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1.
PLoS Genet ; 15(8): e1008301, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31412026

RESUMO

We investigated whether Tbx1, the gene for 22q11.2 deletion syndrome (22q11.2DS) and Foxi3, both required for segmentation of the pharyngeal apparatus (PA) to individual arches, genetically interact. We found that all Tbx1+/-;Foxi3+/- double heterozygous mouse embryos had thymus and parathyroid gland defects, similar to those in 22q11.2DS patients. We then examined Tbx1 and Foxi3 heterozygous, null as well as conditional Tbx1Cre and Sox172A-iCre/+ null mutant embryos. While Tbx1Cre/+;Foxi3f/f embryos had absent thymus and parathyroid glands, Foxi3-/- and Sox172A-iCre/+;Foxi3f/f endoderm conditional mutant embryos had in addition, interrupted aortic arch type B and retroesophageal origin of the right subclavian artery, which are all features of 22q11.2DS. Tbx1Cre/+;Foxi3f/f embryos had failed invagination of the third pharyngeal pouch with greatly reduced Gcm2 and Foxn1 expression, thereby explaining the absence of thymus and parathyroid glands. Immunofluorescence on tissue sections with E-cadherin and ZO-1 antibodies in wildtype mouse embryos at E8.5-E10.5, revealed that multilayers of epithelial cells form where cells are invaginating as a normal process. We noted that excessive multilayers formed in Foxi3-/-, Sox172A-iCre/+;Foxi3f/f as well as Tbx1 null mutant embryos where invagination should have occurred. Several genes expressed in the PA epithelia were downregulated in both Tbx1 and Foxi3 null mutant embryos including Notch pathway genes Jag1, Hes1, and Hey1, suggesting that they may, along with other genes, act downstream to explain the observed genetic interaction. We found Alcam and Fibronectin extracellular matrix proteins were reduced in expression in Foxi3 null but not Tbx1 null embryos, suggesting that some, but not all of the downstream mechanisms are shared.


Assuntos
Síndrome de DiGeorge/patologia , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas com Domínio T/metabolismo , Animais , Região Branquial/embriologia , Síndrome de DiGeorge/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Endoderma/embriologia , Feminino , Fatores de Transcrição Forkhead/genética , Coração/embriologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Miocárdio/patologia , Proteínas com Domínio T/genética
2.
Eur J Med Genet ; 62(8): 103705, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31229682

RESUMO

22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a hemizygous microdeletion on the long arm of chromosome 22 and is associated with a high risk for psychosis and cognitive impairment. One of the genes located in the deleted region of 22q11DS is Proline Dehydrogenase (PRODH) which is important for conversion of proline to glutamate. Glutamate is the primary excitatory neurotransmitter and is involved in the pathophysiology of psychosis as well as in cognition. Excessive concentrations are toxic. Possibly, neuroprotective drugs modulating glutamatergic neurotransmission could be effective in treating psychotic symptoms and cognitive enhancement in patients with 22q11DS. Riluzole is a potent anti-glutamatergic drug that reduces glutamatergic neurotransmission. Here we report acute (single dose) and long-term effects of riluzole on glutamate and GABA levels in the anterior cingulate cortex (ACC) and striatum (measured with magnetic resonance spectroscopy, 1H-MRS) as well as on psychotic symptoms and cognitive functioning in a medication-free 23-year old woman with 22q11DS. Patient presented with frequent auditory and visual hallucinations and mild paranoid ideas. The 1H-MRS measurements showed that after a single dose riluzole (50 mg), glutamate in the ACC and striatum was reduced whereas striatal GABA increased compared to baseline. Strikingly, hallucinations and paranoia disappeared. Therefore, riluzole treatment was initiated and patient was followed up after 18 months of treatment. At follow-up, patient reported no hallucinations or paranoia and several cognitive functions were improved. Furthermore, glutamate concentrations in the ACC and striatum decreased whereas GABA concentrations increased in the striatum but decreased in the ACC. These results suggests that riluzole may be an effective treatment option for psychotic symptoms and cognitive enhancement in 22q11DS. Results warrant replication in a bigger sample.


