Practical guidelines for managing adults with 22q11.2 deletion syndrome.
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ABSTRACT:
SUBMITTER: Fung WL
PROVIDER: S-EPMC4526275 | biostudies-literature | 2015 Aug
REPOSITORIES: biostudies-literature
Publications
Practical guidelines for managing adults with 22q11.2 deletion syndrome.
Fung Wai Lun Alan WL Butcher Nancy J NJ Costain Gregory G Andrade Danielle M DM Boot Erik E Chow Eva W C EW Chung Brian B Cytrynbaum Cheryl C Faghfoury Hanna H Fishman Leona L García-Miñaúr Sixto S George Susan S Lang Anthony E AE Repetto Gabriela G Shugar Andrea A Silversides Candice C Swillen Ann A van Amelsvoort Therese T McDonald-McGinn Donna M DM Bassett Anne S AS
Genetics in medicine : official journal of the American College of Medical Genetics 20150108 8
22q11.2 Deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, estimated to affect up to 1 in 2,000 live births. Major features of this multisystem condition include congenital anomalies, developmental delay, and an array of early- and later-onset medical and psychiatric disorders. Advances in pediatric care ensure a growing population of adults with 22q11.2DS. Informed by an international panel of multidisciplinary experts and a comprehensive review of the existing l ...[more]
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Project description:PURPOSE:To characterize the prevalence of and contributing factors to adult obesity in the most common recurrent copy-number variation (CNV), 22q11.2 deletion, given that other rare CNVs are known to have obesity phenotypes. METHODS:In 207 adults with 22q11.2 deletion syndrome (22q11.2DS), we used available height and weight measurements to calculate body mass index (BMI) and recorded associated factors that could play a role in obesity. We used the maximum BMI per subject and logistic regression to test a model predicting obesity class. RESULTS:The prevalence of obesity (BMI ?30) in 22q11.2DS (n = 90, 43.5%; at median age of 26.7 years) was significantly greater than for Canadian norms (odds ratio (OR) 2.30, 95% confidence interval (CI) = 1.74-3.02, P < 0.0001), even after excluding individuals with a history of antipsychotic use. The regression model was significant (P < 0.0001). Psychotropic medication use and age, but not sex or presence of intellectual disability, were associated with higher obesity level. Ten (4.8%) individuals were diagnosed with type 2 diabetes at a median age of 39.5 years; the prevalence was higher in those with obesity (P < 0.01). CONCLUSION:The results suggest that adult obesity is related to the 22q11.2 deletion. The findings expand the potential genetic causes of obesity and have important implications for management of 22q11.2DS.Genet Med 19 2, 204-208.
| S-EPMC5292049 | biostudies-literature
Project description:22q11.2 deletion syndrome (22q11.2DS) is a multisystem disease with a prevalence of 1/4000. Variable expression of congenital and later onset features contributes to its under-recognition. Longevity in those surviving childhood is believed to be normal but data are limited.We prospectively followed 264 subjects; 102 adults (>17 years) with 22q11.2DS (44 male (M), 58 female (F); mean (SD) age 33.6 (10.9) years) and their 162 unaffected siblings (77 M, 85 F; mean age 36.1 (12.2) years). We compared survival between groups using Kaplan-Meier estimates.Twelve (11.8%; 4 M, 8 F) individuals with 22q11.2DS and no siblings died (p<0.0001). Survival to ages 40 and 50 years was 89.9% and 73.9%, respectively. Median age at death was 41.5 (range 18.1-68.6) years. Deaths included two (7.7%) of 26 subjects with neither major congenital heart disease (CHD) nor schizophrenia. Four of six sudden and unexpected deaths occurred in individuals with no major CHD. There was no evidence of cancer or coronary artery disease or family history of sudden death in the 12 patients who died, six of whom had autopsies.Individuals with 22q11.2DS who survive childhood have diminished life expectancy and increased risk of sudden death not attributable to any single factor. Some sudden and/or premature deaths observed in the general population may represent undiagnosed 22q11.2DS. Increased recognition of the syndrome by family doctors, specialists and coroners will be essential to facilitate the tissue studies needed to determine underlying mechanisms.
