1. Velo-Cardio-Facial Syndrome
PRINCIPAL INVESTIGATOR:
Marek Kubicki, MD, PhD
INVESTIGATORS:
Zora Kikinis, PhD
Sylvain Bouix, PhD
Marc Niethammer, PhD
Martha Shenton, PhD
Christine Finn, MD
Raju Kucherlapati, MD
RESEARCH ASSISTANT:
Doug Markant, BA

2. Velo-Cardio-Facial Syndrome (VCFS)
Condition defined by Sphrintzen in 1978
Chromosome 22 q11.2 deletion. Deletion of 1.5 to 3 Mb (single copies of 30 to 45 genes missing)
Prevalence 1 in every 4000 newborns

3. VCFS Symptoms "velum" latin meaning soft palate
Cleft palate, small or aplastic tonsils,
hypernasal speech
“kardia" greek meaning heart
VSD , right sided aortic arch, tetralogy
of Fallot, aberrant subclavian artery
"facial" latin having to do with the face
maxillary excess, malar flatness, facial asymmetry, thin upper lip, prominent nasal root, large nasal tip, pinched, hypoplastic base

4. Common Cognitive Deficits in VCFS
Psychomotor and perceptual deficits
Learning and memory disabilities
Emotional abnormalities (flat affect and poor social interaction).
High incidence for schizophrenia and/or bipolar disorder in adult (30% VCFS patients develop schizophrenia)

5. Neuroimaging Findings in VCFS
MRI case reports (most)
- high frequency of nonspecific white matter hyperintensities (30% of cases)
- cavum septi pellucidi (in 45% of cases)
MRI quantitative reports (few)
- Reduced volumes of regions related to language and verbal memory (superior temporal gyrus, hippocampus, amygdala and parietal lobe).
- Increased volume and posterior displacement of the corpus callosum
DTI (two studies)
- Reduced anisotropy in frontal, parietal, and temporal white matter
- Reduced anisotropy in white matter tracts connecting frontal and temporal lobes
- Reduced anisotropy in inferior parietal lobule which is correlated with scores from the arithmetic subscale of the WISC/WAIS, after co-varying for IQ and age of subjects.

6. Neuroimaging Findings in VCFS Cases with Schizophrenia
MRI (3 studies, only one with IQ matched populations)
- Decreased total gray and white matter volumes
- Increased total and sulcal CSF volumes.
- Decreased frontal, temporal and parietal gray matter volumes
- Increased corpus callosum volume
Based on scarce findings, VCFS investigators proposed a model, in which a deficiency in frontal maturation leads to a vulnerability for schizophrenia among individuals with VCFS
DTI
- None

7. VCFS Schizophrenia Candidate Genes
COMT (controls dopamine degradation in prefrontal cortex, related to attention and memory)
RTN4R (also known as Nogo 66, related to axonal regeneration and plasticity)
PRODH
ZDH8
SNAP29
TBX1

8. Project Subject recruitment Psychological interview
DNA analysis, genotyping of the 22q11.2 region
Brain imaging (MRI and DTI on 3T)
Analysis of imaging data, and genetic correlations

9. Aims Etiology of schizophrenia and related diseases
Prognosis of mental health diseases in VCFS
Early intervention

10. Hypotheses Regions that we want to study with MRI DLPC (COMT)
Orbital Frontal Gyrus (emotion)
Cingulate Gyrus (attention, emotion)
Hippocampus (memory, learning)
Tracts that we want to study with DTI
Fornix (memory)
Arcuate Fasciculus (language)
Cingulum Bundle (attention)
Uncinate Fasciculus (emotion, affective flattening)

11. Potential Challenges for Atlas Based Scripts
Brain atrophy
Congenital abnormalities
Brain asymmetry
White matter lesions

12. Velo-Cardio-Facial Syndrome (VCFS) as a Genetic Model for Schizophrenia.
PRINCIPAL INVESTIGATOR:
Marek Kubicki, MD, PhD
INVESTIGATORS:
Zora Kikinis, PhD
Sylvain Bouix, PhD
Marc Niethammer, PhD
Christine Finn, MD
Raju Kucherlapati, MD
Martha Shenton, PhD
RESEARCH ASSISTANT:
Doug Markant, BA
BACKGROUND:
VCFS is a rare genetic syndrome (single copies of genes on 22 chromosome are missing)
30% of patients with VCFS develop schizophrenia
AIMS:
To characterize anatomical similarities and dissimilarities between VCFS and Schizophrenia
To find “schizophrenia” genes
DATA:
DTI, MRI, haplotypes, neuropsychology