Assuntos
Síndrome de DiGeorge/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico , Riluzol/administração & dosagem , Adulto , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Feminino , Ácido Glutâmico/metabolismo , Humanos , Prolina/metabolismo , Prolina Oxidase/genética , Transtornos Psicóticos/genética , Transtornos Psicóticos/patologia , Adulto Jovem
3.
Blood ; 133(24): 2586-2596, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31015189

RESUMO

DiGeorge syndrome (DGS) is a primary immunodeficiency characterized by various degrees of T-cell deficiency. In partial DGS (pDGS), other risk factors could predispose to recurrent infections, autoimmunity, and allergy. The aim of this study was to assess the effect of different factors in the development of infections, autoimmunity, and/or allergy in patients with pDGS. We studied 467 pDGS patients in follow-up at Great Ormond Street Hospital. Using a multivariate approach, we observed that palatal anomalies represent a risk factor for the development of recurrent otitis media with effusion. Gastroesophageal reflux/dysphagia and asthma/rhinitis represent a risk factor for the development of recurrent upper respiratory tract infections. Allergy and autoimmunity were associated with persistently low immunoglobulin M levels and lymphopenia, respectively. Patients with autoimmunity showed lower levels of CD3+, CD3+CD4+, and naïve CD4+CD45RA+CD27+ T lymphocytes compared with pDGS patients without autoimmunity. We also observed that the physiological age-related decline of the T-cell number was slower in pDGS patients compared with age-matched controls. The age-related recovery of the T-cell number depended on a homeostatic peripheral proliferation of T cells, as suggested by an accelerated decline of the naïve T lymphocytes in pDGS as well as a more skewed T-cell repertoire in older pDGS patients. These evidences suggest that premature CD4+ T-cell aging and lymphopenia induced spontaneous peripheral T-cell proliferation might contribute to the pathogenesis of autoimmunity in patients with pDGS. Infections in these patients represent, in most of the cases, a complication of anatomical or gastroenterological anomalies rather than a feature of the underlying immunodeficiency.


Assuntos
Autoimunidade/imunologia , Síndrome de DiGeorge/imunologia , Síndrome de DiGeorge/patologia , Adolescente , Adulto , Autoimunidade/genética , Criança , Pré-Escolar , Síndrome de DiGeorge/complicações , Feminino , Humanos , Lactente , Masculino , Adulto Jovem
4.
Transl Psychiatry ; 9(1): 138, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992427

RESUMO

The 22q11.2 Deletion Syndrome (22q11.2 DS) is one of the highest genetic risk factors for the development of schizophrenia spectrum disorders. In schizophrenia, reduced amplitude of the frequency mismatch negativity (fMMN) has been proposed as a promising neurophysiological marker for progressive brain pathology. In this longitudinal study in 22q11.2 DS, we investigate the progression of fMMN between childhood and adolescence, a vulnerable period for brain maturation. We measured evoked potentials to auditory oddball stimuli in the same sample of 16 patients with 22q11.2 DS and 14 age-matched controls in childhood and adolescence. In addition, we cross-sectionally compared an increased sample of 51 participants with 22q11.2 DS and 50 controls divided into two groups (8-14 and 14-20 years). The reported results are obtained using the fMMN difference waveforms. In the longitudinal design, the 22q11.2 deletion carriers exhibit a significant reduction in amplitude and a change in topographic patterns of the mismatch negativity response from childhood to adolescence. The same effect, reduced mismatch amplitude in adolescence, while preserved during childhood, is observed in the cross-sectional study. These results point towards functional changes within the brain network responsible for the fMMN. In addition, the adolescents with 22q11.2 DS displayed a significant increase in amplitude over central electrodes during the auditory N1 component. No such differences, reduced mismatch response nor increased N1, were observed in the typically developing group. These findings suggest different developmental trajectories of early auditory sensory processing in 22q11.2 DS and functional changes that emerge during the critical period of increased risk for schizophrenia spectrum disorders.


