Velocardiofacial (VCFS; 22q11.2; DiGeorge) Syndrome Study
Condition: DiGeorge Syndrome; Velocardiofacial Syndrome; 22q11.2 Syndrome
MeSH terms: DiGeorge Syndrome; Syndrome
Study type: Observational

Summary: 
      Velocardiofacial syndrome, also known as 22q11.2 syndrome or DiGeorge syndrome, has been
      associated with many features such as a cleft palate, heart defects, and learning, speech and
      feeding problems. It is caused by the absence of a number of genes on chromosome 22, but the
      mechanism by which this inborn abnormality causes the clinical problems is not known.

      In this study by the National Institute of Mental Health and the Office of Rare Diseases, we
      are recruiting participants with 22q11.2 syndrome to come for a three-day stay to our main
      campus in Bethesda, MD, to participate in a study in which we will investigate the genetic
      makeup of their cells together with several studies of brain function with advanced research
      imaging. The goal of this study is to understand how the genes missing in 22q11.2 syndrome
      are related to the increased occurrence of psychiatric problems, such as psychosis, in this
      syndrome. Participants must be 18-50 years of age, have some high school education and not
      currently be taking antipsychotic medication. Travel costs to Bethesda for participants and
      an accompanying person will be paid, and participants are reimbursed for their time in
      participating in the study. A blood draw is required. All research procedures have been
      designated as "minimal risk" procedures.

      ...
    

Detailed description: 
      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.
    

Keywords: Velocardiofacial Syndrome; Susceptibility Genes; Neuroimaging; 22q11.2; Psychosis; Mircodeletion; DiGeorge Syndrome; 22q11.2 Syndrome