Velocardiofacial (VCFS; 22q11.2; DiGeorge) Syndrome Study
キーワード
概要
説明
22q11.2 (DiGeorge MIM#188400, Velocardiofacial MIM#192430) syndrome is a hemizygous microdeletion on 22q11.2 of typically 3Mb, encompassing approximately 30 genes and mediated by aberrant homologous recombination and unequal crossing-over events between intrachromosomal flanking low-copy repeats (LCRs). The incidence is 1:4000 live births. While somatic symptoms include congenital cardiovascular and craniofacial abnormalities, recurrent infections and hypocalcemia1 , the most prevalent group of symptoms are neuropsychiatric and include cognitive dysfunction with mild mental retardation, behavioral difficulties and psychosis. The syndrome is associated with a lifetime prevalence of schizophrenia-like illness (phenotypically mostly similar to sporadic schizophrenia) of approximately 25 times that of the general population making the presence of this hemideletion the strongest known risk factor for the development of schizophrenia excepting the presence of a monozygotic twin with the illness. The 22q11 region is implicated in the risk architecture of schizophrenia by several linkage studies and harbors a number of proposed susceptibility genes including genes for Catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH) and ZDHHC8. The neural basis of these pronounced neurocognitive and psychiatric abnormalities is unknown. The present work proposes to (a) study a group of exceptionally high-functioning, normal intelligence, psychosis-free individuals with 21q11.2 syndrome using a hierarchical multimodal imaging approach to define the intermediate systems level phenotype of the disease combined with deletion mapping techniques and (b) to study the functional effects of single nucleotide polymorphisms in genes in the hemideleted region that have been implicated in schizophrenia, taking advantage of the unique fact that the hemizygous deletion allows immediate construction of molecular haplotypes and of potential epistatic allelic effects. This work is expected to (a) elucidate the pathophysiology of the CNS manifestations of the 22q11.2 syndrome and yield a brain intermediate phenotype that will allow studies in small and atypical deletion individuals in an effort to define individual genes responsible for neurocognitive deficit and increased risk for psychosis, (b) facilitate the identification of functional mechanisms underlying increased risk for schizophrenia for individual susceptibility genes in the deletion and for interacting risk alleles within the deleted locus and (c) prepare the ground for a clinical protocol in which the results from (a) and (b) can be applied to a prospective study evaluating early diagnostic and interventional approaches based on genetic risk and intermediate phenotype ascertainment in this group of patients at high risk for the development of psychosis.
日付
最終確認済み: | 02/01/2010 |
最初に提出された: | 03/09/2005 |
提出された推定登録数: | 03/09/2005 |
最初の投稿: | 03/10/2005 |
最終更新が送信されました: | 06/29/2017 |
最終更新日: | 07/01/2017 |
実際の研究開始日: | 03/06/2005 |
研究完了予定日: | 02/01/2010 |
状態または病気
段階
適格基準
研究の対象となる年齢 | 18 Years に 18 Years |
研究に適格な性別 | All |
健康なボランティアを受け入れる | はい |
基準 | - INCLUSION CRITERIA: Only adults between age 18 and 50 will be studied. 22q11.2 participants: 22q11.2 deletion will be confirmed by FISH. IQ (WAIS). In phase 1: IQ in the general range of the population (greater than 85) as ascertained using the 2- and 4-subset forms of the Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999). Informed consent. EXCLUSION CRITERIA: (Phase 1 only) Any lifetime diagnosis of schizophrenia, schizoaffective disorder, or schizotypal disorder and/or current pychotropic medication or any neuroleptic medication in the previous year. (all phases) Chronological age greater 50 years. Contraindication of MRI scanning (ferromagnetic metal implanted in body, prostheses containing such metal, pacemaker devices). Pregnancy. Medication affecting central nervous function. Severe somatic disorders precluding travel to the clinical center or participation in imaging procedures. Hypothyroidism not compensated by medication. Neurological disorders excluding those of exclusively peripheral location. |