Medical Genetics in Pediatric Care: The Science of Medicine

Judith Miles, M.D., Ph.D. Children’s Hospital

The University of Missouri-Columbia

2004 lectures

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”

History of Medical Genetics

• Early Genetics - Biblical, Talmud

• Mendel - 1860s

• Modern Experimental Genetics - 1900s

– Maize, drosophila, mouse

• Medical Genetics - 1960s to the present

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 - 1964

– Cytogenetics

• Trisomy 21 - 1959

– Metabolic Genetics

• PKU newborn screening – 1956

• Extended newborn screening/tandem mass spectroscopy - 2003

– 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

Medical Genetics: 1960s to the present

–DNA Genetics•1953 - Watson and Crick’s Double Helix

•1992 –2003 Human Genome Project

•2003 -> the future of medical dx & tx

Medical Genetics:An Organized Medical Specialty

– American Board of Medical Genetics - 1980

– American Board of Medical Specialties - 1993

– Missouri Genetics:

• Newborn Screening legislation - 1965

• Missouri Genetic Disease Program - 1980

• Genetics Legislation Governor’s Advisory Committee - 1986

• Governor’s Genetics Initiative - 1990

Missouri Genetic Disease Legislation - 1985

House Bill No. 612 ( Reps Betty Hearnes and Judy O’Connor)Senate Bill No. 202 ( Senator Edwin Dirck)

• 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

Why Genetics Should be Part of Primary Care

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

We all look at the world

through our own key holes

Geneticists think about diagnosis differently

We use different tools Family History Dysmorphology exam Diagnostic Databases DNA diagnoses

Syndrome diagnoses heterogeneity expressivity penetrance

Genetic Approach To Diagnosis

Recurrence risk driven

Organized by etiology

Symptoms the etiologic differential diagnosis

Intra vs inter familial variability establishes the etiologic subgroups

• Patterns of Inheritance

– Single Gene Mutations

– Chromosome

– Multifactorial

– Complex/Non-Mendelian/Epigenetic

How Geneticists Think about Diseases

The geneticist adds the inheritance pattern into the diagnostic paradigm

• Dominant Inheritance

• Recessive Inheritance

• X-linked Inheritance

Single Gene Disorders

Autosomal Dominant Inheritance

The Marfan Syndrome

• Chris Patton - 1976 died playing pickup game. On scholarship for two years without diagnosis.

• “dead before he hit the ground.”

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)

Marfans Syndrome

Dominant Pedigree

= Affected

Variable Expression

The nature and severity of the disorder which varies

among affected individuals

Penetrance

Proportion of individuals who carry the gene

and

manifest the trait

Marfans Syndrome Diagnostic Criteria

• Skeletal

• Ocular

• Cardiovascular

• Pulmonary

• Dural ectasia

• Skin and Integument

American Journal of Medical Genetics, 1996

2 major criteria + 3rd organ system

Family history of Marfans + 1 major criteria

+2nd organ system

or

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

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.

Ocular system

• Major criteria:– Ectopia lentis

• Minor criteria:– abnormally flat

cornea– increased axial

length of the globe– hypoplastic iris or

ciliary muscle decreased miosis

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

Cardiovascular - MinorCriteria

• 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

Cardiovascular - MinorCriteria

• 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.

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.

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.

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.

Dura

• Major criteria: – lumbosacral dural ectasia by CT or MRI

• Minor criteria: none

• For the dura to be involved the major criterion must be present.

Heterogeneity

The finding that what had previously been thought to be one disorder, is actually made up of

two or more etiologically distinct disorders

Homocystinuria Marfanoid body habitus Tall stature Arachnodactyly Pectus excurvatum Scoliosis Ophthalmologic

MyopiaLens dislocation

Vascular Intimal hyperplasia Thrombosis

Homocystinuria

Mental retardation - 22% Learning disabilities - high Seizures - 10 to 15% Schizophrenia - case reports Psychiatric symptoms

Flat affect Inappropriateness Odd behavior Concrete thinking

Recessive Pedigree

= Affected

Homocystinuria

Mental retardation - 22% Learning disabilities - high Seizures - 10 to 15% Schizophrenia - case reports Psychiatric symptoms