Assuntos
Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/patologia , Potenciais Evocados Auditivos , Lobo Frontal/fisiopatologia , Lateralidade Funcional , Estimulação Acústica , Adolescente , Criança , Estudos Transversais , Progressão da Doença , Eletroencefalografia , Feminino , Humanos , Estudos Longitudinais , Masculino , Esquizofrenia/etiologia
5.
PLoS One ; 14(4): e0211170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30933971

RESUMO

INTRODUCTION AND HYPOTHESIS: Patients with 22q11 deletion syndrome (22q11.2DS) present, in about 75% of cases, typical patterns of cardiac defects, with a particular involvement on the ventricular outflow tract and great arteries. However, in this genetic condition the dimensions of the pulmonary arteries (PAs) never were specifically evaluated. We measured both PAs diameter in patients with 22q11.2DS without cardiac defects, comparing these data to a normal control group. Moreover, we measured the PAs diameter in Tbx1 mutant mice. Finally, a cell fate mapping in Tbx1 mutants was used to study the expression of this gene in the morphogenesis of PAs. METHODS: We evaluated 58 patients with 22q11.2DS without cardiac defects. The control group consisted of 54 healthy subjects, matched for age and sex. All cases underwent a complete transthoracic echocardiography. Moreover, we crossed Tbx1+/- mice and harvested fetuses. We examined the cardiovascular phenotype of 8 wild type (WT), 37 heterozygous (Tbx1+/-) and 6 null fetuses (Tbx1-/-). Finally, we crossed Tbx1Cre/+mice with R26RmT-mG Cre reporter mice to study Tbx1 expression in the pulmonary arteries. RESULTS: The echocardiographic study showed that the mean of the LPA/RPA ratio in 22q11.2DS was smaller (0.80 ± 0.12) than in controls (0.97 ± 0.08; p < 0.0001). Mouse studies resulted in similar data as the size of LPA and RPA was not significantly different in WT embryos, but in Tbx1+/- and Tbx1-/- embryos the LPA was significantly smaller than the RPA in both mutants (P = 0.0016 and 0.0043, respectively). We found that Tbx1 is expressed near the origin of the PAs and in their adventitia. CONCLUSIONS: Children with 22q11.2DS without cardiac defects show smaller LPA compared with healthy subjects. Mouse studies suggest that this anomaly is due to haploinsufficiency of Tbx1. These data may be useful in the clinical management of children with 22q11.2DS and should guide further experimental studies as to the mechanisms underlying PAs development.


Assuntos
Síndrome de DiGeorge/diagnóstico por imagem , Haploinsuficiência , Artéria Pulmonar/diagnóstico por imagem , Proteínas com Domínio T/genética , Adolescente , Animais , Criança , Pré-Escolar , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Modelos Animais de Doenças , Ecocardiografia , Feminino , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Artéria Pulmonar/patologia , Proteínas com Domínio T/metabolismo , Adulto Jovem
6.
Mol Genet Genomic Med ; 7(2): e00507, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30614210

RESUMO

BACKGROUND: Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. METHODS: We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. RESULTS: We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. CONCLUSION: Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.


Assuntos
Anormalidades Múltiplas/genética , Transtorno do Espectro Autista/genética , Duplicação Cromossômica/genética , Deficiências do Desenvolvimento/genética , Síndrome de DiGeorge/genética , Penetrância , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Transtorno do Espectro Autista/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 22/genética , Deficiências do Desenvolvimento/patologia , Síndrome de DiGeorge/patologia , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Duplicações Segmentares Genômicas , Síndrome
8.
Tunis Med ; 96(8-9): 472-476, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30430523

RESUMO

BACKGROUND: Hypoparathyroidism is a rare pediatric endocrine disease, which is caused by low circulating levels of PTH or insensitivity to its action in the target tissues. AIM: To report the clinical and biochemical characteristics and theoutcome of 8 patients with hypoparathyroidism. METHODS: We analyzed retrospectively the results of clinical, biochemical, radiological findings of patients with hypoparathyroidism diagnosed in pediatric department of Hedi Chaker Hospital during the period 1994-2013. RESULTS: Eight patients (5 females and 3 males) were diagnosed with hypoparathyroidism during 20 years's period. The median age at the onset of first symptoms was 17,5 months (15 days- 5 years and 10 months). Seizures were the most commonly presenting symptom and were seen in seven cases. Eight patients were diagnosed with hypoparathyroidism (Di-Georges syndrome: one case, Sanjad Sakati syndrome: 3 case, kearns sayre syndrome: 1 case, autoimmune polyendocrinopathy candidiasis- ectodermal dystrophy: one case, idiopathic hypoparathyroidism: two cases. Conventional treatment was based on calcium and vitamin D analogs. The average of follow up was 5 years. Nephrocalcinosis was noted in two patients. The death occurred in five patients; it was related to hypocalcaemia in one patient. CONCLUSION: The diagnosis of hyperparathyroidism is easy; it's established on the association of hypocalcaemia and hyperphosphatemia. Etiologic approach is based on molecular findings. Vitamin D analog treatment of hypoparathyroidism in children involves the challenge, of adjusting treatment dosage to minimize both symptomatic hypocalcemia and asymptomatic, but potentially kidney-damaging, hypercalciuria causing nephrocalcinosis and renal insufficiency.


