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1.
Am J Psychiatry ; : appiajp201919060583, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32046535

RESUMO

OBJECTIVE: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group. METHODS: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female). RESULTS: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. CONCLUSIONS: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

2.
Mol Psychiatry ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015465

RESUMO

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

3.
Genet Med ; 22(2): 326-335, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31474763

RESUMO

PURPOSE: The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion in humans, with highly variable phenotypic expression. Whereas congenital heart defects, palatal anomalies, immunodeficiency, hypoparathyroidism, and neuropsychiatric conditions are observed in over 50% of patients with 22q11DS, a subset of patients present with additional "atypical" findings such as craniosynostosis and anorectal malformations. Recently, pathogenic variants in the CDC45 (Cell Division Cycle protein 45) gene, located within the LCR22A-LCR22B region of chromosome 22q11.2, were noted to be involved in the pathogenesis of craniosynostosis. METHODS: We performed next-generation sequencing on DNA from 15 patients with 22q11.2DS and atypical phenotypic features such as craniosynostosis, short stature, skeletal differences, and anorectal malformations. RESULTS: We identified four novel rare nonsynonymous variants in CDC45 in 5/15 patients with 22q11.2DS and craniosynostosis and/or other atypical findings. CONCLUSION: This study supports CDC45 as a causative gene in craniosynostosis, as well as a number of other anomalies. We suggest that this association results in a condition independent of Meier-Gorlin syndrome, perhaps representing a novel condition and/or a cause of features associated with Baller-Gerold syndrome. In addition, this work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to pathogenic variants on the nondeleted chromosome.

4.
Am J Hum Genet ; 106(1): 26-40, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31870554

RESUMO

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.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Cardiopatias Congênitas/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Cardiopatias Congênitas/patologia , Humanos , Desequilíbrio de Ligação , Masculino , Fenótipo , Duplicações Segmentares Genômicas
5.
Genome Res ; 29(9): 1389-1401, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31481461

RESUMO

Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.


Assuntos
Síndrome da Deleção 22q11/genética , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 22/genética , Sequências Repetitivas de Ácido Nucleico , Animais , Linhagem Celular , Instabilidade Cromossômica , Evolução Molecular , Humanos , Hibridização in Situ Fluorescente , Primatas/genética
7.
Birth Defects Res ; 111(13): 888-905, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31222980

RESUMO

Over 50% of patients with 22q11.2 deletion syndrome (DS) have a conotruncal or related cardiac defect (CTRD). We hypothesized that similar genetic variants, developmental pathways and biological functions, contribute to disease risk for CTRD in patients without a 22q11.2 deletion (ND-CTRD) and with a 22q11.2 deletion (DS-CTRD). To test this hypothesis, we performed rare CNV (rCNV)-based analyses on 630 ND-CTRD cases and 602 DS-CTRD cases with comparable cardiac lesions separately and jointly. First, we detected a collection of heart development related pathways from Gene Ontology and Mammalian Phenotype Ontology analysis. We then constructed gene regulation networks using unique genes collected from the rCNVs found in the ND-CTRD and DS-CTRD cohorts. These gene networks were clustered and their predicted functions were examined. We further investigated expression patterns of those unique genes using publicly available mouse embryo microarray expression data from single-cell embryos to fully developed hearts. By these bioinformatics approaches, we identified a commonly shared gene expression pattern in both the ND-CTRD and DS-CTRD cohorts. Computational analysis of gene functions characterized with this expression pattern revealed a collection of significantly enriched terms related to cardiovascular development. By our combined analysis of rCNVs in the ND-CTRD and DS-CTRD cohorts, a group of statistically significant shared pathways, biological functions, and gene expression patterns were identified that can be tested in future studies for their biological relevance.

