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International Journal of Molecular... Oct 2022The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech. The aim of the... (Review)
Review
The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech. The aim of the present study is to systematically review the available data on the prevalence of clinical manifestations and to evaluate the correlation between phenotype and genotype in published cases of patients with CTNNB1 Syndrome. Studies were identified by systematic searches of four major databases. Information was collected on patients' genetic mutations, prenatal and neonatal problems, head circumference, muscle tone, EEG and MRI results, dysmorphic features, eye abnormalities, early development, language and comprehension, behavioral characteristics, and additional clinical problems. In addition, the mutations were classified into five groups according to the severity of symptoms. The study showed wide genotypic and phenotypic variability in patients with CTNNB1 Syndrome. The most common moderate-severe phenotype manifested in facial dysmorphisms, microcephaly, various motor disabilities, language and cognitive impairments, and behavioral abnormalities (e.g., autistic-like or aggressive behavior). Nonsense and missense mutations occurring in exons 14 and 15 were classified in the normal clinical outcome category/group because they had presented an otherwise normal phenotype, except for eye abnormalities. A milder phenotype was also observed with missense and nonsense mutations in exon 13. The autosomal dominant CTNNB1 Syndrome encompasses a wide spectrum of clinical features, ranging from normal to severe. While mutations cannot be more generally categorized by location, it is generally observed that the C-terminal protein region (exons 13, 14, 15) correlates with a milder phenotype.
Topics: Pregnancy; Female; Humans; Codon, Nonsense; Phenotype; Intellectual Disability; Syndrome; Genotype; Mutation; Eye Abnormalities; beta Catenin
PubMed: 36293418
DOI: 10.3390/ijms232012564 -
International Journal of Gynecological... Dec 2023Endometrial cancers with more than one molecular feature- mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple...
BACKGROUND
Endometrial cancers with more than one molecular feature- mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple classifiers'.
OBJECTIVE
To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them.
METHODS
Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification.
RESULTS
Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. sequencing allowed the detection of additional 7 (18.9%) multiple classifiers with normal p53 immunostaining. The incidence of multiple classifiers ranged from 1.8% to 9.8% in 10 published studies including >100 patients. When only p53 immunohistochemistry was performed, the highest incidence was 3.9%.
CONCLUSIONS
The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and sequencing.
PubMed: 38135437
DOI: 10.1136/ijgc-2023-004864 -
Genetics in Medicine : Official Journal... Apr 2013Rare, recurrent chromosome 1q21.1 duplications have been associated with developmental delay, congenital anomalies, and macrocephaly in children. Data on adult clinical... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Rare, recurrent chromosome 1q21.1 duplications have been associated with developmental delay, congenital anomalies, and macrocephaly in children. Data on adult clinical expression would help to inform genetic counseling.
METHODS
A systematic review of 22 studies reporting 107 individuals (59 children and 48 adults) with 1q21.1 duplications was conducted. We compiled the available phenotypic data to attempt to identify the most highly associated clinical features and to determine expression in adults. We also report on seven adult cases newly identified in the studies of schizophrenia and tetralogy of Fallot at our center.
RESULTS
Five cases were ascertained as controls, 32 as relatives of probands, and 70 as having clinical features: autism spectrum disorder (n = 15), congenital heart disease (n = 12), schizophrenia (n = 10), or other, mostly developmental, features (n = 33). The 1q21.1 duplication was significantly enriched in the cohorts with schizophrenia (P = 0.0155) and tetralogy of Fallot (P = 0.0040) at our center as compared with controls. There was a paucity of clinical data for adults; the most common features, other than those used for ascertainment, included macrocephaly and abnormalities of possible connective tissue origin (e.g., carpal tunnel syndrome).
CONCLUSION
Further data are needed to characterize lifetime expression of 1q21.1 duplications. These initial results, however, suggest that anticipatory care should include attention to later-onset conditions such as schizophrenia.
