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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. [ABSTRACT FROM AUTHOR]

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, Truncus arteriosus, 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. [ABSTRACT FROM AUTHOR]

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 MIF gene or in genes associated with monogenic arthritis (LACC1, LPIN2, MAFB, NFIL3, NOD2, PRG4, PRF1, STX11, TNFAIP3, TRHR, UNC13DI). 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 MIF 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to "dual diagnosis", have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation. [ABSTRACT FROM AUTHOR]

The condition known as 22q11.2 deletion syndrome (MIM #188400) is a rare disease with a highly variable clinical presentation including more than 180 features; specific guidelines for screening individuals have been used to support clinical suspicion before confirmatory tests by Brazil's Craniofacial Project. Of the 2568 patients listed in the Brazilian Database on Craniofacial Anomalies, 43 individuals negative for the 22q11.2 deletion syndrome were further investigated through whole-exome sequencing. Three patients (6.7%) presented with heterozygous pathogenic variants in the KMT2A gene, including a novel variant (c.6158+1del) and two that had been previously reported (c.173dup and c.3241C>T); reverse phenotyping concluded that all three patients presented features of Wiedemann–Steiner syndrome, such as neurodevelopmental disorders and dysmorphic facial features (n = 3), hyperactivity and anxiety (n = 2), thick eyebrows and lower-limb hypertrichosis (n = 2), congenital heart disease (n = 1), short stature (n = 1), and velopharyngeal insufficiency (n = 2). Overlapping features between 22q11.2 deletion syndrome and Wiedemann–Steiner syndrome comprised neuropsychiatric disorders and dysmorphic characteristics involving the eyes and nose region; velopharyngeal insufficiency was seen in two patients and is an unreported finding in WDSTS. Therefore, we suggest that both conditions should be included in each other's differential diagnoses. [ABSTRACT FROM AUTHOR]

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 MIF gene or in genes associated with monogenic arthritis (LACC1, LPIN2, MAFB, NFIL3, NOD2, PRG4, PRF1, STX11, TNFAIP3, TRHR, UNC13DI). 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 MIF 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.

Background: 22q11 deletion syndrome (SD22Q11) is a neurogenetic condition that is associated with a high risk of neurodevelopmental disorders and intellectual disability. People with SD22Q11, both children and adults, often experience significant difficulties in social interactions, as well as neurocognitive deficits, and have elevated rates of autism spectrum disorder (ASD). Despite this, the relationship between basic cognitive processes and cognitive ability in this population has not been well investigated. Methods: the main objective of the present research is to describe the neurocognitive profile of people with SD22Q11 using standardized neuropsychological assessment instruments. For this purpose, a sample of 10 participants aged between 7 and 15 years was administered an assessment battery with the following tests: WISC-V, CELF-5, NEPSY-II, CSAT-R, CARAS-R, TP, MABC-2, BRIEF-2, SENA, DABAS, ABAS-II, SCQ, and ADOS-2. Results: the results showed IQ scores in the borderline normal range, as well as difficulties in language functions, social skills, motor skills, and executive functions. Conclusions: an individualized assessment taking into account the globality of its expression, and a therapeutic approach adapted to the specific needs of children with this syndrome is essential. [ABSTRACT FROM AUTHOR]

22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder with an extremely broad phenotypic spectrum. The aim of our study was to investigate how often the additional variants in the genome can affect clinical variation among patients with the recurrent deletion. To examine the presence of additional variants affecting the phenotype, we performed microarray in 82 prenatal and 77 postnatal cases and performed exome sequencing in 86 postnatal patients with 22q11.2DS. Within those 159 patients where array was performed, 5 pathogenic and 5 likely pathogenic CNVs were identified outside of the 22q11.2 region. This indicates that in 6.3% cases, additional CNVs most likely contribute to the clinical presentation. Additionally, exome sequencing in 86 patients revealed 3 pathogenic (3.49%) and 5 likely pathogenic (5.81%) SNVs and small CNV. These results show that the extension of diagnostics with genome-wide methods can reveal other clinically relevant changes in patients with 22q11 deletion syndrome. [ABSTRACT FROM AUTHOR]