Assuntos
Hipoparatireoidismo/epidemiologia , Hipoparatireoidismo/patologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Idade de Início , Causas de Morte , Criança , Pré-Escolar , Estudos de Coortes , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/patologia , Evolução Fatal , Feminino , Transtornos do Crescimento/complicações , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/patologia , Humanos , Hipoparatireoidismo/complicações , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/etiologia , Lactente , Recém-Nascido , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Estudos Longitudinais , Masculino , Osteocondrodisplasias/complicações , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/patologia , Estudos Retrospectivos , Convulsões/complicações , Convulsões/diagnóstico , Convulsões/patologia
9.
Dis Model Mech ; 11(9)2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30166330

RESUMO

The TBX1 gene is haploinsufficient in 22q11.2 deletion syndrome (22q11.2DS), and genetic evidence from human patients and mouse models points to a major role of this gene in the pathogenesis of this syndrome. Tbx1 can activate and repress transcription, and previous work has shown that one of its functions is to negatively modulate cardiomyocyte differentiation. Tbx1 occupies the anterior heart field (AHF) enhancer of the Mef2c gene, which encodes a key cardiac differentiation transcription factor. Here, we show that increased dosage of Tbx1 correlates with downregulation of Mef2c expression and reduced acetylation of its AHF enhancer in cultured mouse myoblasts. Consistently, 22q11.2DS-derived and in vitro-differentiated human induced pluripotent stem cells (hiPSCs) expressed higher levels of MEF2C and showed increased AHF acetylation, compared with hiPSCs from a healthy donor. Most importantly, we show that in mouse embryos, loss of Tbx1 enhances the expression of the Mef2c-AHF-Cre transgene in a specific region of the splanchnic mesoderm, and in a dosage-dependent manner, providing an in vivo correlate of our cell culture data. These results indicate that Tbx1 regulates the Mef2c AHF enhancer by inducing histone deacetylation.


Assuntos
Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento , Coração/embriologia , Histonas/metabolismo , Proteínas com Domínio T/metabolismo , Acetilação , Animais , Sequência de Bases , Diferenciação Celular , Linhagem Celular , Síndrome de DiGeorge/patologia , Embrião de Mamíferos/metabolismo , Feminino , Fator de Transcrição GATA4/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Fatores de Transcrição MEF2/genética , Camundongos Transgênicos , Miocárdio/citologia , Miocárdio/metabolismo
10.
J Neurosci Res ; 96(10): 1631-1640, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30004142

RESUMO

22q11.2 deletion syndrome (22q11.2 DS) is widely known as one of the most compelling genetic models of schizophrenia so far, being almost 40% of the carriers affected by psychotic symptoms. Moreover, most of these subjects also show impairment in social cognition, which is a comprehensive array of function that guides social interaction with the others, leading as well to the acquisition of new cognitive and social skills. In the last decade researchers have argued whether social cognition dysfunctions could be underlined by specific genetic alterations, and whether these are linked to specific clinical features. Some valid candidate genes are RTN4R, that encodes a protein which inhibits axonal sprouting, DGCR8, crucial in mRNA processing, or catechol-O-methyltransferase (COMT) and proline oxydase 1 (PRODH), involved in catecholamine metabolism in frontal cortex. This is the first article to address the topic of social cognition in 22q11.2 DS from a wide perspective, with a highlight on its genetic characteristics. We will provide a narrative review of the most recent findings and we will point out new directions on this research path, in order to achieve an effective characterization of the neurobiological system underlying social behavior.


