1. Medical Genetics in Pediatric Care: The Science of Medicine
2004 lectures
Over the last decade there have been continual predictions that the Human Genome Project was going to revolutionize primary care medicine. However, despite these predictions , genetic practice in primary care has undergone little change. I would like to analyze some of the reasons for this and begin to formulate a prescription for increased use of the tools of genetic medicine in primary care.
Art Beaudet, in his 1998 Presidential Address to the American Society of Human Genetics predicted: …it is likely that primary-care medicine will soon incorporate age-related panels for genetic screening focused on those disorders for which there is compelling therapeutic intervention.
Judith Miles, M.D., Ph.D.
Children’s Hospital
The University of Missouri-Columbia

2. The Genetic Invasion of Primary Care: Fact or fancy?
Michael McGinnis, director of the U.S. Office of Disease Prevention and Health Promotion predicted in 1988 …”most people will be getting genetic profiles by the year 2000”
Art Beaudet, in his 1998 Presidential Address to the American Society of Human Genetics predicted …”it is likely that primary-care medicine will soon incorporate age-related panels for genetic screening focused on those disorders for which there is compelling therapeutic intervention”

3. History of Medical Genetics
Early Genetics - Biblical, Talmud
Mendel s
Modern Experimental Genetics s
Maize, drosophila, mouse
Medical Genetics s to the present

4. Medical Genetics: 1960s to the present
Single Gene Inheritance
Victor McKusick - Mendelian Inheritance in Man (1966)
1,487 entries ---> >10,000 entries (2003)
Dysmorphology
David Smith
Cytogenetics
Trisomy
Metabolic Genetics
PKU newborn screening – 1956
Extended newborn screening/tandem mass spectroscopy

5. Medical Genetics: 1960s to the present
DNA Genetics
Watson and Crick’s Double Helix
1992 –2003 Human Genome Project
2003 -> the future of medical dx & tx
Prenatal Genetics
1970s - Prenatal Ultrasound & Amniocentesis
Inheritance of Genetically Complex Disorders
Non-Mendelian Genetics
Genomic Imprinting
Triple Nucleotide Repeats
Mitochondrial Inheritance
1990s - Neuropsychiatric Disorders, Diabetes, Cardiovascular
Interaction of genes with environmental triggers

6. Medical Genetics: An Organized Medical Specialty
American Board of Medical Genetics
American Board of Medical Specialties
Missouri Genetics:
Newborn Screening legislation
Missouri Genetic Disease Program
Genetics Legislation  Governor’s Advisory Committee
Governor’s Genetics Initiative

7. Missouri Genetic Disease Legislation - 1985
House Bill No. 612 ( Reps Betty Hearnes and Judy O’Connor)
Senate Bill No. 202 ( Senator Edwin Dirck)

8. Why Genetics Should be Part of Primary Care
Spontaneous abortions - 60%
Neonatal deaths - 50%
Birth defects - 70%
Mental Retardation/ Learning disabilities - 70%
Cancers: Breast (BRAC 1 and 2), Colon (FAP)
Cardiovascular and Stroke
Diabetes
Neuropsychiatric - autism, manic depressive disease, alcoholism, ADHD etc
Neurodegenerative: Alzheimers, ataxias

9. Reasons Why Medical Genetics Hasn’t Lived Up to the Predictions
Physicians are uncomfortable with basic genetics
Primary care physicians don’t have time for genetics
Genetics of the “common disorders” hasn’t reached the stage where it is useful
susceptibility genes have a low predictive value
Patients aren’t ready for genetic testing
Issues of screening and presymptomatic testing are very complex

10. We all look at the world through our own key holes
We all look at the workd through our own key hole
I counter that what the specialty of Medical Genetics has to bring to other physicians is not just DNA diagnosis but a different way of approaching diagnosis.

11. Geneticists think about diagnosis differently
We use different tools
Family History
Dysmorphology exam
Diagnostic Databases
DNA diagnoses
Syndrome diagnoses
heterogeneity
expressivity
penetrance

12. Genetic Approach To Diagnosis
Recurrence risk driven
Organized by etiology
Symptoms the etiologic differential diagnosis
Intra vs inter familial variability establishes the etiologic subgroups

13. How Geneticists Think about Diseases
Patterns of Inheritance
Single Gene Mutations
Chromosome
Multifactorial
Complex/Non-Mendelian/Epigenetic
The geneticist adds the inheritance pattern into the diagnostic paradigm
The geneticist adds the inheritance pattern into the diagnostic paradigm

14. Single Gene Disorders Dominant Inheritance Recessive Inheritance
X-linked Inheritance

15. Autosomal Dominant Inheritance
Single gene which is dominant to its allele
50% recurrence risk
males and females equally affected
new mutations
Define alleles
Examples: Marfans, neurofibromatosis, myotonic dystrophy

16. The Marfan Syndrome
Chris Patton died playing pickup game. On scholarship for two years without diagnosis.
“dead before he hit the ground.”