| S-EPMC3188306 | biostudies-literature
Project description:The 22q11.2 deletion syndrome is a common multisystem genomic disorder with congenital and later-onset manifestations, including congenital heart disease, intellectual disability, and psychiatric illness, that may affect long-term functioning. There are limited data on adult functioning in 22q11.2 deletion syndrome.We used the Vineland Adaptive Behavior Scales to assess functioning in 100 adults with 22q11.2 deletion syndrome (n = 46 male; mean age = 28.8 (standard deviation = 9.7) years) where intellect ranged from average to borderline (n = 57) to mild intellectual disability (n = 43).More than 75% of the subjects scored in the functional deficit range. Although personal, vocational, and financial demographics confirmed widespread functional impairment, daily living skills and employment were relative strengths. Intelligence quotient was a significant predictor (P < 0.001) of overall and domain-specific adaptive functioning skills. A diagnosis of schizophrenia was a significant predictor (P < 0.05) of overall adaptive functioning, daily living skills, and socialization scores. Notably, congenital heart disease, history of mood/anxiety disorders, sex, and age were not significant predictors of functioning.Despite functional impairment in adulthood that is primarily mediated by cognitive and psychiatric phenotypes, relative strengths in activities of daily living and employment have important implications for services and long-term planning. These results may help to inform expectations about outcomes for patients with 22q11.2 deletion syndrome.
| S-EPMC3465579 | biostudies-literature
Project description:22q11.2 deletion syndrome (22qDS) is a genetic syndrome associated with a chromosome 22q11.2 deletion and variable phenotypic expression that commonly includes schizophrenia. Approximately 1% of patients with schizophrenia have 22qDS. The schizophrenia in 22qDS appears broadly similar to that found in the general population with respect to core signs and symptoms, treatment response, neurocognitive profile, and MRI brain anomalies. However, individuals with a 22qDS form of schizophrenia typically have distinguishable physical features, have a lower IQ, and may differ in auxiliary clinical features. IQ, length of 22q11.2 deletions, and COMT functional allele do not appear to be major risk factors for schizophrenia in 22qDS. Ascertainment biases and small sample sizes are limitations of most studies. Larger studies over the lifespan and continuing education about this underrecognized condition are needed. 22qDS-schizophrenia is an important genetic subtype and a valuable model of neurodevelopmental mechanisms involved in the pathogenesis of schizophrenia.
| S-EPMC3129332 | biostudies-other
Project description:PurposeGiven limited data available on long-term outcomes in 22q11.2 deletion syndrome (22q11.2DS), we investigated mortality risk in adults with this microdeletion syndrome.MethodsWe studied 309 well-characterized adults (age ≥17 years) with 22q11.2DS and their 1014 unaffected parents and siblings, using a prospective case-control design. We used Cox proportional hazards regression modeling and Kaplan-Meier curves to investigate effects of the 22q11.2 deletion and its associated features on all-cause mortality and survival.ResultsThe 22q11.2 deletion (hazard ratio [HR] 8.86, 95% CI 2.87-27.37) and major congenital heart disease (CHD; HR 5.03, 95% CI 2.27-11.17), but not intellectual disability or psychotic illness, were significant independent predictors of mortality for adults with 22q11.2DS compared with their siblings. Amongst those with 22q11.2DS, there were 31 deaths that occurred at a median age of 46.4 (range 18.1-68.6) years; a substantial minority had outlived both parents. Probability of survival to age 45 years was approximately 72% for those with major CHD, and 95% for those with no major CHD (p < 0.0001).ConclusionFor adults with 22q11.2DS, the 22q11.2 deletion and more severe forms of CHD both contribute to a lower life expectancy than family-based expectations. The results have implications for genetic counseling and anticipatory care.
| S-EPMC6774995 | biostudies-literature
Project description:We derived iPSC from individuals carrying a 22q11.2 deletion and controls and differentiated them into 3D cortical organoids.
2020-07-08 | GSE142041 | GEO
Project description:The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births. These patients may suffer from affection of many organ systems with cardiac malformations, immunodeficiency, hypoparathyroidism, autoimmunity, palate anomalies, and psychiatric disorders being the most frequent. The importance of the complement system in 22q11.2 del has not been investigated. The objective of this study was to evaluate the complement system in relation to clinical and immunological parameters in patients. A national cohort of patients (n?=?69) with a proven heterozygous deletion of chromosome 22q11.2 and a group of age and sex matched controls (n?=?56) were studied. Functional capacity of the classical, lectin, and alternative pathways of the complement system as well as complement activation products C3bc and terminal complement complex (TCC) were accessed and correlated to clinical features. All patients in our study had normal complement activation in both classical and alternative pathways. The frequency of mannose-binding lectin deficiency was comparable to the normal population. The patients had significantly raised plasma levels of C3bc and a slight, but not significant, increase in TCC compared with controls. This increase was associated with the presence of psychiatric disorders in patients. The present study shows no complement deficiencies in 22q11.2 deletion syndrome. On the contrary, there are signs of increased complement activation in these patients. Complement activation is particularly associated with the presence of psychiatric disorders.