Topics: Adolescent; Adult; Anticipation, Genetic; Child; Child, Preschool; Chromosome Duplication; Chromosomes, Human, Pair 1; Female; Genetic Counseling; Humans; Infant; Male; Middle Aged; Phenotype
PubMed: 23018752
DOI: 10.1038/gim.2012.129 -
Pathology, Research and Practice Feb 2023Numerous studies have indicated that the aberrant expression of LINC00963 is extensively present in various human tumors, and that dysregulation of LINC00963 is... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Numerous studies have indicated that the aberrant expression of LINC00963 is extensively present in various human tumors, and that dysregulation of LINC00963 is implicated in the initiation and progression of human cancers. In this meta-analysis, data from diverse malignancies were analyzed to determine whether LINC00963 expression levels were associated with clinical prognosis and immune infiltration in pan-cancer.
MATERIALS AND METHODS
The eligible studies were identified from several electronic databases from the inception to July 2022 through systematic research. LINC00963 expression and survival were estimated using pooled odds ratios and hazard ratios with 95% CI. We used the Kaplan-Meier method and COX analysis for survival analysis. In addition, Spearman's correlation analysis was used to uncover any correlation between LINC00963 and microsatellites instability (MSI), tumor mutational burden (TMB), DNA methyltransferases (DNMTs), immune checkpoint biomarkers, and the related genes of mismatch repair (MMR).
RESULTS
Our findings indicated that overexpression of LINC00963 was related to poor overall survival (OS) (HR =1.32, 95% CI, 1.09-1.59, P = 0.004). The TCGA database also found that abnormal expression of LINC00963 was linked to overall survival in various cancers. Moreover, there is an association between LINC00963 expression and MSI, TMB, and MMR in malignancies of various types.
CONCLUSION
The results of this study indicate that LINC00963 may serve as a prognostic biomarker and a therapeutic target for cancer. By using it, cancer diagnoses can be improved, treatment targets discovered, and prognostic questions improved.
Topics: Humans; RNA, Long Noncoding; Neoplasms; Prognosis; Survival Analysis; Biomarkers, Tumor
PubMed: 36696806
DOI: 10.1016/j.prp.2022.154291 -
Cureus Aug 2023Being one of the most prevalent progressive neurodegenerative disorders (falling second only to Alzheimer's disease) with a clinical pattern affecting millions of lives... (Review)
Review
Being one of the most prevalent progressive neurodegenerative disorders (falling second only to Alzheimer's disease) with a clinical pattern affecting millions of lives all over the world, Parkinson's disease (PD) has never failed to attract a formidable interest from the vast majority of neurologists and researchers worldwide. This review article will analyze the pathophysiology, etiology, genetics, and pathological stages of Parkinson's disease with their corresponding clinical sequels. A review article was conducted using research databases including PubMed, PubMed Central, Springer, and Elsevier. The research articles reviewed using databases were written in English, German, Japanese, and Chinese and published within the preceding 50 years. Based on the article's findings, we concluded that Parkinson's disease is a progressive disorder with a variety of motor and non-motor symptoms that are influenced by a cascade of pathological neuronal abnormalities such as Lewy neurites and Lewy bodies that gradually build up with an eventual consequence of neurodegeneration of dopamine-secreting neurons. Multiple genetic mutations, pathophysiological events, and environmental factors act as the foundation to initiate that cascade.
PubMed: 37664277
DOI: 10.7759/cureus.44353 -
Seizure Jul 2022IRF2BPL is an intronless gene that was mapped to 14q24.3 chromosome in 2000 and codes for the interferon regulatory factor 2 binding like protein. (Review)
Review
BACKGROUND
IRF2BPL is an intronless gene that was mapped to 14q24.3 chromosome in 2000 and codes for the interferon regulatory factor 2 binding like protein.
OBJECTIVE
To analyses the clinical characteristics of the patients reported in the literature and of an additional patient we observed in order to better delineate the phenomenological spectrum of the disease and provide indications to improve clinical recognition and facilitate diagnosis.