17. The Marfan Syndrome Flo Hyman - 1986
Ruptured her aorta during professional volleyball match
Member of U.S. national team for 12 years - Olympic silver medalist (‘84)

18. Marfans Syndrome

19. Dominant Pedigree
= Affected

20. among affected individuals
Variable Expression
The nature and severity of the disorder which varies
among affected individuals

21. Proportion of individuals who carry the gene
Penetrance
Proportion of individuals who carry the gene
and
manifest the trait

22. Marfans Syndrome Diagnostic Criteria
Skeletal
Ocular
Cardiovascular
Pulmonary
Dural ectasia
Skin and Integument
2 major criteria + 3rd organ system or
Family history of Marfans
+ 1 major criteria
+2nd organ system
American Journal of Medical Genetics, 1996

23. Skeletal - Major Criteria
Pectus carinatum
Pectus excavatum requiring surgery
 U/L ratio or span/height  1.05
scoliosis > 20° or spondylolisthesis
+ wrist and thumb signs
 elbow extension (< 170°)
medial displacement of medial malleolus  pes planus
protrusio acetabulae

24. Skeletal - Minor Criteria
Pectus excavatum of moderate severity
joint hypermobility
high arched palate with crowding of teeth
characteristic facies
For skeletal system to be considered involved, at least 2 major criteria or one major plus 2 minor criteria must be present.

25. Ocular system Major criteria: Minor criteria: Ectopia lentis
abnormally flat cornea
increased axial length of the globe
hypoplastic iris or ciliary muscle  decreased miosis

26. Cardiovascular - Major Criteria
Dilatation of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of Valsalva
Dissection of the ascending aorta

27. Cardiovascular - Minor Criteria
Mitral valve prolapse +/- mitral valve regurgitation
Dilatation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis or any other obvious cause, below the age of 40 years

28. Cardiovascular - Minor Criteria
Calcification of the mitral annulus below the age of 40 years
Dilatation or dissection of the descending thoracic or abdominal aorta below the age of 50 years.

29. Cardiovascular
For the cardiovascular system to be involved a major criteria or only one of the minor criteria must be present.
Dilatation of the aortic root is diagnosed when the maximum diameter at the sinuses of Valsalva, measured by echocardiography, CT or MRI, exceeds the upper normal limits for age and body size.

30. Pulmonary System Major criteria: none Minor criteria:
spontaneous pneumothorax
apical blebs on CXR
For the pulmonary system to be involved one of the minor criteria must be present.

31. Skin and Integument Major criteria: none Minor criteria:
striae atriophicae not associated with marked weight changes, pregnancy or repetitive stress
recurrent or incisional herniae
For the skin and integument to be involved one of the minor criteria must be present.

32. Dura Major criteria: Minor criteria: none
lumbosacral dural ectasia by CT or MRI
Minor criteria: none
For the dura to be involved the major criterion must be present.

33. Heterogeneity The finding that what had previously been thought to be one disorder, is actually made up of two or more etiologically distinct disorders

34. Homocystinuria Marfanoid body habitus. Tall stature. Arachnodactyly
Homocystinuria Marfanoid body habitus Tall stature Arachnodactyly Pectus excurvatum Scoliosis Ophthalmologic Myopia Lens dislocation Vascular Intimal hyperplasia Thrombosis

35. Homocystinuria Mental retardation - 22% Learning disabilities - high
Seizures - 10 to 15%
Schizophrenia - case reports
Psychiatric symptoms
Flat affect
Inappropriateness
Odd behavior
Concrete thinking

36. Recessive Pedigree
= Affected

37. Homocystinuria Mental retardation - 22% Learning disabilities - high
Seizures - 10 to 15%
Schizophrenia - case reports
Psychiatric symptoms
Flat affect
Inappropriateness
Autistic behavior
Concrete thinking

38. X - Linked Recessive Inheritance

39. Child with Mental Retardation

40. Dysmorphology

41. Chromosome Disorders are Subtle

42. 47, XYY

43. XYY Male Alan Varrin Behavior Impulsive Low normal IQ
Poor social interactions and self esteem
Non-violent
never smoked, drank, used drugs
Recurrent Car Theft and check cashing x 1
60 year sentence as a recurrent offender
Eligible for disability and vocational rehabilitation under MRDD

44. XYY Karyotype

45. Unbalanced Chromosome Translocation
46, XY, der(16)t(3;16) (p25;p13)mat

46. Pedigree 46,XX, T (3;16) = Unbalanced Translocation Carrier
TAB
SAB
SAB
SAB
= Unbalanced Translocation Carrier
= Balanced Translocation Carrier

47. 22q- Syndrome - CATCH 22

48. Chromosome Deletions DiGeorge Syndrome Williams Syndrome
Prader Willi Syndrome
Angelman Syndrome
Cri de Chat Syndrome
Beckwith Weidemann Syndrome
etc.