8.
Schizophr Res ; 204: 320-325, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30093352

RESUMO

Individuals with 22q11.2 Deletion Syndrome (22q11.2DS) are at substantially heightened risk for psychosis. Thus, prevention and early intervention strategies that target the antecedents of psychosis in this high-risk group are a clinical priority. Attention Deficit Hyperactivity Disorder (ADHD) is one the most prevalent psychiatric disorders in children with 22q11.2DS, particularly the inattentive subtype. The aim of this study was to test the hypothesis that ADHD inattention symptoms predict later psychotic symptoms and/or psychotic disorder in those with 22q11.2DS. 250 children and adolescents with 22q11.2DS without psychotic symptoms at baseline took part in a longitudinal study. Assessments were performed using well-validated structured diagnostic instruments at two time points (T1 (mean age = 11.2, SD = 3.1) and T2 (mean age = 14.3, SD = 3.6)). Inattention symptoms at T1 were associated with development of psychotic symptoms at T2 (OR:1.2, p = 0.01) but weak associations were found with development of psychotic disorder (OR:1.2, p = 0.15). ADHD diagnosis at T1 was strongly associated with development of psychotic symptoms at T2 (OR:4.5, p < 0.001) and psychotic disorder (OR:5.9, p = 0.02). Our findings that inattention symptoms and the diagnosis of ADHD are associated with subsequent psychotic outcomes in 22q11.2DS have important clinical implications. Future studies examining the effects of stimulant and other ADHD treatments on individuals with 22q11.2DS are warranted.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Progressão da Doença , Transtornos Psicóticos/fisiopatologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Criança , Síndrome de DiGeorge/complicações , Feminino , Humanos , Estudos Longitudinais , Masculino , Transtornos Psicóticos/etiologia
9.
Cytogenet Genome Res ; 156(4): 185-190, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30566958

RESUMO

The AT-rich repeat on chromosome 22q11.2 is known to be involved in the recurrent constitutional t(11;22)(q23;q11.2). Segregation of this translocation has been reported in several hundred families, but a de novo translocation event has been identified in only 8 cases, and everytime the translocation originated in paternal germ-line chromosomes. Further, de novo t(11;22) rearrangements have been detected in the sperm of healthy males, leading to the hypothesis that it occurs somewhere along the meiosis-spermatogenesis pathway. This report describes a woman whose constitutional karyotype revealed mosaicism for the recurrent t(11;22) and the subsequent testing performed to determine the origin of the translocation event. Karyotype analysis, translocation-specific PCR, human identity testing, and a SNP genotyping array were performed to detect mosaicism and/or chimerism. As a result, the SNP genotyping array revealed no evidence for mosaicism in genomic DNA beyond mosaicism for the balanced t(11;22). Human identity testing and the SNP genotyping array ruled out chimerism. PCR of the translocation breakpoint followed by sequencing confirmed that the translocation had occurred at the typical t(11;22) breakpoints. In conclusion, these results indicate that the translocation occurred post-fertilization, providing the first evidence of a de novo t(11;22)(q23;q11.2) occurring in a maternal mitotic environment.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Translocação Genética , Aborto Espontâneo/genética , Adulto , Feminino , Humanos , Cariótipo , Mosaicismo , Síndrome do Ovário Policístico/genética , Análise de Sequência de DNA
10.
Am J Med Genet A ; 176(10): 2167-2171, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30380188

RESUMO

Hypocalcemia has been reported in ~50% of patients 22q11.2DS and calcium regulation is known to play a role in neuronal development and synaptic plasticity. Because calcium ions play a role in neuronal function and development, we hypothesized that hypocalcemia would be associated with adverse effects on full scale IQ index (FSIQ) in patients with 22q11.2DS. A retrospective chart review cataloguing the presence or absence of hypocalcemia in 1073 subjects with a laboratory confirmed chromosome 22q11.2 deletion evaluated at the Children's Hospital of Philadelphia was conducted. 852/1073 patients had an endocrinology evaluation with laboratory confirmed calcium levels. 466/852 (54.7%) had a diagnosis of hypocalcemia. 265/1073 subjects ranging from 0 to 51 years of age had both calcium levels measured and a neuropsychological evaluation yielding a FSIQ. The mean FSIQ for 146/265 patients with hypocalcemia was 77.09 (SD = 13.56) and the mean FSIQ for 119/265 patients with normocalcemia was 77.27 (SD = 14.25). The distribution of patients with intellectual disability (ID) (FSIQ<69), borderline IQ (FSIQ 70-79), and average IQ (FSIQ>80) between the hypocalcemic and normocalcemic groups was not statistically significant (χ2 = 0.2676, p = 0.8748). Neonatal hypocalcemic seizures were not found to be associated with ID. We found no difference in FSIQ between the hypocalcemic and non-hypocalcemic patients with 22q11.2DS. As our findings differ from a previous report in adult subjects, we speculate that this may reflect a potential benefit from early treatment of hypocalcemia and may support early 22q11.2 deletion detection in order to offer prompt diagnosis and subsequent treatment of hypocalcemia.


