BACKGROUND: Previous studies have produced conflicting results concerning the extent of magnitude representation deficit and its relationship with arithmetic achievement in children with 22q11.2 deletion syndrome. More specifically, it remains unclear whether deficits are restricted to visuospatial content or are more general and whether they could explain arithmetical impairment.
METHODS: Fifteen 5- to 12-year-old children with 22q11.2 deletion syndrome and 23 age-matched healthy controls performed a non-symbolic magnitude comparison task. Depending on the trial, participants had to compare stimuli with high or low visuospatial load (visuospatial stimuli or temporal sequence of visual stimuli). The participants also completed a battery of arithmetic skills (ZAREKI-R) and a battery of global cognitive functioning (WISC-V or WPPSI-IV), from which working memory and visuospatial indices were derived.
RESULTS: Children with 22q11.2DS responded as fast as healthy controls did but received fewer correct responses, irrespective of visuospatial load. In addition, their performance in the non-symbolic magnitude comparison task did not correlate with the ZAREKI total score, while the working memory index did.
CONCLUSIONS: Children with 22q11.2DS might suffer from a global magnitude representation deficit rather than a specific deficit due to visuospatial load. However, this deficit alone does not seem to be related to arithmetic achievement. Working memory might be a better concern of interest in favoring arithmetic skills in patients with 22q11.2 deletion syndrome.
BACKGROUND: Clinicaltrials, NCT04373226 . Registered 16 September 2020.

OBJECTIVE: We aim to verify velopharyngeal sphincter function in 22q11.2 deletion syndrome patients (22q11.2DS) to establish correlations between aerodynamic and perceptual measures of nasality, and to identify aerodynamic measures differentiating typical from atypical velopharyngeal behavior.
METHODS: Eleven subjects with 22q11.2DS and twenty similar-age control subjects were recruited. The aerodynamic measures were mean Sound Pressure Level, air pressure peak, pressure wave duration, airflow pattern and nasal airflow during the sequence /pi/. The nasality perceptual measures were rhinolalia, rhinophony and nasal air escape.
RESULTS: Airflow patterns and perceptual measures were statistically different in the two groups. Pressure wave duration and air pressure peak were lower in study subjects than in controls. Air pressure peak and nasal airflow were negatively correlated with rhinolalia; pressure wave duration was negatively correlated with nasal air escape and rhinolalia in 22q11.2DS patients.
CONCLUSIONS: This aerodynamic study identified velopharyngeal qualitative and quantitative dysfunctions, suggesting heterogeneous models of velopharyngeal function in syndromic subjects as compared to controls.

BACKGROUND: Minor physical anomalies (MPAs) are congenital morphological abnormalities linked to disruptions of fetal development. MPAs are common in 22q11.2 deletion syndrome (22q11DS) and psychosis spectrum disorders (PS) and likely represent a disruption of early embryologic development that may help identify overlapping mechanisms linked to psychosis in these disorders.
METHODS: Here, 2D digital photographs were collected from 22q11DS (n = 150), PS (n = 55), and typically developing (TD; n = 93) individuals. Photographs were analyzed using two computer-vision techniques: (1) DeepGestalt algorithm (Face2Gene (F2G)) technology to identify the presence of genetically mediated facial disorders, and (2) Emotrics-a semi-automated machine learning technique that localizes and measures facial features.
RESULTS: F2G reliably identified patients with 22q11DS; faces of PS patients were matched to several genetic conditions including FragileX and 22q11DS. PCA-derived factor loadings of all F2G scores indicated unique and overlapping facial patterns that were related to both 22q11DS and PS. Regional facial measurements of the eyes and nose were smaller in 22q11DS as compared to TD, while PS showed intermediate measurements.
CONCLUSIONS: The extent to which craniofacial dysmorphology 22q11DS and PS overlapping and evident before the impairment or distress of sub-psychotic symptoms may allow us to identify at-risk youths more reliably and at an earlier stage of development.

Integrated human genetics and molecular/developmental biology studies have revealed that truncus arteriosus is highly associated with 22q11.2 deletion syndrome. Other congenital malformation syndromes and variants in genes encoding TBX, GATA, and NKX transcription factors and some signaling proteins have also been reported as its etiology.

This chapter discusses the role of cardiac neural crest cells in the formation of the septum that divides the cardiac arterial pole into separate systemic and pulmonary arteries. Further, cardiac neural crest cells directly support the normal development and patterning of derivatives of the caudal pharyngeal arches, including the great arteries, thymus, thyroid, and parathyroids. Recently, cardiac neural crest cells have also been shown to indirectly influence the development of the secondary heart field, another derivative of the caudal pharynx, by modulating signaling in the pharynx. The contribution and function of the cardiac neural crest cells has been learned in avian models; most of the genes associated with cardiac neural crest function have been identified using mouse models. Together these studies show that the neural crest cells may not only critical for normal cardiovascular development but also may be involved secondarily because they represent a major component in the complex tissue interactions in the caudal pharynx and outflow tract. Cardiac neural crest cells span from the caudal pharynx into the outflow tract, and therefore may be susceptible to any perturbation in or by other cells in these regions. Thus, understanding congenital cardiac outflow malformations in human sequences of malformations resulting from genetic and/or environmental insults necessarily requires better understanding the role of cardiac neural crest cells in cardiac development.

BACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with highly variable phenotypic manifestations, even though most patients present the typical 3 Mb microdeletion, usually affecting the same ~ 106 genes. One of the genes affected by this deletion is DGCR8, which plays a crucial role in miRNA biogenesis. Therefore, the haploinsufficiency of DGCR8 due to this microdeletion can alter the modulation of the expression of several miRNAs involved in a range of biological processes.
RESULTS: In this study, we used next-generation sequencing to evaluate the miRNAs profiles in the peripheral blood of 12 individuals with typical 22q11DS compared to 12 healthy matched controls. We used the DESeq2 package for differential gene expression analysis and the DIANA-miTED dataset to verify the expression of differentially expressed miRNAs in other tissues. We used miRWalk to predict the target genes of differentially expressed miRNAs. Here, we described two differentially expressed miRNAs in patients compared to controls: hsa-miR-1304-3p, located outside the 22q11.2 region, upregulated in patients, and hsa-miR-185-5p, located in the 22q11.2 region, which showed downregulation. Expression of miR-185-5p is observed in tissues frequently affected in patients with 22q11DS, and previous studies have reported its downregulation in individuals with 22q11DS. hsa-miR-1304-3p has low expression in blood and, thus, needs more validation, though using a sensitive technology allowed us to identify differences in expression between patients and controls.
CONCLUSIONS: Thus, lower expression of miR-185-5p can be related to the 22q11.2 deletion and DGCR8 haploinsufficiency, leading to phenotypic consequences in 22q11.2DS patients, while higher expression of hsa-miR-1304-3p might be related to individual genomic variances due to the heterogeneous background of the Brazilian population.

UNASSIGNED: Rubinstein-Taybi syndrome (RTS) is a rare autosomal-dominant disease. Almost all cases are sporadic and attributed to de novo variant. Psychotic symptoms in RTS are rare and have been reported in only a few published cases. On the other hand, 22q11.2 deletion syndrome is the most common chromosomal microdeletion in humans. The 22q11.2 deletion is well recognized as a risk factor for schizophrenia. Here, we present a schizophrenic psychosis case clinically diagnosed as RTS but resolved as carrying 22q11.2 deletion by genomic analysis.
UNASSIGNED: A 38-year-old Japanese male was admitted to our hospital due to psychotic symptoms. He had been diagnosed with RTS based on physical characteristics at the age of 9 months. On admission, we performed whole exome sequencing. He had no pathogenic variant in CREBBP or EP300. We detected 2.5 Mb deletion on 22q11.2 and one rare loss-of-function variant in a loss-of-function-constrained gene (MTSS1) and three rare missense variants in missense-constrained genes (CELSR3, HERC1, and TLN1). Psychotic symptoms were ameliorated by the treatment of risperidone.
UNASSIGNED: The psychiatric manifestation and genomic analysis may be a clue to detecting 22q11.2 deletion syndrome in undiagnosed patients. The reason for similarity in physical characteristics in 22q11.2 deletion syndrome and RTS remains unresolved. The 22q11.2 deletion and HERC1 contribute to the patient\'s phenotype.

UNASSIGNED: The 22q11.2 deletion syndrome (22q11DS) is associated with a high prevalence of mental health comorbidities. However, not enough attention has been paid to the elevated prevalence of high trait anxiety that begins early in life and may be enduring. We sought to identify specific medical, welfare, or educational difficulties associated with high trait anxiety in 22q11DS.
UNASSIGNED: A questionnaire-based survey was conducted for the parents of 22q11DS individuals (N = 125). First, a multiple regression analysis was conducted to confirm the hypothesis that high trait anxiety in individuals with 22q11DS would be associated with parents\' psychological distress. This was based on 19 questionnaire options regarding what difficulties the parents currently face about their child\'s disease, characteristics, and traits. Next, we explored what challenges faced in medical, welfare, and educational services would be associated with the trait anxiety in their child.
UNASSIGNED: The multiple regression analysis confirmed that the high trait anxiety was significantly associated with parental psychological distress (β = 0.265, p = 0.018) among the 19 clinical/personal characteristics of 22q11DS. Furthermore, this characteristic was associated with various difficulties faced in the medical care, welfare, and education services, and the parent-child relationship.
UNASSIGNED: To our knowledge, this is the first study to clarify quantitatively how the characteristic of high anxiety level in 22q11DS individuals is related to the caregivers\' perceived difficulties in medical, welfare, and educational services. These results suggest the necessity of designing service structures informed of the fact that high trait anxiety is an important clinical feature of the syndrome.

TANGO2 deficiency disorder (TDD) is a rare, autosomal recessive condition caused by pathogenic variants in TANGO2, a gene residing within the region commonly deleted in 22q11.2 deletion syndrome (22q11.2DS). Although patients with 22q11.2DS are at substantially higher risk for comorbid TDD, it remains underdiagnosed within 22q11.2DS, likely due to overlapping symptomatology and a lack of knowledge about TDD. Initiation of B-vitamin supplementation may provide therapeutic benefit in TDD, highlighting the need for effective screening methods to improve diagnosis rates in this at-risk group. In this retrospective, multicenter study, we evaluated two cohorts of patients with 22q11.2DS (total N = 435) for possible comorbid TDD using two different symptom-based screening methods (free text-mining and manual chart review versus manual chart review alone). The methodology of the cohort 1 screening method successfully identified a known 22q11.2DS patient with TDD. Combined, these two cohorts identified 21 living patients meeting the consensus recommendation for TANGO2 testing for suspected comorbid TDD. Of the nine patients undergoing TANGO2 sequencing with del/dup analysis, none were ultimately diagnosed with TDD. Of the 12 deaths in the suspected comorbid TDD cohort, some of these patients exhibited symptoms (rhabdomyolysis, cardiac arrhythmia, or metabolic crisis) suspicious of comorbid TDD contributing to their death. Collectively, these findings highlight the need for robust prospective screening tools for diagnosing comorbid TDD in patients with 22q11.2DS.

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.