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.

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.

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.

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.

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.

Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.

Velocardiofacial (VCFS; 22q11.2 deletion) syndrome is a genetic disorder that results from a hemizygous deletion of the q11.2 region on chromosome 22, and is associated with greatly increased risk for psychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. There is emerging evidence for the involvement of catechol-O-methyltransferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH) in the psychiatric phenotype of individuals with VCFS. Here, we tested the hypothesis that PRODH and COMT are associated with ASD in youths with VCFS. We found that individuals with VCFS and the low-activity alleles of both PRODH and COMT (rs4819756A and rs4680A) were more likely to present with ASD as compared with individuals with VCFS and the high-activity alleles of these genes [P<0.05; odds ratio=6.0 (95% confidence interval=1.27-28.26; N=87)]. Our results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS.

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.

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.

Cortical gyrification in velo-cardio-facial (22q11.2 deletion) syndrome: a longitudinal study.

INTRODUCTION: Velo-cardio-facial syndrome (VCFS) has been identified as an important risk factor for psychoses, with up to 32% of individuals with VCFS developing a psychotic illness. Individuals with VCFS thus form a unique group to identify and explore early symptoms and biological correlates of psychosis. In this study, we examined if cortical gyrification pattern, i.e. gyrification index (GI) can be a potential neurobiological marker for psychosis. METHOD: GIs of 91 individuals with VCFS were compared with 29 siblings and 54 controls. Further, 58 participants with VCFS, 21 siblings and 18 normal controls were followed up after 3 years and longitudinal changes in GI were compared. Additionally, we also correlated longitudinal changes in GI in individuals with VCFS with prodromal symptoms of psychosis on the Scale of Prodromal Symptoms (SOPS). RESULT: Individuals with VCFS had significantly lower GIs as compared to their siblings and normal controls. Longitudinal examination of GI did not reveal any significant group-time interactions between the three groups. Further, longitudinal change in GI scores in the VCFS group was negatively correlated with positive prodromal symptoms, with the left occipital region reaching statistical significance. CONCLUSION: The study confirms previous reports that individuals with VCFS have reduced cortical folding as compared to normal controls. However over a period of three years, there is no difference in the rate of change of GI among both individuals with VCFS and normal controls. Finally, our results suggest that neuroanatomical alterations in areas underlying visual processing may be an early marker for psychosis.

Cleft palate, retrognathia and congenital heart disease in velo-cardio-facial syndrome: a phenotype correlation study.

OBJECTIVE: Velo-cardio-facial syndrome (VCFS) is caused by a microdeletion of approximately 40 genes from one copy of chromosome 22. Expression of the syndrome is a variable combination of over 190 phenotypic characteristics. As of yet, little is known about how these phenotypes correlate with one another or whether there are predictable patterns of expression. Two of the most common phenotypic categories, congenital heart disease and cleft palate, have been proposed to have a common genetic relationship to the deleted T-box 1 gene (TBX1). The purpose of this study is to determine if congenital heart disease and cleft palate are correlated in a large cohort of human subjects with VCFS. METHODS: This study is a retrospective chart review including 316 Caucasian non-Hispanic subjects with FISH or CGH microarray confirmed chromosome 22q11.2 deletions. All subjects were evaluated by the interdisciplinary team at the Velo-Cardio-Facial Syndrome International Center at Upstate Medical University, Syracuse, NY. Each combination of congenital heart disease, cleft palates, and retrognathia was analyzed by Chi square or Fisher exact test. RESULTS: For all categories of congenital heart disease and cleft palate or retrognathia no significant associations were found, with the exception of submucous cleft palate and retrognathia (nominal p=0.0325) and occult submucous cleft palate and retrognathia (nominal p=0.000013). CONCLUSIONS: Congenital heart disease and cleft palate do not appear to be correlated in human subjects with VCFS despite earlier suggestions from animal models. Possible explanations include modification of the effect of TBX1 by genes outside of the 22q11.2 region that may further influence the formation of the palate or heart, or the presence of epigenetic factors that may effect genes within the deleted region, modifying genes elsewhere, or polymorphisms on the normal copy of chromosome 22. Lastly, it is possible that TBX1 plays a role in palate formation in some species, but not in humans. In VCFS, retrognathia is caused by an obtuse angulation of the skull base. It is unknown if the correlation between retrognathia and cleft palate in VCFS indicates a developmental sequence related to skull morphology, or direct gene effects of both anomalies. Much work remains to be done to fully understand the complex relationships between phenotypic characteristics in VCFS.

