the identity of the triplicated genes, are not well defined. To characterize aneuploidy-driven phenotypes in trisomy 21 cells, we performed global transcriptome, proteome, and phenotypic analyses of primary human fibroblasts from individuals with Patau (trisomy 13), Edwards (trisomy 18), or Down syndromes. On average, mRNA and protein levels were increased by 1.5-fold in all trisomies, with a subset of proteins enriched for subunits of macromolecular complexes showing signs of posttranscriptional regulation. These results support the lack of evidence for widespread dosage compensation or dysregulation of chromosomal domains in human autosomes. Furthermore, we show that several aneuploidy-associated phenotypes are present in trisomy 21 cells, including lower viability and increased dependency on serine-driven lipid synthesis. Our studies establish a critical role of aneuploidy, independent of triplicated gene identity, in driving cellular defects associated with trisomy 21.

[9] 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: 0.383) > 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.

[10] 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: 0.383) > 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.

[11] An Overview of Oxidative Stress in Sex Chromosome Aneuploidies in Pediatric Populations

  • Authors: R. Paparella, Fabiola Panvino, F. Tarani, Benedetto D'Agostino, Lucia Leonardi et al.
  • Year: 2025
  • Venue: Antioxidants
  • URL: https://www.semanticscholar.org/paper/da1e94b42aa80ca885e2c884a219ccb4d8688d81
  • DOI: 10.3390/antiox14050531
  • PMID: 40427413
  • PMCID: 12108347
  • Citations: 3
  • Summary: Early, tailored antioxidant strategies, integrated with syndrome-specific hormonal therapies, could reduce long-term complications and improve patient outcomes and future research should focus on standardizing protocols to optimize these interventions for pediatric patients with SCAs.
  • Evidence snippets:
  • Snippet 1 (score: 0.378) > Sex chromosome aneuploidies (SCAs) are among the most common chromosomal abnormalities, affecting approximately 1 in 500 live births, with the prevalence varying based on the specific condition [1][2][3]. The most frequent SCAs include Klinefelter syndrome (KS), Turner syndrome (TS), 47,XXX syndrome, and 47,XYY syndrome, along with less common variants and mosaicism forms [4,5]. > SCAs are associated with a wide spectrum of clinical manifestations, including developmental delay, cognitive impairment, dysmorphic features, gonadal dysfunction, cardiovascular anomalies, and metabolic disturbances [6,7]. The variability in phenotypic presentation is influenced by the specific aneuploidy, mosaicism degree, and dosage effects of sex chromosome-linked genes [8]. Advances in prenatal diagnostic techniques and improved clinical management have contributed to earlier detection and better outcomes, emphasizing the need for a deeper understanding of underlying pathophysiological mechanisms [9][10][11]. > Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defense mechanisms, has been implicated in the pathogenesis of numerous pediatric disorders [12,13]. Emerging evidence suggests that SCAs may also involve oxidative stress, contributing to the development of associated comorbidities such as cardiovascular disease, diabetes, and neurodevelopmental disorders [14][15][16][17]. Notably, oxidative stress has been extensively studied in autosomal aneuploidies such as trisomy 21, where altered redox homeostasis plays a critical role in phenotypic manifestations [18,19]. The role of oxidative stress in SCAs, however, remains underexplored. Specific genes located on sex chromosomes, such as those regulating oxidative balance and mitochondrial function, as well as autosomal genes, may contribute to increased ROS production and decreased antioxidant capacity [20][21][22][23][24][25]. Understanding these mechanisms could illuminate the etiology of SCA-related complications and inform therapeutic strategies targeting oxidative stress.

