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Biomedicines May 2024Metabolic syndrome (MetS), characterized by visceral obesity, glucose abnormalities, hypertension and dyslipidemia, poses a significant risk of diabetes and...
INTRODUCTION
Metabolic syndrome (MetS), characterized by visceral obesity, glucose abnormalities, hypertension and dyslipidemia, poses a significant risk of diabetes and cardiovascular disease. Turner syndrome (TS), resulting from X chromosome abnormalities, carries health complications. Despite growing evidence of an increased risk of MetS in women with TS, its prevalence and risk factors remain under investigation. These considerations are further complicated by the varying timing and dosages of treatment with growth hormone and sex hormones.
METHODS
We conducted a cross-sectional study comparing 44 individuals with TS with 52 age-matched control subjects. Growth hormone treatment in the study group was administered for varying lengths of time, depending on clinical response. We collected anthropometric, metabolic, endocrine and body composition data. Statistical analyses included logistic regression.
RESULTS
Baseline characteristics, including age, BMI and height, were comparable between the TS and control groups. Hormonally, individuals with TS showed lower levels of testosterone, DHEA-S, and cortisol, as well as elevated FSH. Lipid profiles indicated an atherogenic profile, and the body composition analysis showed increased visceral adipose tissue in those with TS. Other metabolic abnormalities were common in individuals with TS too, including hypertension and impaired fasting glucose levels. The risk of MetS components was assessed in subgroups according to karyotypes: monosomy 45X0 vs. other mosaic karyotypes. Logistic regression analysis showed a significant association between increased visceral adipose tissue in subjects with TS. Those with metabolic complications tended to have less muscle strength compared to those without these complications in both the study and control groups.
CONCLUSIONS
This study highlights the unique metabolic and cardiovascular risk profile of individuals with TS, characterized by atherogenic lipids, higher levels of visceral adipose tissue and increased metabolic abnormalities. These findings underscore the importance of monitoring metabolic health in individuals with TS, regardless of age, BMI or karyotype, and suggest the potential benefits of lifestyle modification, building more muscle strength, and weight control strategies. Further research is needed to better understand and address the metabolic challenges faced by women with TS.
PubMed: 38790996
DOI: 10.3390/biomedicines12051034 -
Molecular Cytogenetics May 2024The incidence of spontaneous abortion (SA), which affects approximately 15-20% of pregnancies, is the most common complication of early pregnancy. Pathogenic copy number...
BACKGROUND
The incidence of spontaneous abortion (SA), which affects approximately 15-20% of pregnancies, is the most common complication of early pregnancy. Pathogenic copy number variations (CNVs) are recognized as potential genetic causes of SA. However, CNVs of variants of uncertain significance (VOUS) have been identified in products of conceptions (POCs), and their correlation with SA remains uncertain.
RESULTS
Of 189 spontaneous abortion cases, trisomy 16 was the most common numerical chromosome abnormality, followed by monosomy X. CNVs most often occurred on chromosomes 4 and 8. Gene Ontology and signaling pathway analysis revealed significant enrichment of genes related to nervous system development, transmembrane transport, cell adhesion, and structural components of chromatin. Furthermore, genes within the VOUS CNVs were screened by integrating human placental expression profiles, PhyloP scores, and Residual Variance Intolerance Score (RVIS) percentiles to identify potential candidate genes associated with spontaneous abortion. Fourteen potential candidate genes (LZTR1, TSHZ1, AMIGO2, H1-4, H2BC4, H2AC7, H3C8, H4C3, H3C6, PHKG2, PRR14, RNF40, SRCAP, ZNF629) were identified. Variations in LZTR1, TSHZ1, and H4C3 may contribute to embryonic lethality.
CONCLUSIONS
CNV sequencing (CNV-seq) analysis is an effective technique for detecting chromosomal abnormalities in POCs and identifying potential candidate genes for SA.
PubMed: 38764094
DOI: 10.1186/s13039-024-00683-3 -
Stem Cell Research Jun 2024Y chromosome deletion and karyotype abnormalities are commonly associated with congenital non-obstructive azoospermia, impairing spermatogenesis. Specifically, the...
