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European Journal of Medical Genetics Feb 2022The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications... (Review)
Review
The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications encompass the LCR-A-to-D region but atypical duplications of various sizes have also been reported. These duplications are responsible for highly variable phenotypes with incomplete penetrance and expressivity, which is challenging for adequate genetic counselling, especially in the prenatal period. To better delineate prenatal phenotypes associated with these CNVs, we report here a clinical and molecular description of twelve cases (9 foetuses and 3 deceased new-borns babies) carrying recurrent 22q11 duplications (diagnosed via aCGH), along with a review of the existing literature. 22q11 duplications were inherited from an apparently healthy parent in almost 60% of the cases. Other CNVs were diagnosed for 8% of the cases. Increased nuchal translucency and cardiac anomalies (CHD) were the most prominent phenotypes observed, along with mild renal and skeletal anomalies. Duplications encompassing the LCR-C-to-D region (and the CRKL gene) seemed more likely to generate CHDs and renal malformations. Cleft lip/palate were observed in foetuses with duplications encompassing the LCR-A-to-B region or the SPECC1L gene, as previously suggested. However, genotype-phenotype correlations remain difficult to ascertain. Second-hit point variants, epigenetic or environmental variations could play a role in the phenotypic variability of 22q11 duplications, but remain a challenge for assessment in the short period of pregnancy.
Topics: Abnormalities, Multiple; Adaptor Proteins, Signal Transducing; Chromosome Duplication; Chromosomes, Human, Pair 22; DiGeorge Syndrome; Female; Fetus; Humans; Infant, Newborn; Male; Phenotype; Phosphoproteins
PubMed: 35026468
DOI: 10.1016/j.ejmg.2022.104422 -
American Journal of Medical Genetics.... Feb 2022The 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disorder with an estimated prevalence of 1:3000 live births. Manifestations show a marked variability in...
The 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disorder with an estimated prevalence of 1:3000 live births. Manifestations show a marked variability in expression and include speech- and language delay, intellectual disability, and neuropsychiatric disorders. We aim to provide an overview of ocular findings in 22q11.2DS in order to optimize recommendations for ophthalmic screening. We combined results from a systematic literature review with results from a multicenter cross-sectional study of patients with 22q11.2DS who were assessed by an ophthalmologist. Our systematic literature search yielded four articles, describing 270 patients. We included 132 patients in our cross-sectional study (median age 8.9 [range 0-56] years). Most reported ocular findings were retinal vascular tortuosity (32%-78%), posterior embryotoxon (22%-50%), eye lid hooding (20%-67%), strabismus (12%-36%), amblyopia (2%-11%), ptosis (4%-6%), and refractive errors, of which hyperopia (6%-48%) and astigmatism (3%-23%) were most common. Visual acuity was (near) normal in most patients (91%-94%). Refractive errors, strabismus, and amblyopia are treatable conditions that are frequently present in patients with 22q11.2DS and should be corrected at an early stage. Therefore, in 22q11.2DS, we recommend ophthalmic and orthoptic screening at the age of 3 years or at diagnosis, and a low-threshold referral in adults.
Topics: Adolescent; Adult; Child; Child, Preschool; Cross-Sectional Studies; DiGeorge Syndrome; Eye Abnormalities; Humans; Infant; Infant, Newborn; Intellectual Disability; Language; Middle Aged; Multicenter Studies as Topic; Young Adult
PubMed: 34773366
DOI: 10.1002/ajmg.a.62556 -
Frontiers in Pediatrics 2021Inflammatory bowel disease (IBD) is a typical polygenic disorder and less frequently shows a monogenic origin. Furthermore, IBD can originate in the context of specific...
