1. Behavioral Science Research
Munroe – Meyer Institute for Genetics and Rehabilitation

2. Clinical Activities
Rate limiting step…..

3. Omaha Clinics Behavioral Genetics
Neurogenetics
Neurosensory Genetics
Pediatric / Adult metabolic disorders
Fetal Alcohol Syndrome (Screening and comprehensive)

4. Omaha Clinics Developmental / Behavioral
Developmental Medicine Clinics
Behavioral Health Clinics
GWR autism consultative clinics
Neurobehavioral clinic
Behavioral Management Clinics
Transition Clinic
Advanced Autism Management Clinic

5. Outreach Clinics In Neurobehavioral Genetics (2006). . .
Pierre
Rapid City . . . .
Scottsbluff
Winnebago .
North Platte
Kearney

7. Defining ‘Endophenotypes’

8. Endophenotype Analysis
Applied Behavioral Analysis of autism
Neuropsychologic assessment of reading disabilities
Characterization of sleep disorders
Genetic categorization of mental retardation and cerebral palsy

9. Molecular Genetics

10. Core Facilities Complex linkage analysis
Commercial and customized fluorescence –in situ hybridization (FISH)
Wave (DHPLC) screening
High throughput gene sequencing
Customized chip micro-array
‘Knock out’ mouse facilities
‘Knock down’ facilities
Whole genome array SNP typing
(TBA) Whole genome SNP typing
Epigenetic modifications (DNA methylation)

11. Areas of Emphasis

12. Behavioral Genetics Autism Apraxia Dyslexia ADHD
Neurosensory disorders

13. Behavioral / Developmental
Integrated Behavioral Health in Rural Primary Care Practice
Pediatric Feeding Disorders
Augmentative Communication
Brain Injury Training
Medical Transition
Program Evaluation
Early Childhood Development
Teratogenic Effects on Early Childhood
Systematic Developmental Follow-up

14. Psychiatry Depression (children, adolescents, adults) Anxiety
pharmacotherapy, psychotherapy, genetics, immune function, vagal nerve stimulation, prevention in head & neck cancer)
Anxiety
pharmacotherpy
Alzheimer's Disease
pharmacotherapy for cognition & apathy
ADHD (children, adolescents, adults)
pharmacotherapy, genetics, rating scale development
Gambling
pharmacotherapy
Consult Liaison

15. How it all works together

16. Genetics of Dyslexia
Twin and family studies establish genetic influence on reading ability
Heritability ~ 0.56
Segregation analysis gives evidence for several major genes
Analyses to identify heritable “endophenotypes”
Phonemic awareness, phonological coding, orthographic coding, single word reading

17. Localization of genes that influence dyslexia
Positional cloning:
Linkage and association analysis
DNA marker typing across the chromosomes leads to identification of markers in a chromosomal region that are inherited along with dyslexia.
Genes in this region are investigated to identify mutations or variants in association with the phenotype
Chromosomal abnormality:
Identification of a gene disrupted by chromosome breakage

18. Reading Disability Loci and Phenotypes
Locus
Region
Population
Phenotype
DYX8
1p36
N. Carolina
Washington
Phonological Decoding, RAN
DYX3
2p11
Norway UK
Reading and Spelling
DYX5
3p12-q13
Finland
Phonologic Awareness
DYX2
6p22
N. Carolina Colorado, UK
Phonemic Awareness Orthographic Choice, Phonologic Decoding
DYX4
6q11-2
Canada
Phonologic Decoding
7q32
DYX7
11p15.5
DYX1
15q21
N. Carolina Germany Norway
Single Word Reading Spelling Reading and Spelling
DYX6
18p11
Colorado, UK
Single word reading, Orthographic Coding
DYX9
Xq27.3
Colorado, UK,
Holland
Multiple phenotypes

19. DYX2: 6p22.2: Linkage Analysis
12. 1
11.
14.
16.2 21 p q
16. 27
12.3 12
16.3
22.1
22.2
22.31
23.1
25.3
25.1
25.2
24.3
24.1
24.2 23
22.3
21.33
21.32
21.3
21.2
21.
12.2 2 13
14.3
14.2 15
22.32
22.33
23.3
23.2 26
0.5
1.0
1.5
2.0
2.5 2 4 6 8 10 12 14 16 18 20 22 24 26
Position (cM)
LOD score
Discrim OC PA
D6S1605
D6S274
D6S1567
D6S422
D6S1597
D6S461
D6S276
D6S1571
D6S1554
D6S105
D6S306
D6S258
D6S1683
MOG3132
D6S273
D6S1568
D6S439
D6S1588
D6S291
D6S1019

20. DYX2: 6p22: Association Analysis
VMP DCDC2
KIAA0319 TTRAP THEM2
Deffenbacher et al., 2004
KIAA0319 TTRAP
Francks et al., 2004

21. DYX2: 6p22.2: DCDC2
PNAS 102: (2005)

22. Figure 3. Interference with KIAA0319 disrupts radial migration in the developing rat neocortex. (A) Depiction of in utero electroporation assay for neuronal migration in fetal neocortex. Combinations of plasmids coding for shRNAs, eGFP and KIAA0319 were injected into the ventricles of the E14 rat forebrain, in order to transfect neuronal progenitor cells at the VZ surface. Over the course of 4 days, neurons migrated radially towards the IZ and CP. (B) Average distance migrated by neurons 4 days following co-transfection of eGFP and one the following five plasmids: (i) KIAA0319shRNA; (ii) shRNA containing scrambled sequence of a KIAA0319shRNA vector.
Paracchini et al., Hum. Molec. Genet. 15: , 2006