Behavioral Science Research

Munroe – Meyer Institute for Genetics and Rehabilitation

Clinical Activities

Rate limiting step…..

Omaha ClinicsBehavioral Genetics

Neurogenetics Neurosensory Genetics Pediatric / Adult metabolic

disorders Fetal Alcohol Syndrome (Screening

and comprehensive)

Omaha ClinicsDevelopmental / Behavioral

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

Clinic

Outreach ClinicsIn Neurobehavioral Genetics (2006)

...

.

Winnebago

Kearney

Rapid City

Scottsbluff

Pierre

.

.

.

.North Platte

Scottsbluff

McCookBenkleman

Imperial

Grant

Ogallala

Cambridge Alma

Franklin

Red Cloud SuperiorHebron Fairbury

Pawnee City

Falls City

Auburn

Nebraska CitySyracuse

Tecumseh

Friend

Seward

Aurora

Central City

Henderson

David CityOsceola

ColumbusSchuyler

OshkoshSidney

Kimball

Alliance

Chadron Gordon Valentine

Ainsworth Bassett

Atkinson

Lynch

Creighton

Bridgeport

OaklandWestpoint

Fremont

Norfolk

Lexington

CozadGothenburg

Callaway

Broken Bow Ord

Grand Island

HastingsMinden

Holdrege

Wahoo

Sioux City, Iowa

BlairGenoa

Nebraska Hospitals

Rural Hospitals

Nebraska Critical Access HospitalsPublic Health Labs

Kansas Critical Access Hospitals

Nebraska Public Health Depts.A. Auburn Southeast District Health Dept.B. Hemingford Panhandle Public Health Dept.C. Burwell Loup Basin Public Health Dept. D. Clay Center Clay County Health Dept.E. Columbus East Central District Health Dept.F. Crete Public Health SolutionsG. David City Butler County Health DeptH. Dakota City Dakota County Health Dept.I. Fremont Three Rivers Health Dept.J. Gering Scotts Bluff County Health Dept. K. Grand Island Central District Health Dept.L. Hastings South Heartland District Health Dept.M. Holdrege Two Rivers Public Health Dept.N. Lincoln Lincoln-Lancaster County Health Dept.O. McCook Red Willow County Health Dept.P. North Platte West Central District Health Dept.Q. Ogallala Sandhills District Health Dept.R. Omaha Douglas County Health Dept.S. O’Neill North Central District Health Dept.T. Osceola Polk County Health Dept.U. Papillion Sarpy/Cass Dept. of Health and WellnessV. Trenton Southwest Nebraska Public Health Dept.

X. Wayne Northeast Nebraska Public Health Dept.Y. Wisner Elkhorn Logan Valley Public Health Dept.Z. York Four Corners Health Dept.

1. Ainsworth Brown County2. Albion Boone County3. Alliance Box Butte General4. Alma Harlan County Health Sys 5. Atkinson West Holt6. Auburn Nemaha County7. Aurora Memorial8. Bassett Rock County9. Beatrice Beatrice Community10. Benkelman Dundy County11. Blair Memorial Community 12. Bridgeport Morrill County13. Broken Bow Jennie Melham14. Callaway Callaway District15. Cambridge Tri-Valley Health System16. Central City Litzenberg Memorial 17. Chadron Chadron Community

19. Columbus Columbus Community20. Cozad Cozad Community21. Creighton Creighton Area22. Crete Crete Area23. David City Butler Area24. Fairbury Jefferson County25. Falls City Community Medical Ctr.26. Franklin Franklin County27. Fremont Fremont Area

Nebraska Telehealth NetworkNovember 15, 2005

Gering

12

3

1731

8

5

4169 53

32

aa

H

Pender

78

Wayne

Dakota City

66

23G

73Clay Center

62

72

Osmond

PlainviewNeligh

Tilden74

49

6461

21

45

16

K

37

79 Z20

26

47

14

13

58

Albion

30

59T

A

B

C Burwell

I

M

S

O’Neill 571

Revised: 11/16/2005 LLR s:\networking\telehealth\nebraska telehealth network 11162005

38

65

Hemingford

22

Beatrice9

28. Friend Warren Memorial 29. Geneva Fillmore County30. Genoa Genoa Community 31. Gordon Gordon Memorial32. Gothenberg Gothenberg Memorial33. Grand Island St. Francis Medical Center34. Grant Perkins County 35. Hastings Mary Lanning Memorial 36. Hebron Thayer County37. Henderson Henderson Health Services38. Holdrege Phelps Memorial39. Imperial Chase County40. Kearney Good Samaritan Health Sys41. Kimball Kimball County42. Lexington Tri-County43. Lincoln Bryan/LGH44. Lincoln St. Elizabeth's45. Lynch Niobrara Valley46. McCook Community Hospital47. Minden Kearney County48. Nebraska City St. Mary's49. Neligh Antelope Memorial50. Norfolk Faith Regional Health Srvcs51. North Platte Great Plains Regional Medical Ctr52. Oakland Oakland Memorial53. Ogallala Ogallala Community Hospital54. Omaha Methodist Hospital