Assuntos
Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/etiologia , Hipocalcemia/psicologia , Testes de Inteligência , Adolescente , Adulto , Cálcio/sangue , Criança , Pré-Escolar , Deleção Cromossômica , Síndrome de DiGeorge/psicologia , Feminino , Humanos , Hipocalcemia/etiologia , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Escalas de Wechsler
11.
Am J Med Genet A ; 176(10): 2058-2069, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30380191

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome-specific, low copy repeat (LCR)-mediated copy-number losses of chromosome 22q11. The Children's Hospital of Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A-LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full-scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age.


Assuntos
Síndrome de DiGeorge/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 22 , Comorbidade , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/epidemiologia , Feminino , Gastroenteropatias/etiologia , Cardiopatias Congênitas/etiologia , Humanos , Estudos Longitudinais , Masculino , Mortalidade , Philadelphia/epidemiologia , Transição para Assistência do Adulto
12.
Am J Med Genet A ; 176(10): 2070-2081, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30380194

RESUMO

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.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 22 , Síndrome de DiGeorge/genética , Mutação , Deleção Cromossômica , Síndrome de DiGeorge/etiologia , Genes Recessivos , Testes Genéticos , Humanos , Meiose
13.
Am J Med Genet B Neuropsychiatr Genet ; 177(8): 765-773, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30444066

RESUMO

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with impairment in multiple domains of cognition and risk for several psychiatric disorders. Musical auditory processing is highly heritable, and is impaired in individuals with schizophrenia and other neurodevelopmental disorders, but has never been studied in 22q11DS, notwithstanding anecdotal evidence of its sparing. We aimed to characterize musical auditory processing in 22q11DS and explore potential relationships with other cognitive domains, musical engagement, and psychiatric disorders. The Distorted Tunes Task and Global Musical Sophistication Index were used to assess pitch discrimination and general musical engagement in 58 individuals with 22q11DS aged 8-29 years. Psychopathology was assessed with sections from the modified Schedule for Affective Disorders and Schizophrenia for School-Age Children and the Structured Interview for Prodromal Syndromes. The Penn computerized neurocognitive battery (CNB) examined four domains of cognition (executive functioning, episodic memory, complex cognition, and social cognition). Significant musical auditory processing impairment and reduced musical engagement were found in individuals with 22q11DS. However, deficits in musical auditory processing were not associated with reduced musical engagement. After covarying for age and sex, episodic memory and overall CNB performance accuracy were significantly related to performance in musical auditory processing. There were no relationships between musical auditory processing and presence of any psychiatric diagnoses. Individuals with 22q11DS experience significant deficits in musical auditory processing and reduced musical engagement. Pitch discrimination is associated with overall cognitive ability, but appears to be largely independent of psychiatric illness.


Assuntos
Percepção Auditiva/genética , Cognição/fisiologia , Síndrome de DiGeorge/fisiopatologia , Síndrome da Deleção 22q11/genética , Síndrome da Deleção 22q11/fisiopatologia , Adolescente , Adulto , Transtornos da Percepção Auditiva/genética , Criança , Síndrome de DiGeorge/genética , Feminino , Humanos , Masculino , Transtornos do Humor/genética , Música/psicologia , Testes Neuropsicológicos , Sintomas Prodrômicos , Psicopatologia/métodos , Transtornos Psicóticos/genética , Esquizofrenia/genética , Comportamento Social , Adulto Jovem
14.
Am J Med Genet A ; 176(10): 2172-2181, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30289625

RESUMO

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.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22 , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/psicologia , Adolescente , Adulto , Criança , Feminino , Humanos , Deficiência Intelectual/genética , Testes de Inteligência , Masculino
16.
Am J Med Genet A ; 176(10): 2203-2214, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30244528