Y chromosome deletion and karyotype abnormalities are commonly associated with congenital non-obstructive azoospermia, impairing spermatogenesis. Specifically, the deletion of the Y chromosome Azoospermia factor a (AZFa) has been identified in infertile males with severely impaired spermatogenesis. AZFa, encompassing megabase-scale of the Y chromosome region, poses challenges in modeling AZFa deletion-related male infertility using gene editing tools. Here, we successfully created an AZFa-deleted human embryonic stem cell line utilizing the CRISPR/Cas9 gene editing tool. Our analysis indicates the AZFa-deleted stem cell line holds promise for differentiation into ectoderm, mesoderm, and endoderm, highlighting its potential for further comprehensive study.
Topics: Humans; Human Embryonic Stem Cells; Male; Cell Line; Chromosomes, Human, Y; Cell Differentiation; CRISPR-Cas Systems; Chromosome Deletion; Gene Editing
PubMed: 38733811
DOI: 10.1016/j.scr.2024.103436 -
Journal of Neurodevelopmental Disorders May 2024Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures....
BACKGROUND
Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome.
METHODS
We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features.
RESULTS
Seizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype-phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers.
CONCLUSIONS
These results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype-phenotype relationships when deletion size is taken into account.
Topics: Humans; Male; Female; Seizures; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 22; Child; Child, Preschool; Adolescent; Longitudinal Studies; Young Adult; Adult; Prospective Studies; Infant; Nerve Tissue Proteins
PubMed: 38730350
DOI: 10.1186/s11689-024-09541-0 -
Urology Journal May 2024Purpose: From a diagnostic standpoint, certain approaches to genetic screening in clinical practice remain ambiguous in the era of assisted reproduction. Even the...
Purpose: From a diagnostic standpoint, certain approaches to genetic screening in clinical practice remain ambiguous in the era of assisted reproduction. Even the most current guidelines do not provide definite guidance on testing protocols, leaving clinicians to carefully determine which tests best serve patients struggling with infertility. The lack of uniformity in the current practice of male fertility evaluation can prove to be quite costly, thus necessitating healthcare practitioners to carefully appraise the necessity and weigh the advantages against potential economic and psychological detriments. The objective of this review is to map the existing literature on the general topic of the clinical indications of routine karyotyping and/or AZF screening in infertile men, identify key concepts, determine where the gaps are, and lastly, provide an overview of the conclusions drawn from a body of knowledge that varies widely in terms of methodologies or disciplines. Materials and Methods: A thorough search was conducted for the published findings up until July 2023, utilizing PubMed (MEDLINE). This comprehensive search involved the use of specific search keywords, either individually or in combination. The search terms employed were as follows: "Karyotype", "Klinefelter" or "KS" or "47,XXY", "AZF" or "Azoospermi*" and/or "microdeletion*" in the title or abstract. Once the titles and abstracts of selected articles were obtained, the complete texts of linked papers were meticulously scrutinized. Results: A total of 191 records were identified from PubMed. During screening, 161 records (84.3%) were eliminated. Finally, 30 papers were included in this scoping review, which was conducted in 18 countries. The number of sequence tag sites (STSs) used in the studies varied from 5 to 59. The rate of AZF deletions among patients with NOA ranged from 1.3% to 53%. The mean frequency was estimated to be 5.6%. The rate of YCM among patients with XXY karyotype was nil in 19 out of 30 studies (63%), whilst, in the remaining studies, the rate varied from 0.8% to 67%. Conclusion: This review provides insights into managing male infertility. The presence of spermatozoa in ejaculation and successful surgical retrieval cannot be excluded for individuals with AZFb/AZFbc microdeletions. Screening for Y chromosome microdeletions is not needed for mosaic or classic KS. Only 1% of individuals with sperm concentration exceeding 1×106 sperm/mL and less than 5×106 sperm/mL exhibit AZF microdeletions; therefore, testing referral for such populations may need reassessment. Individuals with mosaic monosomy X karyotype and certain chromosomal anomalies should be referred for AZF deletion screening. These findings have implications for male infertility management and future research..