METHODS
We reported on 28 patients carrying the IRF2BPL mutation who were identified in 10 papers (n.27), using PUBMED as the search engine, and in our hospital (n. 1).
RESULTS
All patients shared developmental delay/regression. Additional neurological symptoms were present in a large proportion of patients and reflected the involvement of five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances. Correlation analysis suggested a significant positive correlation between the number of affected neurological domains and the presence of MRI abnormalities (rho = 0.45, p = 0.02), while no significant correlation emerged between the number of affected clinical domains and age at disease onset (rho = 0.18, p = 0.35) or variant type (rho = 0.30, p = 0.12).
CONCLUSIONS
Our analysis highlights that the IRF2BPL mutation syndrome is highly specific to the central nervous system. Diagnostic work-up should consider the clinical picture of the IRF2BPL mutation syndrome herein delineated and the existence of conditions that share developmental delay/regression and result from acquired/genetic or unidentifiable underlying etiology.
Topics: Carrier Proteins; Dystonic Disorders; Epilepsy; Humans; Mutation; Nuclear Proteins; Syndrome
PubMed: 35525099
DOI: 10.1016/j.seizure.2022.04.010 -
Scientific Reports Aug 2016Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus... (Review)
Review
Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Following a systematic literature review on ultrastructural defects in mitochondrial myopathy, we investigated skeletal muscle biopsies from seven subjects with genetically defined mtDNA mutations. Mitochondrial ultrastructure and morphology were characterized using two complimentary approaches: transmission electron microscopy (TEM) and serial block face scanning EM (SBF-SEM) with 3D reconstruction. Six ultrastructural abnormalities were identified including i) paracrystalline inclusions, ii) linearization of cristae and abnormal angular features, iii) concentric layering of cristae membranes, iv) matrix compartmentalization, v) nanotunelling, and vi) donut-shaped mitochondria. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease.
Topics: Aged; Biopsy; DNA, Mitochondrial; Female; Humans; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Middle Aged; Mitochondria, Muscle; Mitochondrial Myopathies; Muscle, Skeletal; Mutation; Young Adult
PubMed: 27506553
DOI: 10.1038/srep30610 -
Journal of Orofacial Orthopedics =... Jul 2013The goal of this work was to identify all known gene mutations that have been associated with the development of nonsyndromic oligodontia. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The goal of this work was to identify all known gene mutations that have been associated with the development of nonsyndromic oligodontia.
METHODS
A systematic literature search was performed electronically in two databases (PubMed, Medpilot) supplemented by a hand search. Articles published up to March 2012 were considered. Search terms were combined as follows: oligodontia and genes, oligodontia and mutations, tooth agenesis and genes, and tooth agenesis and mutations. A meta-analysis of the data was conducted based on the Tooth Agenesis Code (TAC).
RESULTS
Seven genes are currently known to have a potential for causing nonsyndromic oligodontia. All these genes vary both in terms of number of identified mutations and in terms of number of documented patients: 33 mutations and 93 patients are on record for PAX9, 10 mutations and 51 patients for EDA, 12 mutations and 33 patients for MSX1, 6 mutations and 17 patients for AXIN2, and 1 mutation in 1 patient for EDARADD, NEMO, and KRT17 each. A total TAC score of 250 was found to have cutoff properties, as 100% of MSX1 and 80% of EDA patients exhibited TAC ≤ 250, whereas 96.9% of PAX9 and 90% of AXIN2 patients exhibited TAC >250. Furthermore, 94.3% of EDA patients but only 28.6% of MSX1 patients exhibited odd-numbered TAC scores in at least one quadrant, and 72.7% of PAX9 but none of the AXIN2 patients were found to show TAC scores of 112 in at least one quadrant.
CONCLUSION
In order of decreasing frequency, PAX9, EDA, MSX1, AXIN2, EDARADD, NEMO, and KRT17 are the seven genes currently known to have a potential for causing nonsyndromic oligodontia. TAC scores enabled us to identify an association between oligodontia phenotypes and genotypes in the patients covered by this meta-analysis.
