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1.
Int J Pediatr Otorhinolaryngol ; 138: 110236, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32890936

RESUMO

INTRODUCTION: Patients with 22q11.2 deletion syndrome (22q11.2DS) have a variety of anatomic anomalies. For surgeons operating in proximity to the retropharynx, the most pertinent is medial displacement of the internal carotid arteries. The purpose of this study is to describe the preoperative use of magnetic resonance angiography (MRA) in surgical planning and update the incidence rate of medial carotid displacement in patients with 22q11.2DS. METHODS: This is a retrospective cohort study of patients with a confirmed diagnosis of 22q11.2 deletion and preoperative MRA <18 years old who underwent tonsillectomy, adenoidectomy, Furlow palatoplasty (FPP), posterior pharyngeal flap (PPF), sphincter pharyngoplasty (SPP), or submucosal cleft palate (SMCP) repair between January 1st, 2008 and December 31st, 2019. RESULTS: Ninety patients who met the inclusion criteria underwent 133 procedures. The majority identified as Caucasian (84.4%); 52.2% were female. Cervical MRA was more likely to be ordered before a PPF (80.9%) and tonsillectomy (72.7%) over a FPP (47.6%) or adenoidectomy (11.1%). Carotid medialization was visualized in 23 patients (25.6%) and was mild in 11 cases, moderate in 7 cases, and significant in 5 cases. There was no association between sex, race/ethnicity, or genetic diagnosis with carotid medialization. Flap shortening was necessary in 20% of PPF cases to avoid injuring the medialized vessel. CONCLUSION: Patients with 22q11.2DS may have higher rates of medialization of the carotid arteries than previously thought. Given the risk for complications in these patients during pharyngeal operations, there may be a critical place for MRA in surgical planning for patients with 22q11.2DS.

2.
Sci Rep ; 10(1): 12235, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699385

RESUMO

The most prevalent microdeletion in humans occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has defied elucidation due to its size, regional complexity, and haplotype diversity, and is not well represented in the human genome reference. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo hemizygous deletion of ~ 3 Mbp occurring by non-allelic homologous recombination (NAHR) mediated by LCR22s. In this study, optical mapping has been used to elucidate LCR22 structure and variation in 88 individuals in thirty 22q11.2DS families to uncover potential risk factors for germline rearrangements leading to 22q11.2DS offspring. Families were optically mapped to characterize LCR22 structures, NAHR locations, and genomic signatures associated with the deletion. Bioinformatics analyses revealed clear delineations between LCR22 structures in normal and deletion-containing haplotypes. Despite no explicit whole-haplotype predisposing configurations being identified, all NAHR events contain a segmental duplication encompassing FAM230 gene members suggesting preferred recombination sequences. Analysis of deletion breakpoints indicates that preferred recombinations occur between FAM230 and specific segmental duplication orientations within LCR22A and LCR22D, ultimately leading to NAHR. This work represents the most comprehensive analysis of 22q11.2DS NAHR events demonstrating completely contiguous LCR22 structures surrounding and within deletion breakpoints.

3.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 392-400, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32715620

RESUMO

The 22q11.2 deletion syndrome (22q11DS) is associated with impaired cognitive functions and increased risk for schizophrenia spectrum disorders. Speech and language deficits are prominent, with evidence of decline anteceding emergence of psychosis. There is paucity of data examining language function in children with 22q11DS with follow-up assessment of psychosis spectrum (PS) symptoms. We examined the association between early language measures, obtained clinically, and PS status, obtained on average 10.1 years later, in 166 youths with 22q11DS, with repeated language testing in 48. Participants were administered the Preschool Language Scale (receptive/expressive), and/or, for school aged children, the Clinical Evaluation of Language Fundamentals (receptive/expressive), and age appropriate IQ tests. The structured interview for prodromal syndromes (SIPS) assessed PS symptoms. We found that performance on all preschool measures showed age associated decline, and males performed more poorly on core composite (receptive/expressive) and receptive language measures. For language assessment later in childhood, poorer performance was consistently associated with subsequent PS status. Furthermore, steeper age-related decline was seen in the PS group across language measures and marginally for full-scale IQ. These findings suggest that while preschool language testing is useful in characterizing performance decline in individuals with 22q11DS, it does not robustly differentiate those with subsequent PS from those without. However, language testing in the school age population can help identify individuals with 22q11DS who are at risk for psychosis. Such data are needed for elucidating a lifespan trajectory for affected individuals and may help understand pathways to psychosis applicable to the general population.

4.
Nat Rev Dis Primers ; 6(1): 33, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327654
5.
Am J Psychiatry ; 177(7): 589-600, 2020 07 01.
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.


Assuntos
Encéfalo/patologia , Síndrome de DiGeorge/patologia , Transtornos Mentais/patologia , Transtornos Psicóticos/patologia , Adolescente , Adulto , Atrofia/patologia , Mapeamento Encefálico , Estudos de Casos e Controles , Criança , Síndrome de DiGeorge/complicações , Feminino , Humanos , Hipertrofia/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/complicações , Adulto Jovem
6.
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.