PubMed: 38716610
DOI: 10.22037/uj.v20i.8008 -
Clinical Epigenetics May 2024Temple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal...
BACKGROUND
Temple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal expressed genes and a silencing the paternally expressed genes in the 14q32 imprinted domain. Classical TS14 phenotypic features include pre- and postnatal short stature, small hands and feet, muscular hypotonia, motor delay, feeding difficulties, weight gain, premature puberty along and precocious puberty.
METHODS
An exon array comparative genomic hybridization was performed on a patient affected by psychomotor and language delay, muscular hypotonia, relative macrocephaly, and small hand and feet at two years old. At 6 years of age, the proband presented with precocious thelarche. Genes dosage and methylation within the 14q32 region were analyzed by MS-MLPA. Bisulfite PCR and pyrosequencing were employed to quantification methylation at the four known imprinted differentially methylated regions (DMR) within the 14q32 domain: DLK1 DMR, IG-DMR, MEG3 DMR and MEG8 DMR.
RESULTS
The patient had inherited a 69 Kb deletion, encompassing the entire DLK1 gene, on the paternal allele. Relative hypermethylation of the two maternally methylated intervals, DLK1 and MEG8 DMRs, was observed along with normal methylation level at IG-DMR and MEG3 DMR, resulting in a phenotype consistent with TS14. Additional family members with the deletion showed modest methylation changes at both the DLK1 and MEG8 DMRs consistent with parental transmission.
CONCLUSION
We describe a girl with clinical presentation suggestive of Temple syndrome resulting from a small paternal 14q32 deletion that led to DLK1 whole-gene deletion, as well as hypermethylation of the maternally methylated DLK1-DMR.
Topics: Humans; Calcium-Binding Proteins; DNA Methylation; Chromosomes, Human, Pair 14; Intercellular Signaling Peptides and Proteins; Genomic Imprinting; Membrane Proteins; Child; Male; Comparative Genomic Hybridization; Female; Chromosome Deletion; Child, Preschool; Phenotype; Abnormalities, Multiple; Imprinting Disorders; Muscle Hypotonia; Facies
PubMed: 38715103
DOI: 10.1186/s13148-024-01652-8 -
Italian Journal of Pediatrics May 2024we aim to discuss the origin and the differences of the phenotypic features and the management care of rare form of disorder of sex development due to Mosaic monosomy X...
BACKGROUND
we aim to discuss the origin and the differences of the phenotypic features and the management care of rare form of disorder of sex development due to Mosaic monosomy X and Y chromosome materiel.
METHODS
We report our experience with patients harboring mosaic monosomy X and Y chromosome material diagnosed by blood cells karyotypes and cared for in our department from 2005 to 2022.
RESULTS
We have included five infants in our study. The current average age was 8 years. In four cases, the diagnosis was still after born and it was at the age of 15 years in one case. Physical examination revealed a variable degree of virilization, ranging from a normal male phallus with unilateral ectopic gonad to ambiguous with a genital tubercle and bilateral not palpable gonads in four cases and normal female external genitalia in patient 5. Karyotype found 45, X/46, XY mosaicism in patient 1 and 2 and 45, X/46, X, der (Y) mosaicism in patient 3, 4 and 5. Three cases were assigned to male gender and two cases were assigned to female. After radiologic and histologic exploration, four patients had been explored by laparoscopy to perform gonadectomy in two cases and Mullerian derivative resection in the other. Urethroplasty was done in two cases of posterior hypospadias. Gender identity was concordant with the sex of assignment at birth in only 3 cases.
CONCLUSION
Because of the phenotypic heterogeneity of this sexual disorders and the variability of its management care, then the decision should rely on a multidisciplinary team approach.
Topics: Humans; Male; Mosaicism; Female; Child; Phenotype; Adolescent; Chromosomes, Human, Y; Chromosomes, Human, X; Infant; Turner Syndrome; Karyotyping; Monosomy; Child, Preschool; Disorders of Sex Development
PubMed: 38715086
DOI: 10.1186/s13052-024-01618-9 -
Environmental Toxicology and... May 2024Nanoparticles (NPs) have become an important part of everyday life, including their application in dentistry. Aside from their undoubted benefits, questions regarding...