Although it is known that copy number variants (CNVs) on chromosome 22, such as 22q11.2 deletion (22q11.2DS) and 22q11.2 duplication (22q11.2Dup) syndromes, are associated with higher risk for neurodevelopmental issues, few studies have examined the language skills across 22q11.2Dup nor compared them with the 22q11.2DS. The current study aims to characterize language abilities in school-aged children with 22q11.2Dup (n = 29), compared to age-matched children with 22q11.2DS (n = 29). Standardized language tests were administered, assessing receptive and expressive language skills across different language domains. Results indicate that children with 22q11.2Dup demonstrate significantly more language problems compared to the general population. Mean language skills were not significantly different among children with 22q11.2 CNVs in this cohort. While children with 22q11.2DS demonstrated language difficulties starting at the word level, the most common language problems in children with 22q11.2Dup started at the sentence level. Importantly, both expressive and receptive language as well as lexico-semantic and morphosyntactic domains were impaired in children with 22q11.2 CNVs. Early identification, therapeutic intervention, and follow-up of language impairments in children with 22q11.2Dup are recommended to support language development and to reduce longitudinal impact of language and communicative deficits. [ABSTRACT FROM AUTHOR]

Background: Research participant feedback is rarely collected; therefore, investigators have limited understanding regarding stakeholders' (affected individuals/caregivers) motivation to participate. Members of the Genes to Mental Health Network (G2MH) surveyed stakeholders affected by copy number variants (CNVs) regarding perceived incentives for study participation, opinions concerning research priorities, and the necessity for future funding. Respondents were also asked about feelings of preparedness, research burden, and satisfaction with research study participation. Methods: Modified validated surveys were used to assess stakeholders´ views across three domains: (1) Research Study Enrollment, Retainment, Withdrawal, and Future Participation; (2) Overall Research Experience, Burden, and Preparedness; (3) Research Priorities and Obstacles. Top box score analyses were performed. Results: A total of 704 stakeholders´ responded from 29 countries representing 55 CNVs. The top reasons for initial participation in the research included reasons related to education and altruism. The top reasons for leaving a research study included treatment risks and side effects. The importance of sharing research findings and laboratory results with stakeholders was underscored by participants. Most stakeholders reported positive research experiences. Conclusions: This study provides important insight into how individuals and families affected with a rare CNV feel toward research participation and their overall experience in rare disease research. There are clear targets for areas of improvement for study teams, although many stakeholders reported positive research experiences. Key findings from this international survey may help advance collaborative research and improve the experience of participants, investigators, and other stakeholders moving forward. [ABSTRACT FROM AUTHOR]

Interruption of the aortic arch (IAA) is a rare but life-threatening congenital heart defect if not corrected in the neonatal period. IAA type B is highly correlated with 22q11.2 deletion syndrome (22q11.2DS); approximately 50% of patients with IAA type B also have 22q11.2DS (Peyvandi et al.; Goldmuntz et al.). Early identification and repair of IAA can prevent severe morbidity and death. However, IAA is challenging to identify prenatally, or even in the neonatal period. In this study, we examined infants with IAA, diagnosed during pregnancy and prior to discharge (PPTD) from the birth hospital vs. those diagnosed following discharge (FD) from the newborn nursery. Our goals were to determine: (1) if early diagnosis improved outcomes; and (2) if patients with IAA and without 22q11.2DS had similar outcomes. In total, 135 patients with a diagnosis of 22q11.2DS and IAA were ascertained through the 22q and You Center at the Children's Hospital of Philadelphia (CHOP). The examined outcomes included: timing of diagnosis; age at diagnosis (days); hospital length of stay (LOS); duration of intensive care unit (ICU) stay; mechanical ventilation (days); duration of inotrope administration (days); year of surgical intervention; birth hospital trauma level; and overall morbidity. These outcomes were then compared with 40 CHOP patients with IAA but without 22q11.2DS. The results revealed that the PPTD neonates had fewer days of intubation, inotrope administration, and hospital LOS when compared to the FD group. The outcomes between deleted and non-deleted individuals with IAA differed significantly, in terms of the LOS (40 vs. 39 days) and time in ICU (28 vs. 24 days), respectively. These results support the early detection of 22q11.2DS via prenatal screening/diagnostics/newborn screening, as IAA can evade routine prenatal ultrasound and postnatal pulse oximetry. However, as previously reported in patients with 22q11.2DS and congenital heart disease (CHD), patients with 22q11.2DS tend to fare poorer compared to non-deleted neonates with IAA. [ABSTRACT FROM AUTHOR]