7.
Spine J ; 20(6): 956-963, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31958577

RESUMO

BACKGROUND CONTEXT: For over four decades, clinicians and researchers have suggested a relationship between congenital heart disease (CHD) and scoliosis, attributed to either the disease itself or to the long-term effects of cardiac surgery on the immature thoracic cage. However, no study has yet accounted for 22q11.2 deletion syndrome (22q11.2DS), the second most common cause of CHD after Down syndrome. 22q11.2DS has a scoliosis risk of 50%, but within 22q11.2DS a previous report found no significant association between scoliosis and CHD. We, therefore, hypothesized that scoliosis within a CHD cohort would be related to an underlying 22q11.2 deletion. PURPOSE: To determine the prevalence of scoliosis in CHD patients with and without 22q11.2DS. STUDY DESIGN/SETTING: Cross-sectional. PATIENT SAMPLE: A well-characterized existing database of 315 adults with CHD (primarily tetralogy of Fallot), with (n=86) and without (n=229) 22q11.2DS, matched by sex and CHD severity, and excluding other known syndromic diagnoses. We compared the scoliosis prevalence of patients with 22q11.2DS and CHD patients to the prevalence of scoliosis in a cohort of adults with 22q11.2DS without CHD based on medical records. OUTCOME MEASURES: Presence of scoliosis (Cobb angle ≥10°). METHODS: We systematically determined the presence of scoliosis in all included patients using chest radiographs, blind to genetic diagnosis. Besides 22q11.2DS, we analyzed other suspected risk factors for scoliosis using a regression model: thoracotomy before the age of 12 years, severe CHD type and sex. RESULTS: The prevalence of scoliosis in adults with CHD and 22q11.2DS (n=46, 53.5%) was significantly greater than in those without 22q11.2DS (n=18, 7.9%, p<.0001). The presence of a 22q11.2 deletion (odds ratio [OR] 25.4, 95% confidence interval [95% CI] 11.2-57.4, p<.0001), a history of thoracotomy before the age of 12 years (OR 3.5, 95% CI 1.6-8.1, p=.0027) and most complex CHD class (OR 2.3, 95% CI 1.1-4.7, p=.0196), but not sex, were significant independent predictors of scoliosis. In the 22q11.2DS group, a right-sided aortic arch was associated with a left thoracic scoliotic curve (p=.036). CONCLUSIONS: The prevalence of scoliosis in those with CHD but without a 22q11.2 deletion approximates that of the general population. However, in the CHD population with a 22q11.2 deletion, the prevalence of scoliosis approximates that of others with 22q11.2DS. The pediatric surgical approach and severity of CHD were weaker independent contributors as compared to the 22q11.2 deletion. The results support the importance of a genetic diagnosis of 22q11.2DS to the risk of developing scoliosis in individuals with CHD. The 22q11.2 deletion may represent a common etiopathogenetic pathway for both CHD and scoliosis, possibly involving early laterality mechanisms.

8.
Cleft Palate Craniofac J ; 57(7): 808-818, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31973553

RESUMO

OBJECTIVE: To determine pre- and postoperative prevalence of obstructive sleep apnea (OSA) in patients with 22q11.2 deletion syndrome (DS) undergoing wide posterior pharyngeal flap (PPF) surgery for velopharyngeal dysfunction (VPD). DESIGN: Retrospective study using pre- and postoperative polysomnography (PSG) to determine prevalence of OSA. Medical records were reviewed for patients' medical comorbidities. Parents were surveyed about snoring. SETTING: Academic tertiary care pediatric hospital. PATIENTS: Forty patients with laboratory confirmed 22q11.2DS followed over a 6-year period. INTERVENTIONS: Pre- and postoperative PSG, speech evaluation, and parent surveys. MAIN OUTCOME MEASURE: Severity and prevalence of OSA, defined by obstructive apnea hypopnea index (OAHI), before and after PPF surgery to determine whether PPF is associated with increased risk of OSA. RESULTS: Mean OAHI did not change significantly after PPF surgery (1.1/h vs 2.1/h, P = .330). Prevalence of clinically significant OSA (OAHI ≥ 5) was identical pre- and postoperatively (2 of 40), with both cases having severe-range OSA requiring positive airway pressure therapy. All other patients had mild-range OSA. Nasal resonance was graded as severe preoperatively in 85% of patients. None were graded as severe postoperatively. No single patient factor or parent-reported concern predicted risk of OSA (OAHI ≥ 1.5). CONCLUSIONS: Patients with 22q11.2DS are medically complex and are at increased risk of OSA at baseline. Wide PPF surgery for severe VPD does not significantly increase risk of OSA. Careful perioperative planning is essential to optimize both speech and sleep outcomes.

9.
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
10.
Hum Mol Genet ; 28(22): 3724-3733, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31884517

RESUMO

The majority (99%) of individuals with 22q11.2 deletion syndrome (22q11.2DS) have a deletion that is caused by non-allelic homologous recombination between two of four low copy repeat clusters on chromosome 22q11.2 (LCR22s). However, in a small subset of patients, atypical deletions are observed with at least one deletion breakpoint within unique sequence between the LCR22s. The position of the chromosome breakpoints and the mechanisms driving those atypical deletions remain poorly studied. Our large-scale, whole genome sequencing study of >1500 subjects with 22q11.2DS identified six unrelated individuals with atypical deletions of different types. Using a combination of whole genome sequencing data and fiber-fluorescence in situ hybridization, we mapped the rearranged alleles in these subjects. In four of them, the distal breakpoints mapped within one of the LCR22s and we found that the deletions likely occurred by replication-based mechanisms. Interestingly, in two of them, an inversion probably preceded inter-chromosomal 'allelic' homologous recombination between differently oriented LCR22-D alleles. Inversion associated allelic homologous recombination (AHR) may well be a common mechanism driving (atypical) deletions on 22q11.2.


Assuntos
Síndrome de DiGeorge/genética , Síndrome de DiGeorge/metabolismo , Recombinação Homóloga/genética , Adulto , Alelos , Pontos de Quebra do Cromossomo , Deleção Cromossômica , Inversão Cromossômica/genética , Mapeamento Cromossômico/métodos , Cromossomos/genética , Cromossomos Humanos Par 22/genética , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Duplicações Segmentares Genômicas/genética , Sequenciamento Completo do Genoma/métodos
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