[12] Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience

  • Authors: Cecelia R. Miller, Kristy Lee, R. Pfau, S. Reshmi, Don Corsmeier et al.
  • Year: 2020
  • Venue: Cold Spring Harbor Molecular Case Studies
  • URL: https://www.semanticscholar.org/paper/ab0fc796600e188cc823d77a1ae52db443027255
  • DOI: 10.1101/mcs.a005231
  • PMID: 32371413
  • PMCID: 7304353
  • Citations: 21
  • Summary: The potential and importance of detecting mosaicism in ES is highlighted, particularly with increased sequence depth attainable from ES, as well as the need to assess diagnostic yield and characteristics of causal variants.
  • Evidence snippets:
  • Snippet 1 (score: 0.374) > Pathogenic variants at very low VAF in affected tissue can be sufficient to cause disease. For example, in diseases such as Sturge-Weber or vascular anomalies with overgrowth (e.g., Proteus syndrome or PIK3CA-related overgrowth spectrum [PROS]), the VAF of pathogenic variants in affected tissue has been reported as low as 1% (Lindhurst et al. 2011;Shirley et al. 2013;Hucthagowder et al. 2016). > Among unselected clinical exome cohort studies of pediatric, and combined pediatric and adult populations, disease-associated mosaic variants were noted at a frequency of ∼1%-1.5% (Yang et al. 2013;Retterer et al. 2016;Cao et al. 2019). The frequency of mosaicism increases when examining for specific phenotypes. For example, in epilepsy-related neurodevelopmental disorders, 3% of the pathogenic variants identified by either an MPS epilepsy panel or ES were mosaic (Stosser et al. 2018). In certain disorders (e.g., McCune-Albright and PROS), mosaic variants are the primary mechanism of disease (Aldred and Trembath 2000;Keppler-Noreuil et al. 2015;Hucthagowder et al. 2016). > We evaluated two years of clinical ES data from our laboratory within a pediatric tertiary care center to determine the characteristics of disease-associated variants within our cohort, as well as to compare the diagnostic yield reported by the laboratory versus the ordering clinical provider's interpretation of laboratory reported variant causality. We sought to evaluate the concordance of the molecular ES diagnostic rate generated by the laboratory with clinical provider-confirmed diagnoses recorded in the electronic medical record (EMR) to test if the laboratory workflow, including selection of genes relevant to the proband phenotype and subsequent variant assessment, resulted in meaningful results being reported back to the ordering provider. We further summarized the characteristics of these provider-confirmed causal variants and evaluated the contribution of mosaic variants to genetic disease within the context of these diagnoses.

[13] Somatic NLRP3 mosaicism in patients with “mutation-negative” CAPS: insights from a single centre UK cohort

  • Authors: S. Melo Gomes, J. I. Arostegui, Ana Mensa-Vilaro, E. Omoyinmi, Ying Hong et al.
  • Year: 2025
  • Venue: Frontiers in Pediatrics
  • URL: https://www.semanticscholar.org/paper/82a19d6e3f0a753dcfea31f9d4a2933ba1eff5bf
  • DOI: 10.3389/fped.2025.1598748
  • PMID: 40538939
  • PMCID: 12176735
  • Citations: 1
  • Summary: Somatic NLRP3 mosaicism was present in 40% of this paediatric cohort, confirming the key role of this phenomenon in disease pathogenesis and in genetic confirmation of CAPS diagnosis, and warrants caution regarding lower detection limits of the sequencing techniques utilized.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > Advances in ADS technology could increase the success rate of genetic diagnosis for mutation-negative CAPS from 60 to 80%, which would greatly benefit the care of these patients by increasing diagnostic yield and help prevent potentially irreversible complications by allowing earlier targeted treatment with IL-1 blockade (8). > Although the phenotype of patients with somatic NLRP3 mosaicism is very typical of the disease, a few studies tried to ascertain if there were any differences in relation to CAPS patients with germline mutations (3,9). Thus, patients with CINCA/NOMID and NLRP3 mosaicism were found to have a lower incidence of intellectual disability, and milder neurological symptoms overall following genotype matched comparison. One possibility to explain this could be the level of mosaicism in central nervous system cells or glial cells (3). Regarding Muckle-Wells Syndrome (MWS), the differences between patients with germline and mosaic mutations were slightly broader. MWS patients with mosaicism seemed to have a reduced incidence of AA-type amyloidosis when compared to patients with germline mutations, an increased incidence of recurrent arthritis, as well as older ages at the onset of the disease and that of sensorineural deafness. Moreover, absence of family history is a requisite in patients with mosaicism, whilst patients with germline mutations may have affected first-degree relatives. However, one of the most important and impactful differences was the significant delay in obtaining access to treatment with anti-IL1 drugs in patients with mosaicism, which was only achieved once the molecular diagnosis of mosaicism was secured (9). > The differences in clinical severity between mosaic and germline CAPS patients can be due to several factors, including the type of amino acid exchange, its location in the cryopyrin protein, the functional consequence of the mutation, as well as the level (percentage of cells) and tissue distribution of the mosaicism (7,9).

