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Genes May 2024The 22q11.2 deletion syndrome (22q11.2DS) is associated with a heterogeneous neurocognitive phenotype, which includes psychiatric disorders. However, few studies have...
The 22q11.2 deletion syndrome (22q11.2DS) is associated with a heterogeneous neurocognitive phenotype, which includes psychiatric disorders. However, few studies have investigated the influence of socioeconomic variables on intellectual variability. The aim of this study was to investigate the cognitive profile of 25 patients, aged 7 to 32 years, with a typical ≈3 Mb 22q11.2 deletion, considering intellectual, adaptive, and neuropsychological functioning. Univariate linear regression analysis explored the influence of socioeconomic variables on intellectual quotient (IQ) and global adaptive behavior. Associations with relevant clinical conditions such as seizures, recurrent infections, and heart diseases were also considered. Results showed IQ scores ranging from 42 to 104. Communication, executive functions, attention, and visuoconstructive skills were the most impaired in the sample. The study found effects of access to quality education, family socioeconomic status (SES), and caregiver education level on IQ. Conversely, age at diagnosis and language delay were associated with outcomes in adaptive behavior. This characterization may be useful for better understanding the influence of social-environmental factors on the development of patients with 22q11.2 deletion syndrome, as well as for intervention processes aimed at improving their quality of life.
Topics: Humans; Male; Adolescent; Female; DiGeorge Syndrome; Child; Brazil; Adult; Young Adult; Neuropsychological Tests; Socioeconomic Factors; Intelligence; Quality of Life; Social Class
PubMed: 38790224
DOI: 10.3390/genes15050595 -
Biochemical and Biophysical Research... May 2024The T-BOX transcription factor TBX1 is essential for the development of the pharyngeal apparatus and it is haploinsufficient in DiGeorge syndrome (DGS), a developmental...
The T-BOX transcription factor TBX1 is essential for the development of the pharyngeal apparatus and it is haploinsufficient in DiGeorge syndrome (DGS), a developmental anomaly associated with congenital heart disease and other abnormalities. The murine model recapitulates the heart phenotype and showed collagen accumulation. We first used a cellular model to study gene expression during cardiogenic differentiation of WT and Tbx1 mouse embryonic stem cells. Then we used a mouse model of DGS to test whether interfering with collagen accumulation using an inhibitor of lysyl hydroxylase would modify the cardiac phenotype of the mutant. We found that loss of Tbx1 in a precardiac differentiation model was associated with up regulation of a subset of ECM-related genes, including several collagen genes. In the in vivo model, early prenatal treatment with Minoxidil, a lysyl hydroxylase inhibitor, ameliorated the cardiac outflow tract septation phenotype in Tbx1 mutant fetuses, but it had no effect on septation in WT fetuses. We conclude that TBX1 suppresses a defined subset of ECM-related genes. This function is critical for OFT septation because the inhibition of collagen cross-linking in the mutant reduces significantly the penetrance of septation defects.
PubMed: 38749189
DOI: 10.1016/j.bbrc.2024.150104 -
Genes Apr 202422q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS...
22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, , pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings.
Topics: Humans; Female; DiGeorge Syndrome; Male; Child; Adolescent; Polymorphism, Single Nucleotide; Phenotype; Child, Preschool; Adult; Chromosomes, Human, Pair 22; Infant; Young Adult
PubMed: 38674452
DOI: 10.3390/genes15040518 -
Genes Apr 2024Juvenile idiopathic arthritis is a heterogeneous group of diseases characterized by arthritis with poorly known causes, including monogenic disorders and multifactorial...
Juvenile idiopathic arthritis is a heterogeneous group of diseases characterized by arthritis with poorly known causes, including monogenic disorders and multifactorial etiology. 22q11.2 proximal deletion syndrome is a multisystemic disease with over 180 manifestations already described. In this report, the authors describe a patient presenting with a short stature, neurodevelopmental delay, and dysmorphisms, who had an episode of polyarticular arthritis at the age of three years and eight months, resulting in severe joint limitations, and was later diagnosed with 22q11.2 deletion syndrome. Investigation through Whole Genome Sequencing revealed that he had no pathogenic or likely-pathogenic variants in both alleles of the gene or in genes associated with monogenic arthritis (, , , , , , , , , , ). However, the patient presented 41 risk polymorphisms for juvenile idiopathic arthritis. Thus, in the present case, arthritis seems coincidental to 22q11.2 deletion syndrome, probably caused by a multifactorial etiology. The association of the gene in individuals previously described with juvenile idiopathic arthritis and 22q11.2 deletion seems unlikely since it is located in the distal and less-frequently deleted region of 22q11.2 deletion syndrome.