Assuntos
Transtornos Cognitivos/genética , Transtornos Cognitivos/psicologia , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/psicologia , Comportamento Social , Animais , Transtornos Cognitivos/patologia , Síndrome de DiGeorge/patologia , Humanos , Transtornos Psicóticos/genética , Esquizofrenia/genética
11.
Artigo em Inglês | MEDLINE | ID: mdl-29735153

RESUMO

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is the third-largest known genetic risk factor for the development of psychosis. Dysconnectivity has consistently been implicated in the physiopathology of psychosis. Structural covariance of cortical morphology is a method of exploring connectivity among brain regions that to date has not been employed in 22q11DS. METHODS: In the present study we employed structural covariance of cortical thickness to explore connectivity alterations in a group of 108 patients with 22q11DS compared with 96 control subjects. We subsequently divided patients into two subgroups of 31 subjects each according to the presence of attenuated psychotic symptoms. FreeSurfer software was used to obtain the mean cortical thickness in 148 brain regions from T1-weighted 3T images. For each population we reconstructed a brain graph using Pearson correlation between the average thickness of each couple of brain regions, which we characterized in terms of mean correlation strength and in terms of network architecture using graph theory. RESULTS: Patients with 22q11DS presented increased mean correlation strength, but there was no difference in global architecture compared with control subjects. However, symptomatic patients presented increased mean correlation strength coupled with increased segregation and decreased integration compared with both control subjects and nonsymptomatic patients. They also presented increased centrality for a cluster of anterior cingulate and dorsomedial prefrontal regions. CONCLUSIONS: These results confirm the importance of cortical dysconnectivity in the physiopathology of psychosis. Moreover they support the significance of aberrant anterior cingulate connectivity.


Assuntos
Encéfalo/patologia , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Processamento de Imagem Assistida por Computador , Adolescente , Adulto , Mapeamento Encefálico/métodos , Criança , Feminino , Humanos , Masculino , Vias Neurais/patologia , Transtornos Psicóticos/genética , Transtornos Psicóticos/patologia , Adulto Jovem
12.
Ann Otol Rhinol Laryngol ; 127(6): 384-389, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29732908

RESUMO

OBJECTIVES: To characterize the frequency of airway anomalies in patients with 22q11.2 deletion syndrome (22q11DS). METHODS: Retrospective review of patients with 22q11DS who had undergone microlaryngoscopy/bronchoscopy (MLB) for aerodigestive symptoms at a tertiary care children's hospital from 2011 to 2016. RESULTS: Thirty patients underwent an MLB due to the following indications: aspiration (11), stridor (10), chronic respiratory failure due to ventilator dependence (8), and difficult intubation (1). Median age at MLB was 6.5 months (range, 0.25-32 months). Forty airway anomalies were identified in 20 (66%) patients. Laryngomalacia (10), tracheomalacia (8), and bronchomalcia (8) were the most common intraoperative findings, followed by laryngeal cleft (5), anterior glottic web (5), subglottic stenosis (3), and subglottic cysts (1). Synchronous airway anomalies were common and identified in 11 (55%) of the patients who had identified anomalies on MLB. Nineteen of the 20 patients required operative intervention due to the anomalies identified. CONCLUSIONS: Structural airway abnormalities are common in children with 22q11DS undergoing MLB, and synchronous anomalies can frequently exist. Providers caring for children with 22q11DS should be vigilant about airway evaluation when aerodigestive symptoms are present.


Assuntos
Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/patologia , Anormalidades do Sistema Respiratório/epidemiologia , Broncoscopia , Pré-Escolar , Síndrome de DiGeorge/cirurgia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Laringoscopia , Masculino , Anormalidades do Sistema Respiratório/patologia , Anormalidades do Sistema Respiratório/cirurgia , Estudos Retrospectivos
13.
J Hum Genet ; 63(7): 795-801, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29691480

