Genetics in Primary Care: An Introduction

January 17, 2001 - by Jerry Sobieraj, MD

Information in part derived from Genetics in Primary Care (GPC) Materials, which is an NIH funded demonstration project

GPC initiative

• Is genetics in Primary Care important?
• What are the goals? Defining cases, ELSI, future
• Is the hypothesis valid? Understanding genetics in primary care important?

Think "genetically" the mantra of genetics in primary care.
Goal 1: learn to expand differential dx to include "genetic" disorders

Defining potential cases:

1. Pedigrees
   Used commonly in Pediatrics and Family Medicine
   May help to identify modes of transmission, and thus, likelihood of genetic Disorder.
   
   • Patterns to recognize:
   • Autosomal Dominant-affects all generations/both sexes
   • Sex Linked-affects males only, skipping generations
   • Autosomal Recessive-affects both sexes & skips gen.
   
   

   A simple way to keep genetic risk in perspective is to use the Amersterdam Criteria, often referred to as the 3, 2, 1 rule. Three affected relatives, 2 generations, 1 affected relative at a young age (e.g. <50 years old). A pattern such as this, is suggestive of a genetic disorder (e.g. 10% probability) and would be an indication to refer to a geneticist.

2. Screening required at an earlier age due to Family History:
   If you need to change screening for a disorder at an age earlier than average risk in the population, consider referral for genetic evaluation.
   Important to establish age at onset of disorder in family members. (e.g. mother or sister had breast cancer. If both over 60 y.o. at dx, then pt is still of avg. risk; if BOTH had breast cancer after age 70, risk is only marginally increased (16% vs 11% that pt would get breast cancer before 80 y.o.).
   
3. Clinical Findings: define sx and findings where genetic testing becomes automatic ("Red Flags").
   • Dysmorphia: notably altered body habitus
   • Arthritis/Abnormal LFTs/Infertility/DM/increased pigmentation (HHC)
   • Hypertrophic Cardiomyopathy
   • • Fabry's: "Seven unrelated patients with atypical variants of hemizygous Fabry's disease were found among 230 men with left ventricular hypertrophy (>13mm). Fabry's disease should be considered as a cause of unexplained left ventricular hypertrophy. (N Engl J Med 1995;333:288-93.)
     • Beta-myosin heavy-chain gene mutations, varied phenotype
     • Troponin-T mutations, little hypertrophy, high incidence sudden death
   • Dilated Cardiomyopathy: "Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and indicate that this intermediate filament protein has an important role in cardiac conduction and contractility". (N Engl J Med 1999;341:1715-24.)

ELSI (Ethical, Legal and Social Issues related to genetic testing):

• Family implications of testing.
• Who will need testing? Can testing be done directly or is linkage required? Who will contact family members who aren¹t your patient? Should an individual be tested if it has unwanted implications for other family members?
• Other reason to refer to geneticist is when expanded discussion about implications of testing required. A U Mass study surveyed 1500 geneticists, who identied 780 patients who had lost their job due to abnormal genetic testing. Protection only at Federal level, no private employer protection. See Science 2001 February 16; 291: 1249-1251
• Non-directive counseling: in genetic testing, it is recommended to not give one¹s opinion about how they would proceed. Just give the people the info, and let them decide.

Other Issues:

• Genetic Testing when no specific tx e.g. apo E4, found in less than 1/2 w/ late onset AD while presenillin, rare, but strongly linked to early onset AD
• Bad gene, mod-low penetrance BRCA1 & 2, only 50% of affected females will get breast CA. That is, when both the patient's mother and sister had breast cancer in their 20s, 1/2 of them will live to 80 w/o ever developing breast cancer. Contrast to Huntington's where high penetrance of autosomal dominant gene.
• Genetic testing doesn't change Tx e.g. recurrent, idiopathic DVT, only 50% of those clotting abnormality identifiable to date, but likely 100% genetic basis.
• Genotypic testing better than phenotypic e.g. Hemochromatosis occurs in approximately 5 white people per 1000 and is usually due to homozygosity for mutations in the HLA-linked HFE gene. When homozygous relatives, mainly siblings, on the basis of HLA identity with the proband had HFE genotyping 214 homozygous relatives were identified from the 291 homozygous probands (38% of homozygous male relatives had an HHC related condition, 10% of women without a clinical diagnosis of HHC. (N Engl J Med 2000;343:1529-35)
• The future? Polymorphisms in metabolism: cytochrome P450 isozymes may have drug clearance and metabolism phenotypes defined based on genotypes. e.g. CYP3A activation by St John's wort exaggerated in some people, has led to clots when on warfarin and transplant rejection when on immunosuppressants (Science 2001 291: 37).

Genetics in Primary Care, April 11, 2001. Discussion of Breast Cancer and Hemochromatosis