Topics: Humans; Arthritis, Juvenile; Male; DiGeorge Syndrome; Whole Genome Sequencing; Intramolecular Oxidoreductases; Child, Preschool; Macrophage Migration-Inhibitory Factors; Child
PubMed: 38674447
DOI: 10.3390/genes15040513 -
Genes Mar 202422q11.2 Deletion Syndrome (22q11.2DS), the most common chromosomal microdeletion, presents as a heterogeneous phenotype characterized by an array of anatomical,... (Review)
Review
22q11.2 Deletion Syndrome (22q11.2DS), the most common chromosomal microdeletion, presents as a heterogeneous phenotype characterized by an array of anatomical, behavioral, and cognitive abnormalities. Individuals with 22q11.2DS exhibit extensive cognitive deficits, both in overall intellectual capacity and focal challenges in executive functioning, attentional control, perceptual abilities, motor skills, verbal processing, as well as socioemotional operations. Heterogeneity is an intrinsic factor of the deletion's clinical manifestation in these cognitive domains. Structural imaging has identified significant changes in volume, thickness, and surface area. These alterations are closely linked and display region-specific variations with an overall increase in abnormalities following a rostral-caudal gradient. Despite the extensive literature developing around the neurocognitive and neuroanatomical profiles associated with 22q11.2DS, comparatively little research has addressed specific structure-function relationships between aberrant morphological features and deficient cognitive processes. The current review attempts to categorize these limited findings alongside comparisons to populations with phenotypic and structural similarities in order to answer to what degree structural findings can explain the characteristic neurocognitive deficits seen in individuals with 22q11.2DS. In integrating findings from structural neuroimaging and cognitive assessments, this review seeks to characterize structural changes associated with the broad neurocognitive challenges faced by individuals with 22q11.2DS.
Topics: Humans; DiGeorge Syndrome; Cognitive Dysfunction; Brain; Neuroimaging
PubMed: 38674375
DOI: 10.3390/genes15040440 -
Journal of Clinical Medicine Apr 2024Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo... (Review)
Review
Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo epithelial-mesenchymal transition (EMT) and upon key developmental gene deregulation, fetuses and neonates are prone to exhibit diverse manifestations depending on the affected area. These conditions are generally rare and often have a genetic basis, with many following Mendelian inheritance patterns, thus making them perfect candidates for precision medicine. Examples include cranial NCPs, like Goldenhar syndrome and Axenfeld-Rieger syndrome; cardiac-vagal NCPs, such as DiGeorge syndrome; truncal NCPs, like congenital central hypoventilation syndrome and Waardenburg syndrome; and enteric NCPs, such as Hirschsprung disease. Additionally, NCCs' migratory and differentiating nature makes their derivatives prone to tumors, with various cancer types categorized based on their NCC origin. Representative examples include schwannomas and pheochromocytomas. This review summarizes current knowledge of diseases arising from defects in NCCs' specification and highlights the potential of precision medicine to remedy a clinical phenotype by targeting the genotype, particularly important given that those affected are primarily infants and young children.
PubMed: 38673496
DOI: 10.3390/jcm13082223 -
American Journal of Human Genetics May 2024Changes in gene regulatory elements play critical roles in human phenotypic divergence. However, identifying the base-pair changes responsible for the distinctive...