RESUMO

Multiple genomic disorders result from recurrent deletions or duplications between low copy repeat (LCR) clusters, mediated by nonallelic homologous recombination. These copy number variants (CNVs) often exhibit variable expressivity and/or incomplete penetrance. However, the population prevalence of many genomic disorders has not been estimated accurately. A subset of genomic disorders similarly characterized by CNVs between LCRs have been studied epidemiologically, including Williams-Beuren syndrome (7q11.23), Smith-Magenis syndrome (17p11.2), velocardiofacial syndrome (22q11.21), Prader-Willi/Angelman syndromes (15q11.2q12), 17q12 deletion syndrome, and Charcot-Marie-Tooth neuropathy type 1/hereditary neuropathy with liability to pressure palsy (PMP22, 17q11.2). We have generated a method to estimate prevalence of highly penetrant genomic disorders by (1) leveraging epidemiological data for genomic disorders with previously reported prevalence estimates, (2) obtaining chromosomal microarray data on genomic disorders from a large medical genetics clinic; and (3) utilizing these in a linear regression model to determine the prevalence of this syndromic copy number change among the general population. Using our algorithm, the prevalence for five clinically relevant recurrent genomic disorders: 1q21.1 microdeletion (1/6882 live births) and microduplication syndromes (1/6309), 15q13.3 microdeletion syndrome (1/5525), and 16p11.2 microdeletion (1/3021) and microduplication syndromes (1/4216), were determined. These findings will inform epidemiological strategies for evaluating those conditions, and our method may be useful to evaluate the prevalence of other highly penetrant genomic disorders.


Assuntos
Doença de Charcot-Marie-Tooth/epidemiologia , Síndrome de DiGeorge/epidemiologia , Genoma Humano , Modelos Genéticos , Síndrome de Prader-Willi/epidemiologia , Síndrome de Smith-Magenis/epidemiologia , Síndrome de Williams/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Deleção Cromossômica , Duplicação Cromossômica , Mapeamento Cromossômico , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Humanos , Análise em Microsséries , Epidemiologia Molecular , Penetrância , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/patologia , Prevalência , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/patologia , Síndrome de Williams/genética , Síndrome de Williams/patologia
14.
Eur Neuropsychopharmacol ; 28(6): 732-742, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29703646

RESUMO

22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk for developing psychosis. The catechol-O-methyltransferase (COMT) gene is located in the deleted region and involved in dopamine (DA) breakdown. Impaired reinforcement learning (RL) is a recurrent feature in psychosis and thought to be related to abnormal striatal DA function. This study aims to examine RL and the potential association with striatal DA-ergic neuromodulation in 22q11DS. Twelve non-psychotic adults with 22q11DS and 16 healthy controls (HC) were included. A dopamine D2/3 receptor [18F]fallypride positron emission tomography (PET) scan was acquired while participants performed a modified version of the probabilistic stimulus selection task. RL-task performance was significantly worse in 22q11DS compared to HC. There were no group difference in striatal nondisplaceable binding potential (BPND) and task-induced DA release. In HC, striatal task-induced DA release was positively associated with task performance, but no such relation was found in 22q11DS subjects. Moreover, higher caudate nucleus task-induced DA release was found in COMT Met hemizygotes relative to Val hemizygotes. This study is the first to show impairments in RL in 22q11DS. It suggests that potentially motivational impairments are not only present in psychosis, but also in this genetic high risk group. These deficits may be underlain by abnormal striatal task-induced DA release, perhaps as a consequence of COMT haplo-insufficiency.


Assuntos
Corpo Estriado/metabolismo , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/patologia , Dopamina/metabolismo , /etiologia , Adulto , Benzamidas/farmacocinética , Mapeamento Encefálico , Catecol O-Metiltransferase/genética , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Síndrome de DiGeorge/genética , Antagonistas dos Receptores de Dopamina D2/farmacocinética , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Testes de Inteligência , Imagem por Ressonância Magnética , Masculino , Metionina/genética , Pessoa de Meia-Idade , Mutação/genética , Tomografia por Emissão de Pósitrons , Análise e Desempenho de Tarefas , Valina/genética
15.
AJNR Am J Neuroradiol ; 39(5): 928-934, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29545254