[14] Mosaic results after preimplantation genetic testing for aneuploidy may be accompanied by changes in global gene expression

  • Authors: A. Martin, A. Mercader, F. Domínguez, A. Quiñonero, M. Perez et al.
  • Year: 2023
  • Venue: Frontiers in Molecular Biosciences
  • URL: https://www.semanticscholar.org/paper/649844fa594d4995c150ce769b856e81fd086dab
  • DOI: 10.3389/fmolb.2023.1180689
  • PMID: 37122560
  • PMCID: 10140421
  • Citations: 14
  • Influential citations: 2
  • Summary: Comparisons of transcriptome profiles of inner cell mass and trophectoderm samples from blastocysts with different levels of chromosomal mosaicism suggest that embryos with mosaic results may have a genuine molecular identity that is compatible with their reproductive potential.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > While this might be the most common scenario, the reproductive potential of these embryos may also be explained by the complex interplay of molecular mechanisms which become deregulated in the presence of aneuploid cells. Our findings also suggest that within mosaic embryos, those with low-level mosaicism may exhibit transcriptome profiles more closely resembling those of euploid embryos, while high-level mosaic embryos represent a distinct biological category characterized by molecular features indicative of a greater extent and burden of the cellular stress arising from aneuploidy. These findings align well with current perspectives on the reproductive potential of mosaic embryos, and contribute to the growing body of evidence suggesting that low and high levels of mosaicism after PGT-A deserve distinct clinical management. > Some limitations of our study should be acknowledged. First, given the difficulty of obtaining embryos with the highest morphological quality for research purposes, our analysis was restricted to embryos graded B or C. In addition, global gene expression may exhibit high heterogeneity even among highquality embryos at the same developmental stage (Shaw et al., 2013;Ntostis et al., 2019). This means that our results may not be generalizable to other embryo populations, especially those with higher morphological scores. Furthermore, beyond the potential effect of chromosome-specific gene expression, the impact of mosaic aneuploidies on global transcriptome profiles may be confounded by specific adaptive mechanisms, particularly considering the extraordinary plasticity of early human development (Coticchio et al., 2021). Finally, while transcriptomics can serve as a sensitive indicator of cellular stress, it provides little to no information on protein activity. Therefore, our results should be interpreted with caution, and further studies focusing on protein are necessary to confirm these findings. > In conclusion, our study demonstrates that mosaic results following PGT-A may be accompanied by significant alterations in gene expression across blastocyst compartments as well as by significant delays in cell cycle timings during the first mitotic divisions. The level of mosaicism was associated with the extent of transcriptome deregulation, and pathways involving apoptosis, mitosis, protein degradation, metabolism, and mitochondrial energy production were among the most deregulated within mosaic embryos.

[15] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

  • Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
  • Year: 2021
  • Venue: Molecular Genetics & Genomic Medicine
  • URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
  • DOI: 10.1002/mgg3.1809
  • PMID: 34519438
  • PMCID: 8580094
  • Citations: 12
  • Influential citations: 2
  • Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