Mapping cortical morphology in youth with velocardiofacial (22q11.2 deletion) syndrome.

OBJECTIVE: Velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) represents one of the highest known risk factors for schizophrenia. Insofar as up to 30% of individuals with this genetic disorder develop schizophrenia, VCFS constitutes a unique, etiologically homogeneous model for understanding the pathogenesis of schizophrenia. METHOD: Using a longitudinal, case-control design, anatomic magnetic resonance images were acquired to investigate cross-sectional and longitudinal alterations in surface cortical morphology in a cohort of adolescents with VCFS and age-matched typical controls. All participants were scanned at two time points. RESULTS: Compared with controls, youth with VCFS exhibited alterations in inferior frontal, dorsal frontal, occipital, and cerebellar brain regions at both time points. Little change was observed over time in surface morphology of either study group. However, within the VCFS group only, worsening psychosocial functioning over time was associated with time 2 surface contractions in left middle and inferior temporal gyri. Further, prodromal symptoms at time 2 were associated with surface contractions in the left and right orbitofrontal, temporal, and cerebellar regions and surface protrusions of the supramarginal gyrus. CONCLUSIONS: These findings advance the understanding of cortical disturbances in VCFS that produce vulnerability for psychosis in this high-risk population.

Neuroanatomic predictors to prodromal psychosis in velocardiofacial syndrome (22q11.2 deletion syndrome): a longitudinal study.

BACKGROUND: Up to 30% of young adults with velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) develop schizophrenia or psychosis. Identifying the neuroanatomic trajectories that increase risk for psychosis in youth with this genetic disorder is of great interest. METHODS: We acquired high-resolution anatomic magnetic resonance images and measures of psychiatric function on 72 youth with VCFS, 26 unaffected siblings, and 24 age-matched community control subjects at two time points: between late childhood (mean age 11.9 years) and mid-adolescence (mean age 15.1 years). RESULTS: With the exception of cranial gray matter and orbitofrontal prefrontal cortex, neuroanatomic trajectories in youth with VCFS were comparable to unaffected siblings and community control subjects during this developmental window. However, in youth with VCFS, longitudinal decreases in the volumes of cranial gray and white matter, prefrontal cortex, mesial temporal lobe, and cerebellum were associated with increased combined prodromal symptoms at Time 2. In contrast, only decreases in temporal lobe gray matter volumes (p < .002) and verbal IQ (p < .002) predicted specifically to positive prodromal symptoms of psychosis at Time 2. CONCLUSIONS: These findings are in line with studies of non-VCFS individuals at risk for schizophrenia and suggest that early decrements in temporal lobe gray matter may be predictive of increased risk of prodromal psychotic symptoms in youth with VCFS.

Cervical vascular and upper airway asymmetry in Velo-cardio-facial syndrome: correlation of nasopharyngoscopy with MRA.

