Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

An examination of adaptive behavior and functional outcomes in adults with 22q11.2 deletion syndrome: A parental perspective.

22q11.2 Deletion Syndrome (22q11DS) is a genetic syndrome caused by a chromosomal microdeletion. It affects approximately 1 in 850-992 pregnancies, and its clinical manifestations include congenital heart disease, gastrointestinal symptoms, and psychiatric illnesses. The study examined the relationship between adaptive behavior and functional outcomes, educational attainment, employment, and independent living, and whether age, gender, intellectual disability, presence of psychiatric disorder, and close friendships could predict levels of adaptive behavior. Parents of adults with 22q11DS (n = 101; 48 male and 54 female) completed the Waisman Activities of Daily Living Scale, demographic details, and questions elicited employment, education, and relationships status. Analysis conducted in SPSS, included descriptive statistics, measures of association, Analysis of Variance, logistic and linear regressions. Differences in levels of overall adaptive behavior were found regarding employment and living status, but not in educational attainment. Having close friendships was associated with adaptive behavior as well as the likelihood of living independently. Further research is needed, ideally using prospective designs and purposive sampling strategies. This needs to examine how social and communication deficits impact relationship building and how they are affected by the clinical manifestations of 22q11DS. It also needs to focus on how different social structures interface with levels of adaptive behavior.

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects.

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

Catatonia in an adolescent with velo-cardio-facial syndrome.

Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans and is probably the most frequent genetic cause of psychosis currently known. Many psychiatric disorders have been reported to occur in people with VCFS including, but not limited to schizophrenia, unipolar and bipolar mood disorders (with or without psychotic features), schizoaffective disorder, psychosis NOS, social phobia, generalized and separation anxiety, obsessive-compulsive disorder, autism spectrum disorder, cognitive impairment, and ADHD. This report describes the psychiatric onset and development of catatonia in an adolescent female with VCFS that was undiagnosed until 15 years of age. Catatonia may be a relatively common presentation in people with VCFS with treatment-refractory psychiatric manifestations.

Adaptive living skills, sleep problems, and mental health disorders in adults with 22q11.21 deletion syndrome.

BACKGROUND: 22q11.21 deletion syndrome (22q11DS) is a neurodevelopmental syndrome caused by a microdeletion of genes at the 22q11.21 locus. It has a prevalence of 1:2000. This study investigated the prevalence of adaptive living skills, sleep problems, and mental health disorders in adults with 22q11DS and examined the relationship between these factors. METHODS: Parents with an adult son or daughter with 22q11DS completed the following: A bespoke Demographic Information Questionnaire, Sleep Questionnaire (SQ-SP), Psychopathology in Autism Checklist (PAC), and Activities of Daily Living (ADL) scale. Descriptive statistics, correlations, and one-way between groups analysis of variance (ANOVA) were conducted. RESULTS: Mental health difficulties, sleep problems, and low levels of adaptive living skills are prevalent in adults with 22q11DS. Strong positive correlations were identified between sleep problems, depression, and anxiety subscale scores and moderate negative correlations between depression, psychosis, and activities of daily living skills. CONCLUSION: Adults with 22q11DS need screening and treatment for mental health and sleep problems.

Aberrant pace of cortical neuron development in brain organoids from patients with 22q11.2 deletion syndrome and schizophrenia.

Adults and children afflicted with the 22q11.2 deletion syndrome (22q11.2DS) exhibit cognitive, social, and emotional impairments, and are at significantly heightened risk for schizophrenia (SCZ). The impact of this deletion on early human brain development, however, has remained unclear. Here we harness organoid models of the developing human cerebral cortex, cultivated from subjects with 22q11.2DS and SCZ, as well as unaffected control samples, to identify cell-type-specific developmental abnormalities arising from this genomic lesion. Leveraging single-cell RNA-sequencing in conjunction with experimental validation, we find that the loss of genes within the 22q11.2 locus leads to a delayed development of cortical neurons. This compromised development was reflected in an elevated proportion of actively proliferating neural progenitor cells, coupled with a decreased fraction of more mature neurons. Furthermore, we identify perturbed molecular imprints linked to neuronal maturation, observe the presence of sparser neurites, and note a blunted amplitude in glutamate-induced Ca2+ transients. The aberrant transcription program underlying impaired development contains molecular signatures significantly enriched in neuropsychiatric genetic liability. MicroRNA profiling and target gene investigation suggest that microRNA dysregulation may drive perturbations of genes governing the pace at which maturation unfolds. Using protein-protein interaction network analysis we define complementary effects stemming from additional genes residing within the deleted locus. Our study uncovers reproducible neurodevelopmental and molecular alterations due to 22q11.2 deletions. These findings have the potential to facilitate disease modeling and promote the pursuit of therapeutic interventions.