[16] Animal models of intellectual disability: towards a translational approach

  • Authors: C. Scorza, E. Cavalheiro
  • Year: 2011
  • Venue: Clinics
  • URL: https://www.semanticscholar.org/paper/cdb05f879079d91e136441e780b0bbb6a819a080
  • DOI: 10.1590/S1807-59322011001300007
  • PMID: 21779723
  • PMCID: 3118438
  • Citations: 16
  • Influential citations: 1
  • Summary: Several animal models of potential intellectual disability risk factors are described and a comparative approach is needed to benefit the most from what each animal model can tell us.
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > The understanding of the pathogenicity of the extra genomic material in trisomy 21 has accelerated in recent years because of the recent advances in genome sequencing, comparative genome analysis, functional genome exploration and the use of animal models. 30 Aneuploidy, defined as an abnormal number of copies of a genomic region, is recognized as a common mechanism of human genetic disease, often leading to abnormal gene expression patterns with overor underexpression of specific genes. 31 Surprisingly, a significant number of human brain cells (both neurons and non-neuronal cells) can be aneuploidy, and the resulting genetic mosaicism is a normal feature of the human central nervous system. 32 But, what could be the mechanisms by which the anatomical, chemical and neurophysiological brain abnormalities underlying ID arise from deregulation of gene expression? Major questions are still unanswered. Genetically modified mouse models have been helping to investigate the contributions of specific gene alterations and gene-environment interactions to the phenotype of several forms of ID. > Fragile X syndrome X-linked disorders may explain why males show a 25-35% higher incidence of mental disabilities than females. It is imperative to gain knowledge of the mechanisms specific to the X-chromosome (e.g., X-inactivation, gene regulation) that may be relevant to understanding some forms of Xlinked mental retardation. Fragile X syndrome (FXS) is the leading cause of heritable intelligence disability, affecting about 1 in 1400 males and 1 in 2500 females. FXS is caused by a trinucleotide expansion in the fragile X mental retardation 1 gene (fmr1) that prevents the expression of the encoded protein, called fragile X mental retardation protein (FMRP). 33 The genetic defect is an unstable region of DNA on the X chromosome that becomes highly expanded when transmitted through the maternal lineage. FXS is a common form of mental retardation associated with attention deficit, autistic behavior, hyperactivity and epileptic seizures. 34 The phenotype of FXS is reproduced in fmr1 knockout (KO) mice that, among others, have regionspecific altered expression of some gamma-aminobutyric acid (GABA) receptor subunits. 35,36

[17] In silico molecular cytogenetics: a bioinformatic approach to prioritization of candidate genes and copy number variations for basic and clinical genome research

  • Authors: I. Iourov, S. Vorsanova, Y. Yurov
  • Year: 2014
  • Venue: Molecular Cytogenetics
  • URL: https://www.semanticscholar.org/paper/a16e86a729a48ff5d168bf0e4b8a94e633fb86ca
  • DOI: 10.1186/s13039-014-0098-z
  • PMID: 25525469
  • PMCID: 4269961
  • Citations: 46
  • Summary: A bioinformatic approach combining filtering and ranking prioritization strategies, which includes analyzing metabolome and interactome data on proteins encoded by candidate genes, is proposed and is able to become useful for increasing the yield of molecular cytogenetic techniques.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > Therefore, such types of GIN/CIN are rarely evaluated by an in silico analysis, even though knowledge of their effects on cellular/ clinical phenotypes is able to shed light on new genetic mechanisms of biodiversity and disease [38]. Alternatively, it has been shown that either SGV or non-mosaic genomic variations can dysregulate chromosome segregation and genomic maintenance producing CIN or GIN [12]. These observations were used for suggesting that bioinformatic approaches might be useful for studying mechanisms and consequences of somatic mosaicism. Finally, the present approach based on prioritizing genetic variants using evaluation of epigenetic variation between tissues and cell types can be utilized in studies of tissue-specific mosaicism. > Until recently, somatic mosaicism has not been a major focus of genome research [33,39]. With the increase of interest in addressing SGV, several studies have posed questions about the relevance of SGV to genetic diversity and morbidity [39][40][41]. It is repeatedly noted that SGV are underrecognized sources of genomic, chromosomal and complex disorders [18,33,39,41]. Additionally, SGV affecting specific tissues often lead not only to cancer, but also to tissue-specific pathology. For instance, numerous brain diseases are associated with SGV (CIN/GIN) manifested as aneuploidy or structural genome variations [14,18,37,[42][43][44][45][46][47][48]. These data have served as a basis for speculations about diagnostic applications of SGV analysis in brain disease and regeneration therapy [49]. Still, the idea remains undeveloped and further theoretical input is needed. It can be expected that molecular cytogenetic studies of SGV would benefit from in silico evaluations of their mechanisms and consequences.

[18] Double homozygosity in CEP57 and DYNC2H1 genes detected by WES: Composite or expanded phenotype?