Nanoparticles (NPs) have become an important part of everyday life, including their application in dentistry. Aside from their undoubted benefits, questions regarding their risk to human health, and/or genome have arisen. However, studies concerning cytogenetic effects are completely absent. A group of women acutely exposed to an aerosol released during dental nanocomposite grinding was sampled before and after the work. Exposure monitoring including nano (PM0.1) and respirable (PM4) fractions was performed. Whole-chromosome painting for autosomes #1, #4, and gonosome X was applied to estimate the pattern of cytogenetic damage including structural and numerical alterations. The results show stable genomic frequency of translocations (F/100), in contrast to a significant 37.8% (p<0.05) increase of numerical aberrations caused by monosomies (p<0.05), but not trisomies. Monosomies were mostly observed for chromosome X. In conclusion, exposure to nanocomposites in stomatology may lead to an increase in numerical aberrations which can be dangerous for dividing cells.
PubMed: 38710242
DOI: 10.1016/j.etap.2024.104462 -
PloS One 2024Somatic Y chromosome loss in hematopoietic cells is associated with higher mortality in men. However, the status of the Y chromosome in cancer tissue is not fully known...
Somatic Y chromosome loss in hematopoietic cells is associated with higher mortality in men. However, the status of the Y chromosome in cancer tissue is not fully known due to technical limitations, such as difficulties in labelling and sequencing DNA from the Y chromosome. We have developed a system to quantify Y chromosome gain or loss in patient-derived prostate cancer organoids. Using our system, we observed Y chromosome loss in 4 of the 13 (31%) patient-derived metastatic castration-resistant prostate cancer (mCRPC) organoids; interestingly, loss of Yq (long arm of the Y chromosome) was seen in 38% of patient-derived organoids. Additionally, potential associations were observed between mCRPC and Y chromosome nullisomy. The prevalence of Y chromosome loss was similar in primary and metastatic tissue, suggesting that Y chromosome loss is an early event in prostate cancer evolution and may not a result of drug resistance or organoid derivation. This study reports quantification of Y chromosome loss and gain in primary and metastatic prostate cancer tissue and lays the groundwork for further studies investigating the clinical relevance of Y chromosome loss or gain in mCRPC.
Topics: Male; Humans; Chromosomes, Human, Y; Chromosome Painting; Neoplasm Metastasis; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Organoids; Chromosome Deletion
PubMed: 38683764
DOI: 10.1371/journal.pone.0301989 -
International Journal of Molecular... Apr 2024Monosomy 3 in uveal melanoma (UM) increases the risk of lethal metastases, mainly in the liver, which serves as the major site for the storage of excessive glucose and...
Monosomy 3 in uveal melanoma (UM) increases the risk of lethal metastases, mainly in the liver, which serves as the major site for the storage of excessive glucose and the metabolization of the dietary flavonoid quercetin. Although primary UMs with monosomy 3 exhibit a higher potential for basal glucose uptake, it remains unknown as to whether glycolytic capacity is altered in such tumors. Herein, we initially analyzed the expression of = 151 genes involved in glycolysis and its interconnected branch, the "pentose phosphate pathway (PPP)", in the UM cohort of The Cancer Genome Atlas Study and validated the differentially expressed genes in two independent cohorts. We also evaluated the effects of quercetin on the growth, survival, and glucose metabolism of the UM cell line 92.1. The rate-limiting glycolytic enzyme was overexpressed whereas the gene (locus: 3q13.31) was downregulated in the patients with metastases in all cohorts. Quercetin was able to impair proliferation, viability, glucose uptake, glycolysis, ATP synthesis, and PPP rate-limiting enzyme activity while increasing oxidative stress. UMs with monosomy 3 display a stronger potential to utilize glucose for the generation of energy and biomass. Quercetin can prevent the growth of UM cells by interfering with glucose metabolism.
Topics: Quercetin; Melanoma; Humans; Uveal Neoplasms; Glucose; Glycolysis; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Pentose Phosphate Pathway; Chromosomes, Human, Pair 3
PubMed: 38673877
DOI: 10.3390/ijms25084292