RESUMO

22q11.2 deletion syndrome (DS) is the most frequent copy number variant (CNV) affecting ~1/1,000 fetuses and ~1/2,000-4,000 children, resulting in recognizable but variable findings across multiple organ systems. Patients with atypical features should prompt consideration of coexisting diagnoses due to additional genome-wide mutations, CNVs, or mutations/CNVs on the other allele, unmasking autosomal recessive conditions. Importantly, a dual diagnosis compounds symptoms and impacts management. We previously reported seven patients with 22q11.2DS and: SCID, Trisomy 8 mosaicism, Bernard-Soulier, and CEDNIK syndromes. Here we present six additional unreported patients with 22q11.2DS and concurrent diagnoses. Records on 1,422 patients with 22q11.2DS, identified via FISH, microarray, or MLPA, followed in our 22q and You Center at the Children's Hospital of Philadelphia (CHOP) were reviewed to identify a dual diagnosis. In addition to our seven previously reported cases, we identified an additional six with 22q11.2DS and another coexisting condition identified via: molecular/cytogenetic studies, newborn screening, coagulation factor studies, or enzyme testing; these include CHARGE syndrome (CHD7 mutation), cystic fibrosis, a maternally inherited 17q12 deletion, G6PD deficiency, von Willebrand disease, and 1q21.1 deletion, resulting in an incidence of dual diagnoses at our center of 0.9%. The range of dual diagnoses identified in our cohort is notable, medically actionable, and may alter long-term outcome and recurrence risk counseling. Thus, our findings may support testing patients with 22q11.2DS using a combination of microarray, mutational analysis of the other allele/WES, to ensure appropriate personalized care, as formulating medical management decisions hinges on establishing the correct diagnoses in their entirety.


Assuntos
Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/genética , Adolescente , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
17.
Schizophr Res ; 202: 113-119, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30007867

RESUMO

Olfactory functioning is a promising biomarker for psychosis in 22q11.2 deletion syndrome (22q11DS) but has not been well studied to date. This is a pilot effort to evaluate the potential for tests of olfactory functioning to contribute to risk and resilience prediction in 22q11DS, and is the first study to evaluate relationships among olfactory deficits, cognition and psychosis-spectrum symptoms. Odor identification and discrimination were evaluated in 32 individuals with 22q11DS and 110 healthy comparison subjects (HC). Individuals with 22q11DS also underwent cognitive testing with the Penn Computerized Neurocognitive Battery, which evaluates executive functioning, episodic memory, complex cognition, and social cognition. Positive, negative, disorganized and general psychosis-spectrum symptoms were rated according to the Scale of Prodromal Symptoms. Age-normalized scores were calculated for odor identification and discrimination based on normative data. Both odor identification (p < 0.001, Cohen's d = -2.15, 95% CI [-2.62, -1.68]) and discrimination (p < 0.001, Cohen's d = -1.81, 95% CI [-2.26, -1.35]) were significantly impaired in 22q11DS relative to HC. There were no sex differences in either group. Neither odor identification nor discrimination was correlated with overall cognition or any specific cognitive domain in 22q11DS. Impairment in odor discrimination was correlated with higher negative and overall psychosis-spectrum symptoms. There was no significant effect of catechol-O-methyltransferase Val(158)Met genotype or presence of velopharyngeal insufficiency on olfactory functioning. Olfactory deficits, particularly olfactory discrimination, are robust in 22q11DS and appear to be independent of cognitive deficits. They are also clinically relevant and related to psychosis-spectrum symptoms. Olfactory functioning appears to be a promising biomarker for psychosis in 22q11DS.


Assuntos
Síndrome da Deleção 22q11/diagnóstico , Disfunção Cognitiva/diagnóstico , Transtornos do Olfato/diagnóstico , Transtornos Psicóticos/diagnóstico , Síndrome da Deleção 22q11/complicações , Síndrome da Deleção 22q11/fisiopatologia , Adolescente , Adulto , Biomarcadores , Criança , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Transtornos do Olfato/etiologia , Transtornos do Olfato/fisiopatologia , Projetos Piloto , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/fisiopatologia , Adulto Jovem
18.
Hum Mol Genet ; 27(11): 1847-1857, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29509905