Atlas-based white matter analysis in individuals with velo-cardio-facial syndrome (22q11.2 deletion syndrome) and unaffected siblings.

BACKGROUND: Velo-cardio-facial syndrome (VCFS, MIM#192430, 22q11.2 Deletion Syndrome) is a genetic disorder caused by a deletion of about 40 genes at the q11.2 band of one copy of chromosome 22. Individuals with VCFS present with deficits in cognition and social functioning, high risk of psychiatric disorders, volumetric reductions in gray and white matter (WM) and some alterations of the WM microstructure. The goal of the current study was to characterize the WM microstructural differences in individuals with VCFS and unaffected siblings, and the correlation of WM microstructure with neuropsychological performance. We hypothesized that individuals with VCFS would have decreased indices of WM microstructure (fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD)), particularly in WM tracts to the frontal lobe, and that these measures would be correlated with cognitive functioning. METHODS: Thirty-three individuals with VCFS (21 female) and 16 unaffected siblings (8 female) participated in DTI scanning and neuropsychological testing. We performed an atlas-based analysis, extracted FA, AD, and RD measures for 54 WM tracts (27 in each hemisphere) for each participant, and used MANOVAs to compare individuals with VCFS to siblings. For WM tracts that were statistically significantly different between VCFS and siblings (pFDR <0.05), we assessed the correlations between DTI and neuropsychological measures. RESULTS: In VCFS individuals as compared to unaffected siblings, we found decreased FA in the uncinate fasciculus, and decreased AD in multiple WM tracts (bilateral superior and posterior corona radiata, dorsal cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, superior cerebellar peduncle, posterior thalamic radiation, and left anterior corona radiata, retrolenticular part of the internal capsule, external capsule, sagittal stratum). We also found significant correlations of AD with measures of executive function, IQ, working memory, and/or social cognition. CONCLUSIONS: Our results suggest that individuals with VCFS display abnormal WM connectivity in a widespread cerebro-anatomical network, involving tracts from/to all cerebral lobes and the cerebellum. Future studies could focus on the WM developmental trajectory in VCFS, the association of WM alterations with psychiatric disorders, and the effects of candidate 22q11.2 genes on WM anomalies.

Genomic disorders on chromosome 22.

PURPOSE OF REVIEW: Chromosome 22, the first human chromosome to be completely sequenced, is prone to genomic alterations. Copy-number variants (CNVs) are common because of an enrichment of low-copy repeat sequences that precipitate a high frequency of nonallelic homologous misalignments and unequal recombination during meiosis. Among these is one of the most common multiple anomaly syndromes in humans and the most common microdeletion syndrome, velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome and DiGeorge syndrome. This review will focus on the recent literature dealing with both the molecular and clinical aspects of chromosome 22 genomic variations. Although the literature covering this area is expansive, the majority is descriptive or analytical of the problems presented by these genomic disorders, and there is little evidence of translational research including treatment outcomes. RECENT FINDINGS: With the increased use of microarray analysis in both research and clinical practice, variations in CNVs are becoming elucidated. Genomic analysis continues to characterize genes and gene effect. Research on the COMT gene continues to yield interesting findings, including a possible sex-mediated effect because of its regulatory role with estrogen. There is a small amount of treatment outcome data relevant to neuropsychiatric disorders in VCFS, but based on small samples and short-term follow-up. SUMMARY: Although hundreds of studies in the past year have focused on genomic disorders of chromosome 22, little progress has been made in the implementation of translational research, even for more common disorders including VCFS.

The effects of gender and catechol O-methyltransferase (COMT) Val108/158Met polymorphism on emotion regulation in velo-cardio-facial syndrome (22q11.2 deletion syndrome): An fMRI study.