Flat affect Inappropriateness Autistic behavior Concrete thinking

X - Linked Recessive Inheritance

Child with Mental Retardation

Dysmorphology

Chromosome Disorders are Subtle

47, XYY

XYY MaleAlan Varrin

Behavior ImpulsiveLow normal IQPoor social interactions and self esteemNon-violent never smoked, drank, used drugs

Recurrent Car Theft and check cashing x 160 year sentence as a recurrent offender

Eligible for disability and vocational rehabilitation under MRDD

XYY Karyotype

Unbalanced Chromosome Translocation

46, XY, der(16)t(3;16) (p25;p13)mat

Pedigree

TAB SAB SAB SAB

= Unbalanced Translocation Carrier

= Balanced Translocation Carrier

46,XX, T (3;16)

22q- Syndrome - CATCH 22

Chromosome Deletions

• DiGeorge Syndrome

• Williams Syndrome

• Prader Willi Syndrome

• Angelman Syndrome

• Cri de Chat Syndrome

• Beckwith Weidemann Syndrome

• etc.

DiGeorge Karyotype

Deletion by FISH Analysis

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

Spina Bifida & Anencephaly

Clinical Genetic Data Bases

• Online Mendelian Inheritance in Man – OMIM• www. Omim.org

• Gene Clinics• www.geneclinics.org

• National Newborn Screening and Genetics Resource Center web site: NNSGRC – • www.genes-r-us.uthscsa.edu/

• Alliance of Genetic Support Groups • www.medhlp.netusa.net/www/agsg.htm

Better Diagnoses

Better Treatments

Better Prevention

Cures

Better informed consumers, health care

providers, lawyers, public policy makers

Future of Medical Genetics

Genetic Testing

USES

• Diagnostic

• Predictive

• Carrier

• Prenatal

• Newborn

Screening

TOOLS

• Cytogenetic

• Metabolic

• DNA

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?

Predictive/Presymptomatic Genetic Testing

• Family history of the disorder

• Huntington disease

• Familial adenomatous polposis - FAP

• Breast cancer

• Population Screening

• Hemochomatosis

HUNTINGTON DISEASE

THE GENE IS CLONED

March 23, 1993

The Huntington Disease Collaborative Research Group

Huntingtons - Clinical Features

Classical Triad

Choreiform Movements (95%)

Dementia (Subcortical/basal ganglion dysfunction)

Personality Changes

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

Presymptomatic Dx Advantages

Ability to have unaffected children

Informed family planning

Career decisions

Relief from fear

Relieve children from fear

Research

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!

= FAP

10 y10 y

d. 35 yd. 35 y63 y63 y

39 y39 y 33 y33 y 28 y28 y

6 y6 y14 y14 y

GENETestswww.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.

–

–

Prenatal Screening vs

Definitive Testing• Population Screening

– MSAFP + testing– Ultrasound– Most other “routing prenatal tests”

• Definitive Testing– amniocentesis – chorionic villus sampling

Prenatal Testing

• Routine: Chromosome abnormalities

– One test

– Sporadic

– Usually indicated by maternal age or abnormal

serum screen or ultrasound findings

– Relatively frequent

Spectral Karyotype

Prenatal Testing

• Non-routine: Single-gene disorders

– Thousands of individual tests

– Heritable

– Usually indicated by family history

– Rare

Osteogeneis Imperfecta Type 2

Osteogenesis Imperfecta Type 2

Carrier Testing

• Carrier of a recessive gene: ex. Cystic Fibrosis, Duchenne Muscular Dystrophy, Tay Sachs, Sickle Cell Anemia

• Carrier of a chromosome translocation

Genetic Testing: Newborn Screening

• Phenylketonuria• Sickle Cell Disease • Galactosemia• Hypothyroidism• Congenital Adrenal Hyperplasia• Expanded Newborn Screening• Maple Syrup Urine Disease• Homocystinuria• Biotinidase Deficiency

• 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

Population Screening

Child’s

Double

Helix

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