Topics: Anodontia; Cytoskeletal Proteins; Genetic Predisposition to Disease; Humans; Mutation; Polymorphism, Single Nucleotide; Prevalence; Risk Assessment; Transcription Factors
PubMed: 23828301
DOI: 10.1007/s00056-013-0138-z -
Orphanet Journal of Rare Diseases Aug 2019Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms. The most common congenital anomalies involve the palate in 80% of patients, and the heart in 50-60% of them. The cause of the phenotypic variability is unknown. Patients usually harbor one of three common deletions sizes: 3, 2 and 1.5 Mb, between low copy repeats (LCR) designated A-D, A-C and A-B, respectively. This study aimed to analyze the association between these 3 deletion sizes and the presence of congenital cardiac and/or palatal malformations in individuals with this condition. A systematic review and meta-analysis were conducted, merging relevant published studies with data from Chilean patients to increase statistical power.
RESULTS
Eight articles out of 432 were included; the data from these studies was merged with our own, achieving a total of 1514 and 487 patients to evaluate cardiac and palate malformations, respectively. None of the compared deleted chromosomal segments were statistically associated with cardiac defects (OR: 0.654 [0.408-1.046]; OR : 1.291 [0.860-1.939]) or palate anomalies (OR: 1.731 [0.708-4.234]; OR : 0.628 [0.286-1.382]).
CONCLUSIONS
The lack of association between deletion size and CHD or PA found in this meta-analysis suggests that deletion size does not explain the incomplete penetrance of these 2 major manifestations, and that the critical region for the development of heart and palatal abnormalities is within LCR A-B, the smallest region of overlap among the three deletion sizes.
Topics: Arachnodactyly; Chromosome Deletion; Craniosynostoses; Humans; Marfan Syndrome; Phenotype
PubMed: 31399107
DOI: 10.1186/s13023-019-1170-x -
Journal of Vascular Surgery Dec 2016Vascular Ehlers-Danlos syndrome (EDS) is a relatively rare genetic syndrome that occurs owing to disorders in the metabolism of fibrillary collagen. These defects affect... (Review)
Review
BACKGROUND
Vascular Ehlers-Danlos syndrome (EDS) is a relatively rare genetic syndrome that occurs owing to disorders in the metabolism of fibrillary collagen. These defects affect the soft connective tissues resulting in abnormalities in the skin, joints, hollow organs, and blood vessels. Patients with these defects frequently present at a young age with spontaneous arterial complications involving the medium-sized arteries. Complications involving the hollow organs, such as spontaneous colonic perforation, are observed as well. Given the fragility of the soft tissue, open and endovascular intervention on patients with vascular EDS is fraught with high complication rates.
METHODS
A PubMed search was performed to identify manuscripts published related to vascular EDS. This search included more than 747 articles. These findings were cross-referenced using key terms, including endovascular, embolization, surgery, genetics, pathophysiology, connective tissue disorders, vascular complications, systematic review, type III collagen, and COL3A1.
RESULTS
The references in key articles and review articles were evaluated for additional resources not identified in the PubMed search. Care must be taken to balance the risk of intervention vs the risk of continued observation. Life-threatening hemorrhage, however, mandates intervention.
CONCLUSIONS
With careful, altered approaches to tissue handling, endovascular approaches may provide a safer option for managing the arterial complications observed in patients with vascular EDS. Additional hope may also be found in the use of pharmacologic agents that reduce the incidence and severity of the arterial complications.
Topics: Aneurysm; Collagen Type III; Computed Tomography Angiography; DNA Mutational Analysis; Ehlers-Danlos Syndrome; Endovascular Procedures; Genetic Predisposition to Disease; Humans; Mutation; Phenotype; Predictive Value of Tests; Risk Factors; Treatment Outcome
PubMed: 27687326
DOI: 10.1016/j.jvs.2016.06.120