Inflammatory bowel disease (IBD) is a typical polygenic disorder and less frequently shows a monogenic origin. Furthermore, IBD can originate in the context of specific genetic syndromes associated with a risk of autoimmune disorders. We aimed to systematically evaluate the prevalence of IBD in specific genetic syndromes and to review the clinical characteristics of the published cases. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, studies describing patients with IBD and a genetic syndrome and/or studies indicating the prevalence or incidence of IBD in subjects with a genetic syndrome were included. Forty-six studies describing a total of 67 cases of IBD in six genetic syndromes and two personally assessed unpublished cases were included in the review. The majority of cases were associated with Turner syndrome (TS) (38 cases), Down syndrome (DS) (18 cases) and neurofibromatosis type 1 (NF1) (8 cases). Sporadic cases were described in DiGeorge syndrome (2), Kabuki syndrome (2), and Williams syndrome (1). The prevalence of IBD ranged from 0.67 to 4% in TS and from 0.2 to 1.57% in DS. The incidence of IBD was increased in TS and DS compared to the general population. Eight cases of IBD in TS had a severe/lethal course, many of which described before the year 2000. Two IBD cases in DS were particularly severe. Evidence of a greater prevalence of IBD is accumulating in TS, DS, and NF1. Management of IBD in patients with these genetic conditions should consider the presence of comorbidities and possible drug toxicities. : PROSPERO, identifier: CRD42021249820.
PubMed: 34765575
DOI: 10.3389/fped.2021.742830 -
European Neuropsychopharmacology : the... Nov 202122q11.2 deletion syndrome (22q11DS) is a severe genetic syndrome characterized by cognitive deficits and neuropsychiatric disorders, particularly schizophrenia.... (Review)
Review
22q11.2 deletion syndrome (22q11DS) is a severe genetic syndrome characterized by cognitive deficits and neuropsychiatric disorders, particularly schizophrenia. Neuroimaging alterations have been extensively reported in 22q11DS, both in gray and white matter structures. However, a considerable variability among the results affects the generalizability of the findings to date. Herein, we reviewed diffusion tensor imaging (DTI) findings in 22q11DS, their association with psychosis and cognition, and the implications of DTI studies on neurodevelopment in 22q11DS. We also investigated differences between 22q11DS and schizophrenic patients without 22q11DS. Using an online search of PubMed and Embase, we identified studies investigating DTI findings in 22q11DS. After selecting eligible studies in accordance with the preferred reporting items for systematic reviews and meta-analyses guideline, we included thirty-one studies. Overall, 22q11DS patients show altered structural connectivity and disrupted microstructural organization of most cortical and subcortical structures and white matter tracts. Moreover, despite a significant heterogeneity in the results, reduced diffusivity measures and elevated fractional anisotropy were observed. However controversial, compared to typically developing children, 22q11DS patients reached the peak of fractional anisotropy (FA) and the trough of radial diffusivity (RD) at an older age, which shows neurodevelopmental delay. DTI measures were also associated with psychotic symptoms and cognitive deficits. In conclusion, this study provides a comprehensive review of microstructural alterations in 22q11DS. Future larger investigations on this syndrome could potentially lead to the detection of early diagnostic imaging markers for genetically induced schizophrenia, thus improving the treatment and, ultimately, the outcome.
Topics: Anisotropy; Brain; Child; DiGeorge Syndrome; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Humans; White Matter
PubMed: 34358796
DOI: 10.1016/j.euroneuro.2021.07.004 -
Journal of Developmental and Behavioral...22q11.2 deletion syndrome (22q11DS) is a common genetic deletion syndrome associated with psychiatric disorders and developmental delays. A significant amount of 22q11DS...
OBJECTIVE
22q11.2 deletion syndrome (22q11DS) is a common genetic deletion syndrome associated with psychiatric disorders and developmental delays. A significant amount of 22q11DS research literature is published annually; here, we focus exclusively on longitudinal data that have been published in the past 5 years regarding psychiatric disorders and/or cognitive and social development. After a review, areas for future research consideration and clinical recommendations are presented.
METHODS
Articles were reviewed and organized in adherence with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for conducting systematic reviews. The literature search identified 852 studies, and 22 studies met inclusion criteria.
RESULTS
Longitudinal study findings indicate that developmental considerations for youth with 22q11DS should focus on the primacy and enduring nature of social and executive functioning deficits, attention-deficit/hyperactivity disorder, anxiety, and negative symptoms of psychosis.
CONCLUSION
From the diathesis of physiological conditions and genetic variance, 22q11DS and its associated phenotype of persistent cognitive deficits, comorbid psychiatric disorders, and social impairments likely conspire to increase the risk for stress in adolescence. The diathesis-stress framework, along with chronic stress, increases psychosis risk in individuals with 22q11DS. The existing literature has a heavy focus on the impact of the deletion on individual skills and attributes, such as cognition, but lacks information on the impact of the environment. Future 22q11DS research should consider specific aspects of social functioning, including interactions with parenting styles and family communication, as well as high demands in educational settings, as possible risk factors for psychosis.