49. DiGeorge Karyotype

50. Deletion by FISH Analysis

51. Multifactorial Disorders
Caused by a combination of genetic and environmental factors
Recurrence Risk is about 3% for 1o relatives
Structural Birth Defects:
Spina Bifida,Cleft lip and palate, Congenital Hearts
Adult Aging Disorders:
Hypertension, Diabetes, Alzheimers
Neuropsychiatric Disorders
Autism, Depression, Alcoholism, Schizophrenia

52. Spina Bifida & Anencephaly

53. Clinical Genetic Data Bases
Online Mendelian Inheritance in Man – OMIM
www. Omim.org
Gene Clinics
National Newborn Screening and Genetics Resource Center web site: NNSGRC –
Alliance of Genetic Support Groups

54. Future of Medical Genetics
Better Diagnoses
Better Treatments
Better Prevention
Cures
Better informed consumers, health care providers, lawyers, public policy makers

55. Genetic Testing USES Diagnostic Predictive Carrier Prenatal
Newborn Screening
TOOLS
Cytogenetic
Metabolic
DNA

56. Questions about genetic testing?
What kind of genetic test is it?
How would the genetic test be used?
Would the genetic test help or hurt my patient?
How is the genetic test applied in this situation?
Where can I find a lab that does the test?
Who will interpret the results?

57. Predictive/Presymptomatic Genetic Testing
Family history of the disorder
Huntington disease
Familial adenomatous polposis - FAP
Breast cancer
Population Screening
Hemochomatosis

58. The Huntington Disease Collaborative Research Group
THE GENE IS CLONED
March 23, 1993
The Huntington Disease Collaborative Research Group

59. Huntingtons - Clinical Features Classical Triad
Choreiform Movements (95%)
Dementia (Subcortical/basal ganglion dysfunction)
Personality Changes

60. Genetics of Huntingtons
Chromosome 4
Autosomal Dominant - 50% risk for offspring
Triple Nucleotide Repeat Disorder
CAG repeat size classification
< 30 = Normal
30-38 = Indeterminate
>39 = considered to be in the HD range

61. Presymptomatic Dx Advantages
Ability to have unaffected children
Informed family planning
Career decisions
Relief from fear
Relieve children from fear
Research

62. Presymptomatic Dx Disadvantages
Loss of hope
Suicide
Marital problems
Pressure to take the test
Insurance problems
Knowledge of risk to children
Every ache and pain --- this is it!

64. 63 y
d. 35 y
33 y
28 y
39 y
14 y
10 y
6 y
= FAP

67. GENETests www.genetests.org
Gene Tests: whose doing what tests?
Directory of Medical Genetics Laboratories
Gene Reviews: A medical knowledge base relating genetic testing to the diagnosis, management, and genetic counseling of individuals and families with specific inherited disorders.
Expert-authored and Peer-reviewed
Gene Clinics: Find appropriate referrals anywhere.

69. Prenatal Screening vs Definitive Testing
Population Screening
MSAFP + testing
Ultrasound
Most other “routing prenatal tests”
Definitive Testing
amniocentesis
chorionic villus sampling

70. Prenatal Testing Routine: Chromosome abnormalities One test Sporadic
Usually indicated by maternal age or abnormal serum screen or ultrasound findings
Relatively frequent

72. Spectral Karyotype

73. Prenatal Testing Non-routine: Single-gene disorders
Thousands of individual tests
Heritable
Usually indicated by family history
Rare

74. Osteogeneis Imperfecta Type 2

75. Osteogenesis Imperfecta Type 2

76. Carrier Testing
Carrier of a recessive gene: ex. Cystic Fibrosis, Duchenne Muscular Dystrophy, Tay Sachs, Sickle Cell Anemia
Carrier of a chromosome translocation

77. Genetic Testing: Newborn Screening
Phenylketonuria
Sickle Cell Disease
Galactosemia
Hypothyroidism
Congenital Adrenal Hyperplasia
Expanded Newborn Screening
Maple Syrup Urine Disease
Homocystinuria
Biotinidase Deficiency

78. Population Screening NIH consensus panel - April 1997
Cystic Fibrosis Screening
NIH consensus panel - April 1997
recommended offering testing to:
family members
partners of carriers
couples planning a pregnancy
couples seeking prenatal testing
Adult Screening
Hemochomatosis Screening

79. Child’s Double Helix

80. GENEClinics www.geneclinics.org
A medical knowledge base relating genetic testing to the diagnosis, management, and genetic counseling of individuals and families with specific inherited disorders.
Expert-authored and Peer-reviewed