  • Authors: L. Pezzani, L. Pezzoli, Alessandra Pansa, B. Facchinetti, D. Marchetti et al.
  • Year: 2020
  • Venue: Molecular Genetics & Genomic Medicine
  • URL: https://www.semanticscholar.org/paper/3aec92f37c87b59c0db11d3f9606950caffb1088
  • DOI: 10.1002/mgg3.1064
  • PMID: 31943948
  • PMCID: 7057129
  • Citations: 10
  • Summary: Three‐whole exome sequencing (WES) analysis has demonstrated its potential in obtaining genetic diagnoses even in nonspecific clinical pictures and in atypical presentations of known diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > Mosaic variegated aneuploidy is a genetically heterogeneous autosomal recessive disease caused by mutations of three different genes: BUB1B (MVA1, OMIM # 257,300) (Hanks et al., 2004), CEP57 (MVA2, OMIM # 614,114) (Snape et al., 2011), and TRIP13 (MVA3, OMIM # 617,598) (Yost et al., 2017). The presence of constitutional mosaic aneuploidies due to gain or loss of multiple different chromosomes is the hallmark of MVA syndromes, while the related clinical phenotype can vary according to the involved causal gene. Cancer predisposition is one of the most important associations of MVA due to BUB1B and TRIP13 variants, with substantial increased risk of childhood malignancies, particularly Wilms tumor, rhabdomyosarcoma, and leukemia (Hanks et al., 2004;Jacquemont, Bocéno, Rival, Méchinaud, & David, 2002;Yost et al., 2017). On the contrary none of the seven patients with CEP57 mutation reported to date in the literature developed cancer (Brightman, Ejaz, & Dauber, 2018;De la Torre-García et al., 2019;Pinson et al., 2014) even if a recent work proved that MVA2 syndrome or haploinsufficiency in CEP57 are associated with impaired tumor suppression (Aziz et al., 2018). Cancer proneness in MVA2 thus deserves further investigation since our patient died at 6 months of life and none of the reported MVA2 patients have reached adulthood yet. So, the careful description of additional cases, and the follow-up of the already reported patients will be important to better delineate this important aspect.

[19] A Massively Parallel Pipeline to Clone DNA Variants and Examine Molecular Phenotypes of Human Disease Mutations

  • Authors: Xiaomu Wei, Jishnu Das, Robert Fragoza, Jin Liang, F. M. Bastos de Oliveira et al.
  • Year: 2014
  • Venue: PLoS Genetics
  • URL: https://www.semanticscholar.org/paper/830329784c911d37c86ddcd3fc4af6d8b3a0ac53
  • DOI: 10.1371/journal.pgen.1004819
  • PMID: 25502805
  • PMCID: 4263371
  • Citations: 52
  • Summary: This work describes a massively-parallel site-directed mutagenesis approach, “Clone-seq”, leveraging next-generation sequencing to rapidly and cost-effectively generate a large number of mutant alleles, and develops a comparative interactome-scanning pipeline integrating high-throughput GFP, yeast two-hybrid, and mass spectrometry assays to systematically evaluate the functional impact of mutations on protein stability and interactions.
  • Evidence snippets:
  • Snippet 1 (score: 0.364) > We then analyzed whether the molecular phenotypes measured by our high-throughput GFP and Y2H assays are correlated with corresponding disease phenotypes. We first examined how mutation pairs on the same gene affect protein stability and its relationship to their corresponding diseases. We find that pairs of mutations that are either both stable or both unstable cause the same disease in 68% and 70% of cases, respectively. However, pairs comprising one stable and one unstable mutation cause the same disease in only 30% of cases (P = 6610 29 and 8610 210 , respectively, Fig. 5a). For example, we find that the mutations R727C and L844F on the spindle checkpoint kinase Bub1b both cause the protein to become unstable and lose all its interactors. These mutations are both associated with the same disease, mosaic variegated aneuploidy, an autosomal recessive disorder that causes predominantly trisomies and monosomies of different chromosomes [22,23]. Since our GFP assay shows that these two mutations cause loss of protein product, our results are consistent with Matusuura et al.'s finding that a more than 50% decrease in Bub1b activity leads to abnormal mitotic spindle checkpoint function and mosaic variegated aneuploidy [24]. > We then examined whether mutation pairs on the same gene disrupt the same set or different sets of interactions (i.e., their interaction disruption profiles) and investigated whether their disruption profiles correlates with disease phenotypes. We found that mutation pairs with the exact same disruption profile are significantly more likely to cause the same disease than those with different profiles (70% and 61% respectively, P = 3610 25 , Fig. 5b). For example, we found that two mutations on Smad4, R361C and Y353S, disrupt its interactions with Smad3 and Smad9 while leaving the interactions with Lmo4 and Rassf5 unaltered (Fig. 5c). These two mutations both cause juvenile polyposis coli [25,26], a disease is known to be caused by disruption of the core Smad/Bmp signaling pathways [27].

Notes

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