Background: Aortic root dilation (ARD) has been described in 22q11.2DS, even without congenital heart disease (CHD). However, the clinical implications and longitudinal course are unclear. In this study, we evaluated aortic root (AR) dimensions in 22q112.DS adolescents/adults without major intracardiac CHDs, analyzed the progression over time and investigated correlations with extracardiac comorbidities. Methods: AR dimensions were evaluated in 74 patients, measuring the sinus of Valsalva (VS) and proximal ascending aorta (AA), using Z-score to define mild, moderate and severe degrees. Changes in AR dimensions during longitudinal echocardiographic follow-up were investigated. Phenotypic characteristics have been collected. Results: Twenty-four patients (32.4%) showed ARD in terms of VS Z-score (2.43; IQR 2.08–3.01), eight (33.3%) of a moderate/severe degree. Thirteen (54.2%) had concomitant AAD (Z-score 2.34; IQR 1.60–2.85). The risk of ARD was significantly directly related to skeletal/connective tissue disorders (OR 12.82, 95% CI 1.43–115.31; p = 0.023) and inversely related to BMI (OR 0.86, 95% CI 0.77–0.97; p = 0.011). A significant increase in AR diameter's absolute value (p = 0.001) over time has been detected. Conclusion: Isolated ARD is common in 22q11.2DS. Although some clinical risk factors have been identified, pathogenetic mechanisms and risk of complications are undefined. Regular cardiac evaluations should be part of the 22q11.2DS follow-up, and also in non-CHDs patients, to improve long-term outcome. [ABSTRACT FROM AUTHOR]

Tonsillectomy is one of the most common procedures performed in children, however there are currently no published studies evaluating tonsillectomy in children with 22q11.2 deletion syndrome (22q11DS). With this study, our goal was to investigate the indications, efficacy, and complications of tonsillectomy in a pediatric cohort of patients with 22q11DS. This is a retrospective chart review of patients in our 22q Center's repository. Inclusion criteria were a diagnosis of 22q11DS and a history of tonsillectomy or adenotonsillectomy. Data collected included: indications for tonsillectomy, preoperative and postoperative polysomnography (PSG) results, and surgical complications. In total, 33 patients were included. Most common indications for tonsillectomy were facilitation with speech surgery (n = 21) and sleep-disordered breathing (SDB)/obstructive sleep apnea (OSA) (n = 16). Average length of stay was 1.15 days. Most patients (69%) had some degree of persistent OSA on postoperative PSG. Complications occurred in 18% of patients and included respiratory distress, hemorrhage, and hypocalcemia. This study demonstrates tonsillectomy was a commonly performed procedure in this cohort of patients with 22q11DS. These data highlight the potential need for close postoperative calcium and respiratory monitoring. The data were limited with respect to PSG outcomes, and future studies are needed to better characterize OSA outcomes and complications in this patient population. [ABSTRACT FROM AUTHOR]

The most frequent microdeletion, 22q11.2 deletion syndrome (22q11.2DS), has a wide and variable phenotype that causes difficulties in diagnosis. 22q11.2DS is a contiguous gene syndrome, but due to the existence of several low-copy-number repeat sequences (LCR) it displays a high variety of deletion types: typical deletions LCR A–D—the most common (~90%), proximal deletions LCR A–B, central deletions (LCR B, C–D) and distal deletions (LCR D–E, F). Methods: We conducted a retrospective study of 59 22q11.2SD cases, with the aim of highlighting phenotype–genotype correlations. All cases were tested using MLPA combined kits: SALSA MLPA KIT P245 and P250 (MRC Holland). Results: most cases (76%) presented classic deletion LCR A–D with various severity and phenotypic findings. A total of 14 atypical new deletions were identified: 2 proximal deletions LCR A–B, 1 CES (Cat Eye Syndrome region) to LCR B deletion, 4 nested deletions LCR B–D and 1 LCR C–D, 3 LCR A–E deletions, 1 LCR D–E, and 2 small single gene deletions: delDGCR8 and delTOP3B. Conclusions: This study emphasizes the wide phenotypic variety and incomplete penetrance of 22q11.2DS. Our findings contribute to the genotype–phenotype data regarding different types of 22q11.2 deletions and illustrate the usefulness of MLPA combined kits in 22q11.2DS diagnosis. [ABSTRACT FROM AUTHOR]