Topics: Adolescent; Anxiety Disorders; Cognition; DiGeorge Syndrome; Humans; Longitudinal Studies; Psychotic Disorders
PubMed: 34110308
DOI: 10.1097/DBP.0000000000000927 -
Movement Disorders : Official Journal... Sep 2021The landscape of genetic forms of Parkinson's diseases (PD) has grown exponentially in recent years. Today, around 10% of PD cases are estimated to be of genetic... (Review)
Review
The landscape of genetic forms of Parkinson's diseases (PD) has grown exponentially in recent years. Today, around 10% of PD cases are estimated to be of genetic etiology. However, the link between parkinsonism or tremor and chromosome disorders, both numerical and structural, has been neglected. We reviewed the occurrence and characteristics of parkinsonism and tremor syndromes in patients with chromosomic disorders. We searched PubMed for articles published until December 2018, using the non-MESH terms "Chromosomopathy," "karyotype," "chromosome," "aneuploidy," "deletion," "inversion," "insertion," "duplication," and "Parkinson," "Parkinsonism," "Tremor," and "Parkinsonian disorder." We restricted the search to human studies and selected articles for further analysis after abstract review. Tremor syndromes in which patients had another possible clinical reason for syndromes were excluded, as well as tremor syndromes associated with point mutations, imprinting syndromes, and patients presenting with other hyperkinetic disorders. Fifty-four articles were reviewed. Aneuploidies of sex chromosomes were the most common chromosomopathy. These patients more commonly exhibited postural and kinetic tremor, often meeting the description of essential tremor. In structural chromosomopathies, the most frequent association was PD and 22q11.2 deletion syndrome, but we found case reports and case series of several additional deletion and duplication syndromes. © 2021 International Parkinson and Movement Disorder Society.
Topics: DiGeorge Syndrome; Essential Tremor; Humans; Parkinson Disease; Parkinsonian Disorders; Tremor
PubMed: 34056754
DOI: 10.1002/mds.28663 -
BMC Psychiatry Mar 2021The 22q11.2 deletion syndrome (22q11DS) is a genetic syndrome that results in a highly variable profile of affected individuals of which impairments in the social domain...
BACKGROUND
The 22q11.2 deletion syndrome (22q11DS) is a genetic syndrome that results in a highly variable profile of affected individuals of which impairments in the social domain and increased psychopathology are the most prominent. Notably, 25-30% of affected individuals eventually develop schizophrenia/psychosis, predisposing persons with the syndrome to increased risk for this disorder. Because social cognition is considered to underlie social behavior and to be related to psychopathology, this systematic review investigated social cognition in individuals with 22q11DS and examined reported links across its domains with psychopathology and social outcomes. This can provide the basis for a closer understanding of the path from risk to disorder and will inform on the specific domains that can be targeted with preventive intervention strategies.
METHOD
Systematic literature review of studies that reported the links between social cognitive domains and psychopathology and/or social outcomes in individuals with 22q11DS. Electronic databases searched were PubMed and PsycINFO.
RESULTS
Defined eligibility criteria identified a total of ten studies to be included in the present review. Selected studies investigated links between two domains of social cognition (emotion processing and theory of mind (ToM)) and psychopathology and/or social outcomes. With respect to the links to psychopathology, two aspects of social cognition were related primarily to negative symptoms. Results regarding the associations to positive and emotional symptoms (anxiety/depression) are limited and require further investigation. Even though both aspects of social cognition were associated with social outcomes, several studies also found no links between these two domains. Both reports invite for an additional examination of reported results and specific considerations regarding chosen constructs.
CONCLUSION
Although equivocal, results of the present review provide sufficient evidence that social cognition is a useful domain for the closer elucidation of clinical outcomes and social difficulties in this population. At the same time, longitudinal studies and consideration of other variables are also necessary for a timely understanding of affected persons in this respect.