RESUMO

BACKGROUND AND PURPOSE: The 22q11.2 deletion syndrome is characterized by a heterogenic phenotype, including hearing loss. The underlying cause of hearing loss, especially sensorineural hearing loss, is not yet clear. Therefore, our objective was to describe anatomic malformations in the middle and inner ear in patients with 22q11.2 deletion syndrome. MATERIALS AND METHODS: A retrospective case series was conducted in 2 tertiary referral centers. All patients with 22q11.2 deletion syndrome who had undergone CT or MR imaging of the temporal bones were included. Radiologic images were evaluated on predetermined parameters, including abnormalities of the ossicular chain, cochlea, semicircular canals, and vestibule. RESULTS: There were 26 patients (52 ears) with a CT or MR imaging scan available. A dense stapes superstructure was found in 18 ears (36%), an incomplete partition type II was suspected in 12 cochleas (23%), the lateral semicircular canal was malformed with a small bony island in 17 ears (33%), and the lateral semicircular canal and vestibule were fused to a single cavity in 15 ears (29%). CONCLUSIONS: Middle and inner ear abnormalities were frequently encountered in our cohort, including malformations of the lateral semicircular canal.


Assuntos
Síndrome de DiGeorge/patologia , Orelha Interna/anormalidades , Orelha Média/anormalidades , Adolescente , Adulto , Criança , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/efeitos adversos
16.
J Autism Dev Disord ; 48(8): 2886-2889, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29589274

RESUMO

The 22q11.2 duplication is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we report on pathogenic HUWE1 and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in HUWE1 and KIF1A respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.


Assuntos
Anormalidades Múltiplas/genética , Transtorno do Espectro Autista/genética , Duplicação Cromossômica/genética , Síndrome de DiGeorge/genética , Penetrância , Anormalidades Múltiplas/patologia , Transtorno do Espectro Autista/patologia , Criança , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/patologia , Feminino , Testes Genéticos/normas , Humanos , Cinesina/genética , Masculino , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética
17.
Gene Expr Patterns ; 28: 95-103, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29571919

RESUMO

22q11.2 deletion syndrome (22q11.2DS) carries increased risk for both physical and psychiatric symptoms, including a high risk for schizophrenia. Understanding the genetic elements within the deletion region therefore has the potential to unlock the mysteries of both diseases. While most of the protein-coding genes in this region have been characterized, novel elements, such as non-coding RNAs and small Open Reading Frames (sORFs) remain unstudied. We have identified a novel, highly-conserved mouse sORF in a region of the mouse genome that is orthologous to a portion of the 22q11.2 deletion. This region was previously associated with age-dependent synaptic plasticity abnormalities. We refer to it as the Plasticity Associated Neural Transcript Short, or Pants. In developing and aging mouse brain, Pants expression is strongest in hippocampus, especially in areas CA3 and CA2, throughout the dorsoventral axis. The Pants peptide is expressed throughout the hippocampus, with an age-dependent increase in stratum lucidum at 16 weeks of age. This expression pattern suggests a potential role for Pants in many hippocampal behaviors, as well as a potential role in the age-dependent neurologic deficits displayed by 22q11.2DS model mice and patients.


Assuntos
Encéfalo/metabolismo , Deleção Cromossômica , Síndrome de DiGeorge/genética , Fases de Leitura Aberta/genética , Fragmentos de Peptídeos/metabolismo , Fatores Etários , Animais , Síndrome de DiGeorge/metabolismo , Síndrome de DiGeorge/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
18.
Curr Allergy Asthma Rep ; 18(3): 14, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29470661

RESUMO

PURPOSE OF REVIEW: Granulomatous-lymphocytic interstitial lung disease (GLILD) has classically been associated with common variable immune deficiency (CVID), but is increasingly being reported in other immunodeficiencies. We describe the second reported case of GLILD in a patient with 22q11.2 deletion syndrome (22q11.2DS) and review the recent literature surrounding GLILD. RECENT FINDINGS: GLILD is characterized by granulomata and lymphoproliferation. Consensus statements and retrospective and case-control studies have better elucidated the clinicopathological and radiographic manifestations of GLILD, allowing for its differentiation from similar conditions like sarcoidosis. Gaps of knowledge remain, however, particularly regarding optimal management strategies. Combination therapies targeting T and B cell populations have recently shown favorable results. GLILD is associated with poorer outcomes in CVID. Its recognition as a rare complication of 22q11.2DS and other immunodeficiencies therefore has important therapeutic and prognostic implications. Additional research is needed to better understand the natural history and pathogenesis of GLILD and to develop evidence-based practice guidelines.