The 22q11.2 deletion syndrome (22q11.2DS) manifests as a wide range of medical conditions across a number of systems. Pediatric growth deficiency with some catch-up growth is reported, but there are few studies of final adult height. We aimed to investigate how final adult height in 22q11.2DS compared with general population norms, and to examine predictors of short stature in in a cohort of 397 adults with 22q11.2DS (aged 17.6–76.3 years) with confirmed typical 22q11.2 microdeletion (overlapping the LCR22A to LCR22B region). We defined short stature as <3rd percentile using population norms. For the subset (n = 314, 79.1%) with 22q11.2 deletion extent, we used a binomial logistic regression model to predict short stature in 22q11.2DS, accounting for effects of sex, age, ancestry, major congenital heart disease (CHD), moderate-to-severe intellectual disability (ID), and 22q11.2 deletion extent. Adult height in 22q11.2DS showed a normal distribution but with a shift to the left, compared with population norms. Those with short stature represented 22.7% of the 22q11.2DS sample, 7.6-fold greater than population expectations (p < 0.0001). In the regression model, moderate-to-severe ID, major CHD, and the common LCR22A-LCR22D (A-D) deletion were significant independent risk factors for short stature while accounting for other factors (model p = 0.0004). The results suggest that the 22q11.2 microdeletion has a significant effect on final adult height distribution, and on short stature with effects appearing to arise from reduced gene dosage involving both the proximal and distal sub-regions of the A-D region. Future studies involving larger sample sizes with proximal nested 22q11.2 deletions, longitudinal lifetime data, parental heights, and genotype data will be valuable. [ABSTRACT FROM AUTHOR]

22q11.2 deletion syndrome (22q11DS) is a clinically heterogeneous genetic syndrome, associated with a wide array of neuropsychiatric symptoms. The clinical presentation is likely to be influenced by environmental factors, yet little is known about this. Here, we review the available research literature on the role of the environment in 22q11DS. We find that within-patient design studies have mainly investigated the role of parental factors, stress, and substance use, reporting significant effects of these factors on the clinical profile. Case-control studies have been less successful, with almost no reports of significant moderating effects of the environment. We go on to hypothesize which specific environmental measures are most likely to interact with the 22q11 deletion, based on the genes in this region and their involvement in molecular pathways. We end by discussing potential reasons for the limited findings so far, including modest sample sizes and limited availability of environmental measures, and make recommendations how to move forward. [ABSTRACT FROM AUTHOR]

In 2018, the first 22q11.2 multidisciplinary program in the state of Florida was created at Joe DiMaggio Children's Hospital following the new paradigm for best care of 22q11.2 deletion patients. Since inauguration, the clinic flourished despite challenges. Our 22q clinic has 149 patients ranging from ages 0–21. From that total, 138 are 22q11.2DS: 74 females and 64 males (44% Hispanics, 35% Caucasians, 11% African American, 3% Asian and 7% multiracial). Eleven patients are in the 22q11.2 duplication group; 7 females and 4 males (50% Hispanics, 30% Caucasians 10% Asian and 10% multiracial). Our multidisciplinary team has grown to include twelve different specialties to better serve our growing patient population and has adapted to the pandemic by offering virtual clinics. Although there are many 22q multidisciplinary clinics worldwide, our clinic has special characteristics. We have an ethnically diverse group of patients and a large team of mostly bilingual providers who are passionate about and have expertise on 22q Deletion/Duplication Syndromes. Our 22q clinic is based at a community hospital and counts on the partnership of local 22q patient support groups. The program is also unique in that it is now expanding to care for adult 22q patients. Our clinic is another live example of how multidisciplinary care is the best way to achieve the most optimal outcomes in 22q patients, and that if there is a passionate and dedicated team of providers willing to collaborate for these patients, a 22q multidisciplinary program can thrive, succeed and grow at a community hospital. [ABSTRACT FROM AUTHOR]