RESUMO

Non-allelic homologous recombination events on chromosome 22q11.2 during meiosis can result in either the deletion (22q11.2DS) or duplication (22q11.2DupS) syndrome. Although the spectrum and frequency of congenital heart disease (CHD) are known for 22q11.2DS, there is less known for 22q11.2DupS. We now evaluated cardiac phenotypes in 235 subjects with 22q11.2DupS including 102 subjects we collected and 133 subjects that were previously reported as a confirmation and found 25% have CHD, mostly affecting the cardiac outflow tract (OFT). Previous studies have shown that global loss or gain of function (LOF; GOF) of mouse Tbx1, encoding a T-box transcription factor mapping to the region of synteny to 22q11.2, results in similar OFT defects. To further evaluate Tbx1 function in the progenitor cells forming the cardiac OFT, termed the anterior heart field, Tbx1 was overexpressed using the Mef2c-AHF-Cre driver (Tbx1 GOF). Here we found that all resulting conditional GOF embryos had a persistent truncus arteriosus (PTA), similar to what was previously reported for conditional Tbx1 LOF mutant embryos. To understand the basis for the PTA in the conditional GOF embryos, we found that proliferation in the Mef2c-AHF-Cre lineage cells before migrating to the heart, was reduced and critical genes were oppositely changed in this tissue in Tbx1 GOF embryos versus conditional LOF embryos. These results suggest that a major function of TBX1 in the AHF is to maintain the normal balance of expression of key cardiac developmental genes required to form the aorta and pulmonary trunk, which is disrupted in 22q11.2DS and 22q11.2DupS.


Assuntos
Desenvolvimento Embrionário/genética , Cardiopatias Congênitas/genética , Coração/crescimento & desenvolvimento , Proteínas com Domínio T/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Animais , Aorta/fisiopatologia , Duplicação Cromossômica/genética , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/genética , Coração/fisiopatologia , Cardiopatias Congênitas/patologia , Recombinação Homóloga/genética , Humanos , Meiose/genética , Camundongos , Mutação , Persistência do Tronco Arterial/genética , Persistência do Tronco Arterial/fisiopatologia
19.
Hum Mol Genet ; 27(7): 1150-1163, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29361080

RESUMO

Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22A+, resulting in LCR22A+-B or LCR22A+-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22A+ region with a breakpoint in LCR22A+. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-A+ duplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22A+ maps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.


Assuntos
Alelos , Mapeamento Cromossômico , Síndrome de DiGeorge/genética , Meiose , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Feminino , Humanos , Masculino
20.
Schizophr Bull ; 44(4): 824-833, 2018 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-29040797

RESUMO

OBJECTIVE: 22q11.2 Deletion Syndrome (22q11.2DS) is associated with increased risk for schizophrenia in adulthood while Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent diagnosis in childhood. Inattention symptoms are pronounced in 22q11.2DS and given that attentional impairment is a core feature of schizophrenia, inattention symptoms may reflect underlying ADHD, psychosis, or both. We investigate whether inattention is associated with psychosis in 22q11.2DS and in other groups at risk for psychosis but without the deletion (ND) (idiopathic clinical risk and first degree family members of individuals with schizophrenia). METHODS: One hundred thirty-seven individuals with 22q11.2DS (mean age: 14.0), 84 ND individuals with subthreshold psychosis (mean age: 16.9) and 31 ND individuals with family history of psychosis (mean age: 17.0) were included in the study. Psychopathology was assessed using research diagnostic assessments. RESULTS: ADHD total symptoms were associated with overall levels of subthreshold psychosis symptoms in 22q11.2DS (ß = .8, P = .04). Inattention symptoms were specifically associated with positive (ß = .5, P = .004), negative (ß = .5, P = .03), and disorganized (ß = .5, P < .001) symptoms, while hyperactivity-impulsivity symptoms were associated with disorganized symptoms (ß = .5, P = .01). The prevalence of ADHD inattention symptoms was higher in 22q11.2DS with subthreshold psychosis compared to ND individuals with subthreshold psychosis (P < .001), even when adjusting for cognitive impairment and overall psychopathology. The pattern was similar when comparing individuals with 22q11.2DS and ND individuals with family history of psychosis. CONCLUSIONS: This is the first study to examine the associations between ADHD symptoms and psychosis in 22q11.2DS. Our findings support a potentially important role of ADHD inattention symptoms in psychosis in 22q11.2DS.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Comportamento Impulsivo/fisiologia , Transtornos Psicóticos/fisiopatologia , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Comorbidade , Síndrome de DiGeorge/epidemiologia , Feminino , Humanos , Masculino , Transtornos Psicóticos/epidemiologia , Adulto Jovem
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