Velo-cardio-facial syndrome (VCFS) is caused by a micro-deletion of over 40 genes at the q11.2 locus of chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. COMT, one of the genes located in the deleted region, has been considered as a major candidate gene for genetic susceptibility in psychiatric diseases. Its functional polymorphism Val108/158Met has been shown to affect prefrontal function and working memory and has been associated with emotional dysregulation. We utilized a functional magnetic resonance imaging (fMRI) event-related paradigm to asses COMT genotype and gender-moderated effects on the neural activation that are elicited by viewing emotionally salient images charged with pleasant, unpleasant, and neutral content. Since estrogen down-regulates COMT activity resulting in lower COMT activity in women than men, we hypothesized an allele-by-gender interaction effect on neural activation. Participants included 43 VCFS individuals (Val/male=9, Val/female=17, Met/male=9, Met/female=8). We observed a gender effect on processing positive emotions, in that girls activated the cingulate gyrus more than boys did. We further observed a significant gender-by-allele interaction effect on neural function specific to the frontal lobe during the processing of pleasant stimuli, and specific to limbic regions during the processing of unpleasant stimuli. Our results suggest that in VCFS, the effect of the COMT Val108/158Met polymorphism is moderated by gender during the processing of emotional stimuli and could contribute to the understanding of the way in which this COMT polymorphism affects vulnerability to neuropsychiatric disorders.

The neural correlates of non-spatial working memory in velocardiofacial syndrome (22q11.2 deletion syndrome).

Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is a neurogenetic disorder that is associated with both learning disabilities and a consistent neuropsychological phenotype, including deficits in executive function, visuospatial perception, and working memory. Anatomic imaging studies have identified significant volumetric reductions in the parietal lobe of individuals with VCFS, but several studies have reported that the frontal lobe is relatively preserved. We used functional magnetic resonance imaging to investigate the neural correlates of non-spatial working memory in 17 youths with VCFS, 10 of their unaffected siblings, and 10 community controls (with the same proportion of learning disabilities as the VCFS youths). Task performance of siblings tended to be more accurate than children with VCFS, who did not differ from community controls. All three-study groups recruited parietal regions that were equivalent in location and magnitude. Whereas the sibling group also recruited the dorsolateral prefrontal cortex (DLPFC), Broca's area, and anterior cingulate, DLPFC activation was absent in the whole brain analyses of children with VCFS and controls. Moreover, the magnitude of frontal activation in VCFS participants was restricted relative to both siblings and controls. These findings suggest that VCFS participants exhibit frontal hypoactivation that is not attributable to performance. In addition, VCFS children and controls (many with idiopathic learning disabilities) appear to rely on phonological rehearsal to hold information on line instead of the DLPFC. Despite previous anatomic MRI reports of preserved frontal lobe volumes in VCFS therefore, these fMRI findings suggest that the frontal component of the distributed network subserving executive function and working memory may be disrupted in youth with this disorder.

Autistic spectrum disorders in velo-cardio facial syndrome (22q11.2 deletion).

The extent to which the phenotype of children comorbid for velocardiofacial syndrome (VCFS) and autism spectrum disorders (ASD) differs from that of VCFS-only has not been studied. The sample consisted of 41 children (20 females) with VCFS, ranging in age from 6.5 years to 15.8 years. Eight children with VCFS met formal DSM-IV diagnostic criteria for autism based upon the ADI-R. These eight plus an additional nine participants met diagnostic criteria for an autistic spectrum disorder (VCFS + ASD). Ninety-four percent of the children with VCFS + ASD had a co-occurring psychiatric disorder while 60% of children with VCFS had a psychiatric disorder. Children with VCFS + ASD had larger right amygdala volumes. All other neuroanatomic regions of interest were statistically similar between the two groups.

A novel, single nucleotide polymorphism-based assay to detect 22q11 deletions.

Velocardiofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome, now collectively referred to as 22q11deletion syndrome (22q11DS) are caused by microdeletions on chromosome 22q11. The great majority ( approximately 90%) of these deletions are 3 Mb in size. The remaining deleted patients have nested break-points resulting in overlapping regions of hemizygosity. Diagnostic testing for the disorder is traditionally done by fluorescent in situ hybridization (FISH) using probes located in the proximal half of the region common to all deletions. We developed a novel, high-resolution single-nucleotide polymorphism (SNP) genotyping assay to detect 22q11 deletions. We validated this assay using DNA from 110 nondeleted controls and 77 patients with 22q11DS that had previously been tested by FISH. The assay was 100% sensitive (all deletions were correctly identified). Our assay was also able to detect a case of segmental uniparental disomy at 22q11 that was not detected by the FISH assay. We used Bayesian networks to identify a set of 17 SNPs that are sufficient to ascertain unambiguously the deletion status of 22q11DS patients. Our SNP based assay is a highly accurate, sensitive, and specific method for the diagnosis of 22q11 deletion syndrome.

22q11.2DS deletion syndrome: developmental milestones in infants and toddlers.

BACKGROUND: The majority of children with 22q11.2DS deletion syndrome (22q11.2DS) have learning disabilities, and a substantial number have mental retardation. Although cognitive data have been reported on several samples of children with 22q11.2DS, data on their early developmental milestones are limited. METHODS: The present study used a retrospective design and asked parents to recall developmental milestones. The participants were 88 children with 22q11.2DS, 47 community controls, and 29 sibling controls. RESULTS: Although very early gross motor and expressive language milestones did not differ significantly from comparison groups, subsequent gross motor and expressive language milestones did, suggesting that children with 22q11.2DS may begin to lag behind their peers sometime after the first year of life in these two domains. These patterns were also apparent when a subset of intellectually comparable children (22q11.2DS, n = 40 vs community controls, n = 24) was analyzed. We further found that receptive language and social adaptive milestones did not differ from comparison samples in either the early or later period. Receptive language delays were predictive of later Wechsler Intelligence Scale for Children-Third Edition Perceptual Organization Index scores, particularly in girls with 22q11.2DS. CONCLUSIONS: This suggests that although receptive language may be an area of relative strength in the developmental profile of young children with 22q11.2DS, even mild receptive delays should not be overlooked in early interventions with children with this disorder.

Pharyngeal flap and obstructive apnea: maximizing speech outcome while limiting complications.

OBJECTIVE: To assess speech results and rate of obstructive sleep apnea using a modified, superiorly based pharyngeal flap performed after staged adenotonsillectomy in a group with velopharyngeal insufficiency. METHODS: In this nonrandomized, retrospective case series (July 1, 1996, through June 30, 2003), patients were mainly children referred to a multispecialty craniofacial clinic. Patients underwent staged adenotonsillectomy 2 months before width-customized pharyngeal flap surgery. Short flaps were created high above the level of the palate, just long enough to reach the nasal surface. Donor sites were closed by superior advancement of the inferior posterior pharyngeal wall tissue. Cardiopulmonary and oximetry data were analyzed for immediate obstructive apnea. Speech results and airway symptoms were assessed at 6-month and yearly follow-up examinations. RESULTS: In the 54 consecutive patients who underwent staged adenotonsillectomy, no apnea occurred immediately after surgery. Long-term clinical examination revealed 4 cases of loud snoring. Polysomnographic results were negative in all cases. Complications included 3 cases of bleeding, 1 requiring transfusion. Velopharyngeal insufficiency was eliminated in 94% of patients. CONCLUSION: Complications related to obstructive sleep apnea have been significantly reduced while maintaining excellent speech results by a staged approach of removing tonsils and adenoids and by creating a short, high, wide, superiorly based pharyngeal flap with superior advancement of the inferior posterior wall to close the donor site.

Upper airway asymmetry in velo-cardio-facial syndrome.