Maturation of microRNAs (miRNAs) begins by the "Microprocessor" complex, containing the Drosha endonuclease and its partner protein, "DiGeorge Syndrome Critical Region 8" (DGCR8). Although the main function of the two proteins is to coordinate the first step of precursor miRNAs formation, several studies revealed their miRNA-independent functions in other RNA-related pathways (e.g., in snoRNA decay) or, for the DGCR8, the role in tissue development. To investigate the specific roles of DGCR8 in various cellular pathways, we previously established a human embryonic stem-cell (hESC) line carrying a monoallelic DGCR8 mutation by using the CRISPR-Cas9 system. In this study, we genetically characterized single-cell originated progenies of the cell line and showed that DGCR8 heterozygous mutation results in only a modest effect on the mRNA level but a significant decrease at the protein level. Self-renewal and trilineage differentiation capacity of these hESCs were not affected by the mutation. However, partial disturbance of the Microprocessor function could be revealed in pri-miRNA processing along the human chromosome 19 miRNA cluster in several clones. With all these studies, we can demonstrate that the mutant hESC line is a good model to study not only miRNA-related but also other "noncanonical" functions of the DGCR8 protein. [ABSTRACT FROM AUTHOR]

The guidelines for management of children with 22q11.2 deletion syndrome (22q11DS) highlight the risk for developing hypocalcemia after surgery and recommend monitoring calcium perioperatively. Despite this guidance, little has been published on postoperative hypocalcemia and 22q11DS. Our goals were to evaluate the frequency of perioperative calcium monitoring and examine how often postoperative hypocalcemia was identified. This is a retrospective chart review of patients in our 22q Center's repository. Inclusion criteria were a diagnosis of 22q11DS and a history of a non-cardiac surgical procedure. Data collected included all non-cardiac surgeries and perioperative calcium labs. In total, 68 patients were included and underwent 305 on-cardiac surgeries. Patients in only 17% of these surgeries had postoperative calcium testing, but of those tested, 58% showed hypocalcemia. Patients with history of hypocalcemia at the time of chart review undergoing non-cardiac surgeries were tested postoperatively 40% of the time; however, 67% of these had hypocalcemia. Similarly, for patients without history of hypocalcemia, postoperative testing occurred 60% of the time, with 52% of these having hypocalcemia. This study demonstrates that postoperative hypocalcemia in children with 22q11DS following non-cardiac surgeries is common and affects patients both with and without prior history of hypocalcemia. These data support establishing a protocol for perioperative testing/management of hypocalcemia for patients with 22q11DS. [ABSTRACT FROM AUTHOR]

22q11.2 deletion (22q11.2DS) and 22q11.2 duplication (22q11.2Dup) confer risk for neurodevelopmental difficulties, but the characterization of speech-language and social skills in 22q11.2Dup is still limited. Therefore, this study aims to delineate social-communicative skills in school-aged children with 22q11.2Dup (n = 19) compared to their non-carrier siblings (n = 11) and age-matched children with 22q11.2DS (n = 19). Parents completed two standardized questionnaires: the Children's Communication Checklist (CCC-2), screening speech, language, and social skills, and the Social Responsiveness Scales (SRS-2), assessing deficits in social behavior. Parents report that both children with 22q11.2Dup and 22q11.2DS show more social-communicative deficits than the general population; children with 22q11.2Dup seem to take an intermediate position between their siblings and children with 22q11.2DS. Compared to 22q11.2DS, they demonstrate less frequent and less severe problems, and more heterogeneous social-communicative profiles, with fewer restricted interests and repetitive behaviors. In siblings of 22q11Dup, milder social-communicative difficulties and equally heterogeneous profiles are reported, which might indicate that-in addition to the duplication-other factors such as the broader genetic context play a role in social-communicative outcomes. [ABSTRACT FROM AUTHOR]