PURPOSE: Velo-cardio-facial syndrome (VCFS), the most common genetic syndrome causing cleft palate, is associated with internal carotid and vertebral artery anomalies, as well as upper airway asymmetry. Medially displaced internal carotid arteries, often immediately submucosal, present a risk of vascular injury during pharyngeal flap surgery for velopharyngeal insufficiency (VPI). We evaluate the frequency and spectrum of cervical vascular anomalies in a large cohort of VCFS patients correlating MRA with nasopharyngolaryngoscopy in detecting at risk carotid arteries. Furthermore, we assess the relationship with respect to laterality between cervical vascular patterns and the asymmetric abnormalities of these subjects' upper airways. METHODS: Cervical MRAs of 86 subjects with VCFS and 50 control subjects were independently reviewed by three neuroradiologists. The course of the internal carotid and vertebral arteries was identified within the pharyngeal soft tissues. Medial deviation, level of bifurcation, dominance, anomalous origin, and vessel tortuosity were recorded. Nasopharyngoscopy examinations were available for retrospective review in 43 patients and were assessed for palatal and posterior pharyngeal wall symmetry, true vocal cord motion and size, and for the presence or absence of carotid pulsations. The endoscopic findings were compared with MRA results. RESULTS: Of the 86 subjects, 80 (93%) had one or more vascular anomalies. 42 subjects (49%) were found to have medial deviation of at least one internal carotid artery. In 24 subjects (28%) the anomalous internal carotid artery was directly submucosal; four of these were bilateral (5% of the total sample, 17% of those with a submucosal internal carotid). Other carotid anomalies included low carotid bifurcation (44 subjects or 51%), anomalous origin of the right common carotid (32 cases, or 37%), and two cases of internal carotid agenesis/hypoplasia. Vertebral artery anomalies included vessel tortuosity (34 cases, or 40%), hypoplasia (10 cases, or 12%), looping (4 cases, or 5%), and one case of a double left vertebral artery. Though patients in our study showed an asymmetric distribution of vascular anomalies, no association was found between the laterality of palatal motion, pharyngeal fullness, or laryngeal movement and structure with ipsilateral vertebral or carotid artery anomalies. Of the 33 pulsatile carotid arteries visualized at nasopharyngoscopy, only nine were found to be submucosal on MRA. In contrast, 11 submucosal carotid arteries confirmed at MRA demonstrated no visible pulsations. Positive and negative predictive values of pulsative arteries seen endoscopically for MRA confirmation of a submucosal carotid course was 27% and 79% respectively. CONCLUSIONS: Carotid and vertebral artery anomalies are common in VCFS including marked medial deviation of the internal carotid artery in close proximity to the donor site for pharyngeal flap surgery. Lack of correlation between laterality of vascular anomalies and upper airway structural asymmetry in VCFS does not support the hypothesis that palatal, pharyngeal, and laryngeal anomalies are due to secondary developmental sequences caused by in utero vascular insufficiency. The presence or absence of carotid pulsations seen by nasopharyngoscopy does not correlate with the carotid arterial depth identified on MRA. Furthermore, identification of the relative medial-lateral retropharyngeal position of a submucosal carotid affords the opportunity to modify the surgical approach. These findings further support the routine use of pre-operative neck MRA in VCFS patients in surgical planning.

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.

Velopharyngeal insufficiency: diagnosis and management.

PURPOSE OF REVIEW: Journal articles relevant to the diagnosis and treatment of velopharyngeal insufficiency were reviewed. All studies ascertained by PubMed search were included. RECENT FINDINGS: Studies reported on the application of magnetic resonance scanning, reliability tests of the International Working Group diagnostic protocol, the use of nasometry, and techniques designed to assess the function of the velopharyngeal mechanism. Treatment studies focused on outcomes in small samples of cases and complication rates from pharyngeal flap. One study discussed ineffective speech therapy procedures. SUMMARY: There were relatively few studies this past year. Those that were published were hindered by small and heterogeneous sample sizes and occasionally by inappropriate methods for assessing outcomes. None of the findings will have a major impact on the current state-of-the-art for diagnosis of velopharyngeal insufficiency. The speech therapy study has a very important message that should be taken to heart by all clinicians involved in the management of children with clefts and craniofacial disorders.

Velo-Cardio-Facial Syndrome.