| S-EPMC7142058 | biostudies-literature
Project description:22q11.2 deletion syndrome is characterised by a well defined microdeletion that is associated with a high risk of neuropsychiatric disorders, including intellectual disability, schizophrenia, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety disorders, seizures and epilepsy, and early-onset Parkinson's disease. Preclinical and clinical data reveal substantial variability of the neuropsychiatric phenotype despite the shared underlying deletion in this genetic model. Factors that might explain this variability include genetic background effects, additional rare pathogenic variants, and potential regulatory functions of some genes in the 22q11.2 deletion region. These factors might also be relevant to the pathophysiology of these neuropsychiatric disorders in the general population. We review studies that might provide insight into pathophysiological mechanisms underlying the expression of neuropsychiatric disorders in 22q11.2 deletion syndrome, and potential implications for these common disorders in the general (non-deleted) population. The recurrent hemizygous 22q11.2 deletion, associated with 22q11.2 deletion syndrome, has attracted attention as a genetic model for common neuropsychiatric disorders because of its association with substantially increased risk of such disorders.1 Studying such a model has many advantages. First, 22q11.2 deletion has been genetically well characterised.2 Second, most genes present in the region typically deleted at the 22q11.2 locus are expressed in the brain.3-5 Third, genetic diagnosis might be made early in life, long before recognisable neuropsychiatric disorders have emerged. Thus, this genetic condition offers a unique opportunity for early intervention, and monitoring individuals with 22q11.2 deletion syndrome throughout life could provide important information on factors contributing to disease risk and protection. Despite the commonly deleted region being shared by about 90% of individuals with 22q11.2 deletion syndrome, neuropsychiatric outcomes are highly variable between individuals and across the lifespan. A clear link remains to be established between genotype and phenotype.3,5 In this Review, we summarise preclinical and clinical studies investigating biological mechanisms in 22q11.2 deletion syndrome, with a focus on those that might provide insight into mechanisms underlying neuropsychiatric disorders in 22q11.2 deletion syndrome and in the general population.
| S-EPMC7008533 | biostudies-literature
Project description:The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric disorder caused by meiotic chromosome rearrangements. One of the goals of this review is to summarize the current state of basic research studies of 22q11.2DS. It highlights efforts to understand the mechanisms responsible for the 22q11.2 deletion that occurs in meiosis. This mechanism involves the four sets of low copy repeats (LCR22) that are dispersed in the 22q11.2 region and the deletion is mediated by nonallelic homologous recombination events. This review also highlights selected genes mapping to the 22q11.2 region that may contribute to the typical clinical findings associated with the disorder and explain that mutations in genes on the remaining allele can uncover rare recessive conditions. Another important aspect of 22q11.2DS is the existence of phenotypic heterogeneity. While some patients are mildly affected, others have severe medical, cognitive, and/or psychiatric challenges. Variability may be due in part to the presence of genetic modifiers. This review discusses current genome-wide efforts to identify such modifiers that could shed light on molecular pathways required for normal human development, cognition or behavior.
| S-EPMC6214629 | biostudies-literature
Project description:Background:22q11.2 deletion syndrome (22q11.2DS) is a multisystem condition associated with an increased risk of early-onset Parkinson's disease (PD). Methods:We review the clinical, neuroimaging, and neuropathological observations, as well as diagnostic challenges, of PD in 22q11.2DS. We conducted a search of PubMed up until June 1, 2018 and personal files to identify relevant publications. Results:22q11.2DS-associated PD is responsible for approximately 0.5% of early-onset PD. The hallmark motor symptoms and neuropathology of PD, and typical findings of reduced striatal dopamine transporter binding with molecular imaging, are present in 22q11.2DS-associated PD. Mean age at PD onset in 22q11.2DS is relatively young (?40 years). Patients with 22q11.2DS-associated PD show a good response to levodopa. Conclusions:Further recognition of 22q11.2DS and study of PD in people with 22q11.2DS could provide insights into the mechanisms that cause PD in the general population. 22q11.2DS may serve as an identifiable PD model to study prodromal PD and disease-modifying treatments.
| S-EPMC6335527 | biostudies-literature