Topics: Cognition; DiGeorge Syndrome; Humans; Psychopathology; Social Behavior; Social Cognition; Theory of Mind
PubMed: 33676445
DOI: 10.1186/s12888-020-02975-5 -
Neuroscience and Biobehavioral Reviews Dec 201922q11.2 deletion syndrome (DS) is considered to be the most robust genetic model of psychosis. In the last decade, there has been increased interest in the brain... (Meta-Analysis)
Meta-Analysis
22q11.2 deletion syndrome (DS) is considered to be the most robust genetic model of psychosis. In the last decade, there has been increased interest in the brain abnormalities associated with these genetic changes. Most imaging findings in this population come from small samples. This increases the risk of reporting spurious effects that reflect the idiosyncrasies of each study. Thus, the current work is aimed at identifying whether there are spatially consistent structural and functional brain abnormalities in individuals with 22q11.2 DS through (i) a comprehensive label-based systematic review and (ii) a coordinate-based meta-analysis of magnetic resonance imaging studies. The systematic review identified the frontal middle gyri, posterior cingulum, right cuneus and bilateral precuneus as the most affected regions. The meta-analysis revealed consistent abnormalities in the bilateral inferior parietal lobe, right precuneus, right superior temporal gyrus and posterior cingulate cortex. This study provides an important starting point for future research as it sheds light on possible genetically determined psychosis susceptibility regions.
Topics: Brain; Brain Mapping; DiGeorge Syndrome; Humans; Magnetic Resonance Imaging; Nerve Net
PubMed: 31493414
DOI: 10.1016/j.neubiorev.2019.09.004 -
American Journal of Medical Genetics.... Nov 2019The 22q11.2 deletion syndrome (22q11.2DS) is a multisystem condition and the most prevalent microdeletion syndrome in humans. Approximately 25% of individuals with... (Meta-Analysis)
Meta-Analysis
The 22q11.2 deletion syndrome (22q11.2DS) is a multisystem condition and the most prevalent microdeletion syndrome in humans. Approximately 25% of individuals with 22q11.2DS receive antipsychotic treatment. To assess whether patients with 22q11.2DS are vulnerable to adverse effects of antipsychotic medication, we carried out a literature review. A systematic search strategy was performed using PubMed (Medline), Embase, PsychInfo, and Cochrane Database of Systematic Reviews. Publications describing adverse effects of antipsychotic medication in patients with 22q11.2DS were included in the review and assessed for their methodological quality. A total of 11 publications reporting on eight trials, cross-sectional or cohort studies, and 30 case reports were included. The most commonly reported adverse effects can be classified into the following categories: movement disorders, weight gain, seizures, cardiac side effects, and cytopenias. Many of these symptoms are manifestations of 22q11.2DS, also in the absence of antipsychotic medication. Based on the reviewed literature, a causal relation between antipsychotic medication and the reported adverse effects could not be established in the majority of cases. Randomized clinical trials are needed to make firm conclusions regarding risk of adverse effects of antipsychotics in patients with 22q11.2DS.
Topics: Antipsychotic Agents; DiGeorge Syndrome; Diagnosis, Differential; Drug-Related Side Effects and Adverse Reactions; Humans; Phenotype
PubMed: 31407842
DOI: 10.1002/ajmg.a.61324 -
Orphanet Journal of Rare Diseases Aug 2019Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms. The most common congenital anomalies involve the palate in 80% of patients, and the heart in 50-60% of them. The cause of the phenotypic variability is unknown. Patients usually harbor one of three common deletions sizes: 3, 2 and 1.5 Mb, between low copy repeats (LCR) designated A-D, A-C and A-B, respectively. This study aimed to analyze the association between these 3 deletion sizes and the presence of congenital cardiac and/or palatal malformations in individuals with this condition. A systematic review and meta-analysis were conducted, merging relevant published studies with data from Chilean patients to increase statistical power.
RESULTS
Eight articles out of 432 were included; the data from these studies was merged with our own, achieving a total of 1514 and 487 patients to evaluate cardiac and palate malformations, respectively. None of the compared deleted chromosomal segments were statistically associated with cardiac defects (OR: 0.654 [0.408-1.046]; OR : 1.291 [0.860-1.939]) or palate anomalies (OR: 1.731 [0.708-4.234]; OR : 0.628 [0.286-1.382]).
CONCLUSIONS
The lack of association between deletion size and CHD or PA found in this meta-analysis suggests that deletion size does not explain the incomplete penetrance of these 2 major manifestations, and that the critical region for the development of heart and palatal abnormalities is within LCR A-B, the smallest region of overlap among the three deletion sizes.
Topics: Arachnodactyly; Chromosome Deletion; Craniosynostoses; Humans; Marfan Syndrome; Phenotype
PubMed: 31399107
DOI: 10.1186/s13023-019-1170-x