Learning and intellectual disabilities are hallmark features of 22q11.2 deletion syndrome. Data are limited, however, regarding influences on full-scale IQ (FSIQ). Here, we investigated possible 22q11.2 deletion parent-of-origin effects. In 535 individuals, we compared FSIQ (≥50), 481 with de novo and 54 with inherited 22q11.2 deletions. In the subsets with data available, we examined parent-of-origin effects on FSIQ. We used linear regression models to account for covariates. Median FSIQ was significantly higher in de novo vs. inherited deletions (77; range 50–116 vs. 67; range 50–96, p < 0.0001). Results remained significant using a regression model accounting for age at IQ testing, sex and cohort site. No significant parent-of-origin differences in FSIQ were observed for de novo deletions (n = 81, 63.0% maternal; p = 0.6882). However, median FSIQ was significantly lower in maternally than in paternally inherited familial deletions (65, range 50–86 vs. 71.5, range 58–96, respectively, p = 0.0350), with the regression model indicating an ~8 point decrement in FSIQ for this variable (p = 0.0061). FSIQ is higher on average in de novo than in inherited 22q11.2 deletions, regardless of parental origin. However, parent-of-origin appears relevant in inherited deletions. The results have potential clinical implications with further research needed to delineate possible actionable mechanisms. [ABSTRACT FROM AUTHOR]

Background: Individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk of developing psychosis and cognitive impairments, which may be related to dopaminergic and glutamatergic abnormalities. Therefore, in this exploratory study, we examined the association between dopaminergic and glutamatergic functioning in 22q11DS. Additionally, the associations between glutamatergic functioning and brain volumes in 22q11DS and healthy controls (HC), as well as those between dopaminergic and cognitive functioning in 22q11DS, were also examined. Methods: In this cross-sectional, multimodal imaging study, glutamate, glutamine, and their combined concentration (Glx) were assessed in the anterior cingulate cortex (ACC) and striatum in 17 22q11DS patients and 20 HC using 7T proton magnetic resonance spectroscopy. Ten 22q11DS patients also underwent 18F-fallypride positron emission tomography to measure dopamine D2/3 receptor (D2/3R) availability in the ACC and striatum. Cognitive performance was assessed with the Cambridge Neuropsychological Test Automated Battery. Results: No significant associations were found between ACC or striatal (1) glutamate, glutamine, or Glx concentrations and (2) D2/3R availability. In HC but not in 22q11DS patients, we found a significant relationship between ACC volume and ACC glutamate, glutamine, and Glx concentration. In addition, some aspects of cognitive functioning were significantly associated with D2/3R availability in 22q11DS. However, none of the associations remained significant after Bonferroni correction. Conclusions: Although our results did not reach statistical significance, our findings suggest an association between glutamatergic functioning and brain volume in HC but not in 22q11DS. Additionally, D2/3R availability seems to be related to cognitive functioning in 22q11DS. Studies in larger samples are needed to further elucidate our findings. [ABSTRACT FROM AUTHOR]

The most prevalent microdeletion in the human population occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has eluded characterization due to a combination of size, regional complexity, and haplotype diversity. To further complicate matters, it is not well represented in the human reference genome. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo, hemizygous deletion approximately 3 Mbp in size occurring by non-allelic homologous recombination (NAHR) mediated by the LCR22s. The ability to fully delineate an individual's 22q11.2 regional structure will likely be important for studies designed to assess an unaffected individual's risk for generating rearrangements in germ cells, potentially leading to offspring with 22q11.2DS. Towards understanding these risk factors, optical mapping has been previously employed to successfully elucidate the structure and variation of LCR22s across 30 families affected by 22q11.2DS. The father in one of these families carries a t(11;22)(q23;q11) translocation. Surprisingly, it was determined that he is the parent-of-deletion-origin. NAHR, which occurred between his der(22) and intact chromosome 22, led to a 22q11.2 deletion in his affected child. The unaffected sibling of the proband with 22q11.2DS inherited the father's normal chromosome 22, which did not aberrantly recombine. This unexpected observation definitively shows that haplotypes that engage in NAHR can also be inherited intact. This study is the first to identify all structures involving a rearranged chromosome 22 that also participates in NAHR leading to a 22q11.2 deletion. [ABSTRACT FROM AUTHOR]