Changes in gene regulatory elements play critical roles in human phenotypic divergence. However, identifying the base-pair changes responsible for the distinctive morphology of Homo sapiens remains challenging. Here, we report a noncoding single-nucleotide polymorphism (SNP), rs41298798, as a potential causal variant contributing to the morphology of the skull base and vertebral structures found in Homo sapiens. Screening for differentially regulated genes between Homo sapiens and extinct relatives revealed 13 candidate genes associated with basicranial development, with TBX1, implicated in DiGeorge syndrome, playing a pivotal role. Epigenetic markers and in silico analyses prioritized rs41298798 within a TBX1 intron for functional validation. CRISPR editing revealed that the 41-base-pair region surrounding rs41298798 modulates gene expression at 22q11.21. The derived allele of rs41298798 acts as an allele-specific enhancer mediated by E2F1, resulting in increased TBX1 expression levels compared to the ancestral allele. Tbx1-knockout mice exhibited skull base and vertebral abnormalities similar to those seen in DiGeorge syndrome. Phenotypic differences associated with TBX1 deficiency are observed between Homo sapiens and Neanderthals (Homo neanderthalensis). In conclusion, the regulatory divergence of TBX1 contributes to the formation of skull base and vertebral structures found in Homo sapiens.
Topics: T-Box Domain Proteins; Humans; Animals; Mice; Polymorphism, Single Nucleotide; DiGeorge Syndrome; Neanderthals; Mice, Knockout; Skull; Alleles; Spine; Chromosomes, Human, Pair 22; Phenotype
PubMed: 38608674
DOI: 10.1016/j.ajhg.2024.03.012 -
SAGE Open Medical Case Reports 2024Reversed flow in the basilar artery can be acquired or congenital. Acquired reversed flow in the basilar artery can result from acute thrombosis of the basilar artery or...
Reversed flow in the basilar artery can be acquired or congenital. Acquired reversed flow in the basilar artery can result from acute thrombosis of the basilar artery or retrograde vertebral artery flow. Congenital continuous retrograde basilar artery flow has not been described. We report a 2-day-old male presenting with hypocalcemic seizures which led us to obtain a Duplex echoencephalogram. An echocardiogram was subsequently ordered. In the coronal plane through the anterior fontanelle, retrograde flow was seen in the basilar artery and the right vertebral artery. In the axial plane through the temporal window, the flow was anteroposterior in both posterior communicating arteries. In the posterior cerebral arteries, the flow was retrograde in the P1 segment and anterograde in the P2 and P3 segments. An interrupted aortic arch was suspected. The echocardiogram showed a large perimembranous ventricular septal defect with bidirectional shunting, a hypoplastic and bicuspid aortic valve, an aortic arch interrupted between the left common carotid artery and the left subclavian artery (type B interrupted aortic arch), and a 5 mm patent ductus arteriosus with predominant right to left flow. Because of the patency of the large patent ductus arteriosus, our patient showed no sign of posterior circulation insufficiency. Prostaglandin E1 therapy was initiated immediately. Diagnosis of DiGeorge syndrome was proven. The infant underwent interrupted aortic arch repair and anterograde flow was established in the basilar artery. We conclude that congenital asymptomatic continuous retrograde flow in the basilar artery and left vertebral artery is a medical emergency as it implies the presence of type B interrupted aortic arch with large patent ductus arteriosus in a neonate.
PubMed: 38595944
DOI: 10.1177/2050313X241245281 -
Genetics Research 202422q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes,...
22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes, involving ∼3 Mb of DNA. In a relatively large population of a Brazilian 22q11.2DS cohort (60 patients), we investigated genetic variants that could act as genetic modifiers and contribute to the phenotypic heterogeneity, using a targeted NGS (Next Generation Sequencing) with a specific Ion AmpliSeq panel to sequence nine candidate genes (, , , , , , , , and ), mapped in and outside the 22q11.2 hemizygous deleted region. prediction was performed, and the whole-genome sequencing annotation analysis package (WGSA) was used to predict the possible pathogenic effect of single nucleotide variants (SNVs). For the prediction of the indels, we used the genomic variants filtered by a deep learning model in NGS (GARFIELD-NGS). We identified six variants, 4 SNVs and 2 indels, in , , and genes with possibly synergistic deleterious effects in the context of the 22q11.2 deletion. Our results provide the opportunity for the discovery of the co-occurrence of genetic variants with 22q11.2 deletions, which may influence the patients´ phenotype.
Topics: Humans; DiGeorge Syndrome; Phenotype; Brazil; Chromosome Deletion
PubMed: 38586596
DOI: 10.1155/2024/5549592