Velocardiofacial syndrome (VCFS) also known as DiGeorge, conotruncal anomaly face and Cayler syndromes is caused by a microdeletion in the long arm of chromosome 22. We review the history of the syndrome from the first clinical reports almost half a century ago to the current intriguing molecular findings associating genes from the microdeletion region and the physical and neuropsychiatric phenotype of the syndrome. Velocardiofacial syndrome has a wide spectrum of more than 200 physical manifestations including palate and cardiac anomalies. Yet, the most challenging manifestations of VCFS are the learning disabilities and neuropsychiatric disorders. As VCFS is relatively common and as up to one third of the subjects with VCFS develop schizophrenia like psychotic disorder the syndrome is the most commonly known genetic risk factor to schizophrenia. Identifying the genetic, cognitive and psychiatric risk factors for VCFS-schizophrenia is under the focus of intensive research.

Velo-cardio-facial syndrome: 30 Years of study.

Velo-cardio-facial syndrome is one of the names that has been attached to one of the most common multiple anomaly syndromes in humans. The labels DiGeorge sequence, 22q11 deletion syndrome, conotruncal anomalies face syndrome, CATCH 22, and Sedlacková syndrome have all been attached to the same disorder. Velo-cardio-facial syndrome has an expansive phenotype with more than 180 clinical features described that involve essentially every organ and system. The syndrome has drawn considerable attention because a number of common psychiatric illnesses are phenotypic features including attention deficit disorder, schizophrenia, and bipolar disorder. The expression is highly variable with some individuals being essentially normal at the mildest end of the spectrum, and the most severe cases having life-threatening and life-impairing problems. The syndrome is caused by a microdeletion from chromosome 22 at the q11.2 band. Although the large majority of affected individuals have identical 3 megabase deletions, less than 10% of cases have smaller deletions of 1.5 or 2.0 megabases. The 3 megabase deletion encompasses a region containing 40 genes. The syndrome has a population prevalence of approximately 1:2,000 in the United States, although incidence is higher. Although initially a clinical diagnosis, today velo-cardio-facial syndrome can be diagnosed with extremely high accuracy by fluorescence in situ hybridization and several other laboratory techniques. Clinical management is age dependent with acute medical problems such as congenital heart disease, immune disorders, feeding problems, cleft palate, and developmental disorders occupying management in infancy and preschool years. Management shifts to cognitive, behavioral, and learning disorders during school years, and then to the potential for psychiatric disorders including psychosis in late adolescence and adult years. Although the majority of people with velo-cardio-facial syndrome do not develop psychosis, the risk for severe psychiatric illness is 25 times higher for people affected with velo-cardio-facial syndrome than that of the general population. Therefore, interest in understanding the nature of psychiatric illness in the syndrome remains strong.

Comparing phenotypes in patients with idiopathic autism to patients with velocardiofacial syndrome (22q11 DS) with and without autism.

At least three research groups have reported that autism is diagnosed in up to 20% of children with velocardiofacial syndrome (VCFS). However the degree of phenotypic overlap between VCFS-affected children with autism and those with idiopathic autism has not been established. The purpose of this study was to define and differentiate the behavioral phenotype of autism in samples of children with either (VCFS) or idiopathic autism. Five groups of children ages 5-15 were included in the between-group design. Parent report of autism behaviors (based on the Autism Diagnostic Interview-Revised, ADI-R) were compared between children with VCFS, children with VCFS and autism (VCFS + autism), siblings of the children with VCFS, a community control group, and a group of children with idiopathic autism. Autism diagnoses were based according to the ADI-R. Parental responses to the ADI-R indicated that relative to children with VCFS-only, children with idiopathic autism and children with VCFS + autism exhibited less make believe play and more rituals, motor stereotypies and repetitive use of objects. However several other core autism behaviors, including difficulties sharing attention, deficits in gestural communication and initiating conversation, and presence of circumscribed interests, appear to be phenotypic VCFS behaviors, characterizing children with VCFS regardless of an autism diagnosis. Accordingly, the autism phenotype in VCFS differs to some extent from that of idiopathic autism. Several features of idiopathic autism are spared in VCFS, and other features appear to be a function of the VCFS phenotype independent of autism. These findings carry implications for clinicians who diagnose and treat VCFS or autism, and for researchers who study genotype-phenotype associations in autism.