Background. Chromosome 22q11.2 Deletion Syndrome (22q11.2DS) is the most frequent microdeletion syndrome and is mainly characterized by congenital cardiac defects, dysmorphic features, hypocalcemia, palatal dysfunction, developmental delay, and impaired immune function due to thymic hypoplasia or aplasia. Thyroid anomalies are frequently reported in patients with 22q11.2DS, although only a few well-structured longitudinal studies about autoimmune thyroid disease (ATD) have been reported. Aim. To longitudinally evaluate the frequency of thyroid anomalies and ATD in patients with 22q11.2DS. Patients and Methods. Pediatric patients with a confirmed genetic diagnosis of 22q11.2DS were recruited and followed up on longitudinally. Clinical, biochemical, and immunological data were collected, as well as thyroid function, autoimmunity, and thyroid sonographic data. Results. The study included 73 children with 22q11.2DS, with a mean follow-up duration of 9.51 ± 5.72 years. In all, 16 of the 73 enrolled patients (21.9%) developed ATD before 18 years of age (mean age 12.92 ± 3.66 years). A total of 20.5% developed Hashimoto's Thyroiditis (HT), of whom 50% required L-thyroxine treatment; 1.4% developed Graves Disease. Thyroid hypoplasia was found in 6/16 patients with ATD and left lobe hypoplasia in 9/16 patients. These features were also found in patients affected by 22q11.2DS without ATD. Among patients who developed ATD, at the first altered ultrasound scan, the most frequent anomalies suggestive of thyroiditis were inhomogeneous echotexture, diffuse or irregular hypo-echogenicity, and vascular overflow. Conclusion. We strongly recommend periodic screening of thyroid function and for autoimmunity in patients affected by 22q11.2DS. Along with blood tests, ultrasound scans of the thyroid gland should be performed periodically since some patients who go on to develop an ATD could have specific anomalies on ultrasound prior to any other anomaly. [ABSTRACT FROM AUTHOR]

In recent years, findings from genetic and other biological studies are starting to reveal the role of various molecular mechanisms that contribute to the etiology of ASD. The relevance is at least twofold: on the one hand, this domain may be more directly linkable to specific and traceable neurobiological abnormalities in comparison to other ASD domains falling within the broader realm of social cognition; on the other hand, abnormal sensory processing is increasingly emerging as a relevant source of maladaptive behaviors with measurable impact on the quality of life of individuals with ASD and their families. Despite these efforts, DNA variation alone is unlikely to explain the majority of phenotypic variance, since epigenetic variation is as efficient as deletions in down-regulating expression of critical ASD genes [[41]] and the modulation of ASD gene promoter methylation is emerging as a significant cause of association between ASD and many common SNPs [[42]]. These and other studies suggest that many of the synaptic genes found to be associated with ASD are expressed prenatally and throughout early development, spatially and temporally coinciding with synaptic organization in brain regions relevant for ASD. [Extracted from the article]

Background: 22q11 deletion syndrome (SD22Q11) is a neurogenetic condition that is associated with a high risk of neurodevelopmental disorders and intellectual disability. People with SD22Q11, both children and adults, often experience significant difficulties in social interactions, as well as neurocognitive deficits, and have elevated rates of autism spectrum disorder (ASD). Despite this, the relationship between basic cognitive processes and cognitive ability in this population has not been well investigated. Methods: the main objective of the present research is to describe the neurocognitive profile of people with SD22Q11 using standardized neuropsychological assessment instruments. For this purpose, a sample of 10 participants aged between 7 and 15 years was administered an assessment battery with the following tests: WISC-V, CELF-5, NEPSY-II, CSAT-R, CARAS-R, TP, MABC-2, BRIEF-2, SENA, DABAS, ABAS-II, SCQ, and ADOS-2. Results: the results showed IQ scores in the borderline normal range, as well as difficulties in language functions, social skills, motor skills, and executive functions. Conclusions: an individualized assessment taking into account the globality of its expression, and a therapeutic approach adapted to the specific needs of children with this syndrome is essential.

