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

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

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 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: 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)

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

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 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.

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

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

Single Gene Disorders Dominant Inheritance Recessive Inheritance X-linked Inheritance

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

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

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

Proportion of individuals who carry the gene 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 2 major criteria + 3rd organ system or Family history of Marfans + 1 major criteria +2nd organ system American Journal of Medical Genetics, 1996

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: Minor criteria: Ectopia lentis 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 - 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

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.

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: 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.

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 Homocystinuria Marfanoid body habitus Tall stature Arachnodactyly Pectus excurvatum Scoliosis Ophthalmologic Myopia Lens 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 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

XYY Karyotype

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

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

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

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

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

The Huntington Disease Collaborative Research Group 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!

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

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.

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

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

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