Behavioral Science Research Munroe – Meyer Institute for Genetics and Rehabilitation

Clinical Activities Rate limiting step…..

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

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

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

Defining ‘Endophenotypes’

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

Molecular Genetics

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)

Areas of Emphasis

Behavioral Genetics Autism Apraxia Dyslexia ADHD Neurosensory disorders

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

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

How it all works together

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

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

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

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

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

DYX2: 6p22.2: DCDC2 PNAS 102:17053-17058 (2005)

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: 1659-1666, 2006