The 22q11.2 microdeletion and its associated conditions could affect reproductive outcomes but there is limited information on this important area. We investigated reproductive outcomes in a sample of 368 adults with typical 22q11.2 deletions (median age 32.8, range 17.9–76.3 years; 195 females), and without moderate-severe intellectual disability, who were followed prospectively. We examined all reproductive outcomes and possible effects of diagnosis as a transmitting parent on these outcomes. We used logistic regression to investigate factors relevant to reproductive fitness (liveborn offspring). There were 63 (17.1%) individuals with 157 pregnancy outcomes, 94 (60.3%) of which involved live births. Amongst the remainder involving a form of loss, were seven (5.77%) stillbirths, significantly greater than population norms (p < 0.0001). For 35 (55.6%) individuals, diagnosis of 22q11.2 deletion syndrome (22q11.2DS) followed diagnosis of an offspring, with disproportionately fewer individuals had major congenital heart disease (CHD) in that transmitting parent subgroup. The regression model indicated that major CHD, in addition to previously identified factors, was a significant independent predictor of reduced reproductive fitness. There was evidence of persisting diagnostic delay and limited prenatal genetic testing. The findings indicate that pregnancy loss is an important health issue for adults with 22q11.2DS. CHD and/or its absence is a factor to consider in reproductive outcome research. Further studies are warranted to better appreciate factors that may contribute to reproductive outcomes, including technological advances. The results suggest the need for ongoing efforts to provide optimal education and supports to individuals with 22q11.2DS, and their clinicians, around reproductive issues and early diagnosis.

The 22q11.2 deletion syndrome (22q11.2DS) manifests as a wide range of medical conditions across a number of systems. Pediatric growth deficiency with some catch-up growth is reported, but there are few studies of final adult height. We aimed to investigate how final adult height in 22q11.2DS compared with general population norms, and to examine predictors of short stature in in a cohort of 397 adults with 22q11.2DS (aged 17.6–76.3 years) with confirmed typical 22q11.2 microdeletion (overlapping the LCR22A to LCR22B region). We defined short stature as n = 314, 79.1%) with 22q11.2 deletion extent, we used a binomial logistic regression model to predict short stature in 22q11.2DS, accounting for effects of sex, age, ancestry, major congenital heart disease (CHD), moderate-to-severe intellectual disability (ID), and 22q11.2 deletion extent. Adult height in 22q11.2DS showed a normal distribution but with a shift to the left, compared with population norms. Those with short stature represented 22.7% of the 22q11.2DS sample, 7.6-fold greater than population expectations (p < 0.0001). In the regression model, moderate-to-severe ID, major CHD, and the common LCR22A-LCR22D (A-D) deletion were significant independent risk factors for short stature while accounting for other factors (model p = 0.0004). The results suggest that the 22q11.2 microdeletion has a significant effect on final adult height distribution, and on short stature with effects appearing to arise from reduced gene dosage involving both the proximal and distal sub-regions of the A-D region. Future studies involving larger sample sizes with proximal nested 22q11.2 deletions, longitudinal lifetime data, parental heights, and genotype data will be valuable.

The 22q11.2 microdeletion and its associated conditions could affect reproductive outcomes but there is limited information on this important area. We investigated reproductive outcomes in a sample of 368 adults with typical 22q11.2 deletions (median age 32.8, range 17.9-76.3 years; 195 females), and without moderate-severe intellectual disability, who were followed prospectively. We examined all reproductive outcomes and possible effects of diagnosis as a transmitting parent on these outcomes. We used logistic regression to investigate factors relevant to reproductive fitness (liveborn offspring). There were 63 (17.1%) individuals with 157 pregnancy outcomes, 94 (60.3%) of which involved live births. Amongst the remainder involving a form of loss, were seven (5.77%) stillbirths, significantly greater than population norms ( p < 0.0001). For 35 (55.6%) individuals, diagnosis of 22q11.2 deletion syndrome (22q11.2DS) followed diagnosis of an offspring, with disproportionately fewer individuals had major congenital heart disease (CHD) in that transmitting parent subgroup. The regression model indicated that major CHD, in addition to previously identified factors, was a significant independent predictor of reduced reproductive fitness. There was evidence of persisting diagnostic delay and limited prenatal genetic testing. The findings indicate that pregnancy loss is an important health issue for adults with 22q11.2DS. CHD and/or its absence is a factor to consider in reproductive outcome research. Further studies are warranted to better appreciate factors that may contribute to reproductive outcomes, including technological advances. The results suggest the need for ongoing efforts to provide optimal education and supports to individuals with 22q11.2DS, and their clinicians, around reproductive issues and early diagnosis.