OBJECTIVE: Various forms of asymmetry have been recognized as a feature of velo-cardio-facial syndrome (VCFS). This study was implemented to determine the frequency of anatomic and functional asymmetry of the velum, pharynx and larynx in children with VCFS. METHODS: Individuals with VCFS underwent prospective, blinded analysis by an expert panel who assessed the velum, pharynx and larynx with multi-view videofluoroscopy (MVF) and nasopharyngolaryngoscopy (NPL). The VCFS group was compared to an age-matched group of normal individuals. Eight different parameters were assessed in both groups for functional and anatomic symmetry including: velar elevation, adenoid size, posterior pharyngeal wall size, carotid pulsations, epiglottis size and shape, arytenoid size, true vocal cord size and true vocal cord motion. RESULTS: One hundred and twenty-one subjects with VCFS and 20 normal individuals underwent examination. Children with VCFS showed significantly more asymmetry compared to the normal group (69% versus 20%, P=0.01) with greatest differences seen with palatal motion, posterior pharyngeal wall size and epiglottis shape. On average, subjects with VCFS had three asymmetric parameters versus one parameter in the normal group. CONCLUSION: Asymmetric development of the pharynx and larynx in children with VCFS appears to be a distinct clinical feature of this syndrome. This finding may provide an important diagnostic clue for patients presenting with subtle features of the 22q11.2 microdeletion. These developmental abnormalities may increase the risk of speech impairment, aspiration and airway obstruction in affected individuals.

Velo-cardio-facial syndrome: the pediatric otolaryngologist's perspective.

PURPOSE OF REVIEW: The understanding of velo-cardio-facial syndrome has grown markedly since the initial descriptions of this common genetic disorder nearly 30 years ago. Our knowledge of the syndrome has advanced in part from opportunities to monitor many patients into adulthood because of advances in the fields of cardiothoracic surgery and immunology. Longitudinal study has brought to light psychiatric and behavioral features of the syndrome that are often not apparent until late adolescence or the early adult years. Certain endocrine and immunologic features of the syndrome thought to be resolved in childhood are now witnessed in older patients. Variable expression and lack of disease awareness are two major factors that contribute to the delays in diagnosis in many cases. To address this, there has been a call to delineate screening parameters for patients at risk of carrying the deletion. RECENT FINDINGS: Several areas are highlighted in this review, reflecting the focus of scholarly work on velo-cardio-facial syndrome in the past year. Molecular genetics has shown smaller deletions in many families with the syndrome. The gene TBX1 has been found to be important to the phenotype. Surgical outcomes data reveal the greater challenges involved in correcting velopharyngeal insufficiency. SUMMARY: Defining the genetic basis of velo-cardio-facial syndrome will allow clinicians and basic scientists to make further inroads into understanding the variable expressivity of this syndrome. It is also important to be aware of the continued diagnostic challenges encountered by clinicians in attempts to improve the detection of patients with this syndrome.

22q11.2 deletion syndrome: genetics, neuroanatomy and cognitive/behavioral features keywords.

This paper presents a conceptual review of the genetic underpinnings of 22q11.2 Deletion Syndrome. The neuroanatomical, neuropsychological, behavioral, and psychiatric phenotype associated with 22q11.2 Deletion Syndrome is also explored, including variables that are thought to affect symptom expression. The history of the deletion syndrome is described, and future directions for continued research are discussed.

Pharyngeal flap and the internal carotid in velocardiofacial syndrome.

Internal carotid artery anomalies have been documented as a common clinical feature in velocardiofacial syndrome. There has been some controversy over the need for preoperative imaging procedures, such as magnetic resonance angiography, when planning pharyngeal surgery for correcting velopharyngeal insufficiency. The purpose of this article is to describe 20 patients with velocardiofacial syndrome who received comprehensive evaluation and underwent pharyngeal flap surgery within a 2-year period and to report the technique used for dissecting the flap and the surgical outcomes. Anomalies of the major neck vessels were present in all cases, but 5 of these 20 cases had particularly severe anomalies of the internal carotid arteries that placed the vessels directly deep within the donor site for the pharyngeal flap. Surgery was carried out successfully in all 20 cases using a modified approach after radiographic imaging was performed to locate the arteries. In the 5 cases with severe malpositioning of the internal carotid arteries, it was clear that the vessels could have been injured had their location not been identified and the surgical approach modified to avoid them.

Craniometaphyseal dysplasia: a case report and review of medical and surgical management.

Craniometaphyseal dysplasia (CMD) is a genetic syndrome involving cranial and tubular bone anomalies that commonly present at a young age, often with otolaryngologic manifestations. In this paper, we report a rare case of a sporadic form of the disease resulting in an early state of hypocalcemia with secondary hyperparathyroidism. A conductive hearing loss is also documented prior to 12 months of age. The clinical aspects of CMD will be covered along with its pathogenesis. The current concepts surrounding medical and surgical treatments will be reviewed, and the management of our patient will be discussed.