55. Omaha University of Nebraska Medical Ctr56. Omaha Alegant Health Immanuel57. O'Neill Avera St. Anthony's58. Ord Valley County59. Osceola Annie Jeffrey60. Oskosh Garden County61. Osmond Osmond General 62. Pawnee City Pawnee County 63. Pender Pender Community64. Plainview Plainview Public65. Red Cloud Webster County66. Schuyler Alegent Health 67. Scottsbluff Regional West Medical Center68. Seward Seward Memorial69. Sidney Memorial Health70. St. Paul Howard County71. Superior Broadstone Memorial72. Syracuse Community Memorial73. Tecumseh Johnson County Hospital74. Tilden Tilden Community75. Valentine Cherry County76. Wahoo Saunders County77. Wayne Providence78. West Point St. Francis79. York York General80. Omaha Creighton Hospital81. Winnebago Winnebago Indian Hospital82. Grand Island College Park

F

15

34

O

Q

J

6381

Winneabago

Regional Hub Hospital

T-1 Connection

Aggregate T-1 Connection between Hub Hospitals

19

N

D

56

29

42

51P

10

39

E

2

6

R

52

University Hub

ByranLGH/HHA FastEthernet

Six T1s

St. Paul

40

77

11

687

43

55

70

L35

Single T-1 Connection between Hub Hospitals

Hospitals From Other Statesaa. Sioux City, Iowabb. Norton, Ks Norton County Hospitalcc. Oberlin, Ks Decatur County Hospitaldd. Phillipsburg, Ks Phillips County Hospitalee. Smith Center, Ks Smith County Memorial ff. Mankato, Ks Jewell County Hospital

Dark Fiber Solutions Network Hubsi. Lincoln Bryan LGH, 1600 S. 48thii. Wilber Head End, 901 N. Main, Wilberiii. DFS York, 600 ½ Grand Ave, York

iv. NP GPRMC, 601 W. Leota St., North Plattev. Geneva Head End, 300 C. St, Genevavi. Kearney Head End, 804 Ave. A., Kearney

DFS Network Hub

DFS T-1 connection

46

60

75

iv

North Platte

vii

4

823 T1s

4433

76

vii

vii

WilberiiCrete

3624

28v

Geneva

Norton, Ks Phillipsburg, KsOberlin, Ks cc bb eeSmith Center

ffffMankato

67

York

80

Cable connection

Lincoln

48

2571

2754

U

Kearney

dd

50

3Mb

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)

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

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

Genetics of 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

Localization of genes that influence dyslexia

Locus Region Population Phenotype

DYX8 1p36 N. CarolinaWashington

Phonological Decoding, RAN

DYX3 2p11 NorwayUK

Reading and Spelling

DYX5 3p12-q13 Finland Phonologic Awareness

DYX2 6p22 N. CarolinaColorado, UK

Phonemic AwarenessOrthographic Choice, Phonologic Decoding

DYX4 6q11-2 Canada Phonologic Decoding

7q32 Norway Reading and Spelling

DYX7 11p15.5 Canada Phonologic Decoding

DYX1 15q21 N. CarolinaGermanyNorway

Single Word ReadingSpellingReading and Spelling

DYX6 18p11 Colorado, UK Single word reading, Orthographic Coding

DYX9 Xq27.3 Colorado, UK,Holland

Multiple phenotypes

Reading Disability Loci and Phenotypes

0 0.5

1.0

1.5

2.0

2.5

02

46

810

1214

1618

2022

2426

Po

si tion

(c M)

LOD score

Dis crim

OC

PA

D6S1605 D6S274

D6S1567

D6S422

D6S1597

D6S461

D6S276

D6S1571 D6S1554

D6S105

D6S306 D6S258 D6S1683 MOG3132 D6S273

D6S1568 D6S439

D6S1588

D6S291

D6S1019

12.1

11.1

14.1

16.2

21

p

q

16.1

27

12.3

12

16.3

22.122.2

22.31

23.1

25.3

25.125.2

24.3

24.124.2

23

22.3

22.2

22.1

21.3321.32

21.31

21.2

21.1

12.2

11.2

11.2

13

11.1

14.3

14.2

15

22.32

22.33

23.3

23.2

24.1

24.3

24.2

25.1

25.2

25.3

26

DYX2: 6p22.2: Linkage Analysis

DYX2: 6p22: Association Analysis

VMP DCDC2 KIAA0319 TTRAP THEM2

Deffenbacher et al., 2004

KIAA0319 TTRAPFrancks 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