Assuntos
Imunodeficiência de Variável Comum/complicações , Síndrome de DiGeorge/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Adolescente , Imunodeficiência de Variável Comum/patologia , Síndrome de DiGeorge/patologia , Feminino , Humanos , Doenças Pulmonares Intersticiais/patologia , Masculino , Estudos Retrospectivos
19.
Psychol Med ; 48(14): 2375-2383, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29338796

RESUMO

BACKGROUND: Patients with 22q11.2 deletion syndrome (22q11DS) present a high risk of developing psychosis. While clinical and cognitive predictors for the conversion towards a full-blown psychotic disorder are well defined and largely used in practice, neural biomarkers do not yet exist. However, a number of investigations indicated an association between abnormalities in cortical morphology and higher symptoms severities in patients with 22q11DS. Nevertheless, few studies included homogeneous groups of patients differing in their psychotic symptoms profile. METHODS: In this study, we included 22 patients meeting the criteria for an ultra-high-risk (UHR) psychotic state and 22 age-, gender- and IQ-matched non-UHR patients. Measures of cortical morphology, including cortical thickness, volume, surface area and gyrification, were compared between the two groups using mass-univariate and multivariate comparisons. Furthermore, the development of these measures was tested in the two groups using a mixed-model approach. RESULTS: Our results showed differences in cortical volume and surface area in UHR patients compared with non-UHR. In particular, we found a positive association between surface area and the rate of change of global functioning, suggesting that higher surface area is predictive of improved functioning with age. We also observed accelerated cortical thinning during adolescence in UHR patients with 22q11DS. CONCLUSIONS: These results, although preliminary, suggest that alterations in cortical volume and surface area as well as altered development of cortical thickness may be associated to a greater probability to develop psychosis in 22q11DS.


Assuntos
Córtex Cerebral/patologia , Síndrome de DiGeorge/patologia , Progressão da Doença , Imagem por Ressonância Magnética/métodos , Transtornos Psicóticos/patologia , Esquizofrenia/patologia , Adolescente , Adulto , Córtex Cerebral/diagnóstico por imagem , Estudos Transversais , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/diagnóstico por imagem , Feminino , Humanos , Estudos Longitudinais , Masculino , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/etiologia , Risco , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/etiologia , Adulto Jovem
20.
Clin Genet ; 93(2): 293-300, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28696552

RESUMO

Single-nucleotide polymorphism (SNP)-based non-invasive prenatal testing (NIPT) can currently predict a subset of submicroscopic abnormalities associated with severe clinical manifestations. We retrospectively analyzed the performance of SNP-based NIPT in 80 449 referrals for 22q11.2 deletion syndrome and 42 326 referrals for 1p36, cri-du-chat, Prader-Willi, and Angelman microdeletion syndromes over a 1-year period, and compared the original screening protocol with a revision that reflexively sequenced high-risk calls at a higher depth of read. The prevalence of these microdeletion syndromes was also estimated in the referral population. The positive predictive value of the original test was 15.7% for 22q11.2 deletion syndrome, and 5.2% for the other 4 disorders combined. With the revised protocol, these values increased to 44.2% for 22q11.2 and 31.7% for the others. The 0.33% false-positive rate (FPR) for 22q11.2 deletion syndrome decreased to 0.07% with the revised protocol. Similarly, the FPR for the other 4 disorders combined decreased from 0.56% to 0.07%. Minimal prevalences were estimated to be 1 in 1255 for 22q11.2 deletion syndrome and 1 in 1464 for 1p36, cri-du-chat, and Angelman syndromes combined. Our results show that these microdeletions are relatively common in the referral population, and that the performance of SNP-based NIPT is improved with high-depth resequencing.


Assuntos
Síndrome de Angelman/diagnóstico , Síndrome de DiGeorge/diagnóstico , Testes Genéticos , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Síndrome de Angelman/genética , Síndrome de Angelman/patologia , Deleção Cromossômica , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Feminino , Feto/patologia , Humanos , Gravidez , Diagnóstico Pré-Natal/métodos , Adulto Jovem
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