CHRISTINA M. LAUKAITIS, MD, PHD, FACP

7 APRIL 2013

Adult Genetics in Primary Care

Disclosures

� I have nothing to disclose.

Outline

� Review of genetics & testing issues

� Cancer syndromes

� Genetic diagnoses commonly encountered in IM

� Managing adults with “congenital” disorders

� Resources

Genetics contributes to patient care

Genetic diagnosis can suggest treatment

Germline DNA mutations cause inherited disease

� Somatic DNA changes are a major factor in SPORADIC cancer

� Also may cause mosaicism

� Autosomal Dominant

� Incompletely Dominant

� Autosomal Recessive

� Sex-linked

� Multi-factorial /Complex Disease� Genes & environment

� Multiple genes, small effect sizes

Two Minute Review of Genetics

� Mutations in structural proteins� Incomplete penetrance

� Age-related penetrance

� Variable expressivity

� Anticipation

� Examples� Marfan syndrome

� Breast/ovarian cancer syndrome

� BRCA1, BRCA2

� Polycystic kidney disease

� Neurofibromatosis 1

� Huntington disease

Autosomal Dominant Inheritance

Autosomal Recessive Inheritance

X-linked Inheritance

Male-pattern baldness is AD with sex-limited expression!!!!!

XY XX

XY XX XX

� X-chromosome genes� Males affected

� Females unaffected

or less affected

� Examples� Color blindness

� Hemophilia

� Fragile X

� Anticipation

� Pre-mutation carriers have

ataxia, premature ovarian failure

� Multiple influencing factors� Multiple interacting genes

� Small effect sizes

� Synergy between genes

� Environmental influence

� Examples� Alzheimer disease

� Heart disease

Multifactorial (Complex) Disease

Mutation typeMutation type Disease causedDisease caused

� Gene sequence� Early termination

� Missense

� Gene structure� Repeat expansions

� Exon deletions, duplications

� Chromosomal� Microdeletion, duplication

� Monosomy/Trisomy

� Most BRCA1 & BRCA2

� Huntington disease, SCA

� Some BRCA1

� VCFS

� Down & Turner syndrome

Mutations can be of different types

� Review of genetics & testing issues

� Cancer syndromes

� Genetic diagnoses commonly encountered in IM

� Managing adults with “congenital” disorders

� Resources

Germline & somatic mutation influence cancer

Indications for evaluation for a cancer genetic syndrome

Suspicion of inherited cancer susceptibility syndromes

Multiple affected family members in successive generations

Early age of onset

Multifocal or bilateral tumors

Questions about cancer risk in offspring or extended family

members

Occurrence of cancer frequently associated with germ line

mutations (e.g. pheochromocytoma)

� CC: “My sister was just diagnosed with breast cancer at age 44, my aunt had both breast and ovarian cancer. I’m worried about my cancer risk.”

42 y/o new female patient

a) The new guidelines say to start screening at 50, that’s fine for you. Don’t worry about your ovaries.

b) OMG, I’ll refer you to a surgeon to remove your breasts, ovaries, gallbladder and appendix immediately!

c) I’d like you to see a genetic counselor for evaluation and testing, I’ll order a screening mammogram and performing a breast exam today.

d) I just got a 23andme brochure, let’s see what they say about your risk!

e) I’ll take a cheek swab and send it to Myriad. I think insurance will pay, if not, we’ll split the $3500 bill.

What is the best response?

Pedigree

Breast cancer

Ovarian cancer

44 42

Br-48Ov-52

� Your patient’s sister was tested for BRCA mutations and has a deleterious mutation.

� The counselor coordinates testing your patient for this mutation, keeping you informed of the process and the results.

Follow Up

?

She is at VERY high risk for cancer

Risk by age %

Breast cancer Ovarian cancer

BRCA1 BRCA2 BRCA1 BRCA1

30 3 0 <2 1

40 21 17 5 2

50 39 34 20 10

60 58 48 40-50 18

70 69 74 50-60 18

80 81 85 62 25

Lifetime 85 85 62 25

Male carriers 6 7 NA NA

General population

12.5% (females)<1% (males)

1-2%

� She limits alcohol, improves her diet to maintain a healthy weight and intensifies her exercise

� You refer her to a provider experienced in managing women at high risk of cancer

� She is screened q6 mo. for breast cancer with alternating mammography & MRI

� She is screened q6 mo. for ovarian cancer with TVUS & CA-125

� She is considering other risk reduction options:� Chemoprevention

� Risk-reducing oophorectomy

� Risk-reducing mastectomy

You manage her care appropriately

Outcome 2: Your patient and her sister have a VUS

Variants of Uncertain Significance

BRCA2 1505T Uncertain significance

� Her mother three DVTs, and a maternal aunt died of PE

Outcome 3: The unexpected disease

Breast cancer

Ovarian cancer

Thrombosis

� Your patient’s mother is tested and found to have a prothrombin gene mutation� Prothrombin 20210A

� Your patient is tested and carries the same mutation

� Your patient also carries a BRCA mutation� Based on her genetically increased clotting risk, you astutely advise her that she should NOT take tamoxifen for chemoprevention

Alternative outcomes…

a) You have twice the average risk of breast cancer

b) 75% of women like you will NOT get breast cancer

c) You have a high risk of developing breast cancer

d) 1 of 4 women like you will develop breast cancer

Which statement conveys the highest amount of risk?

Your next patient…

Genes & disease influence colon cancer risk

Risk factorLifetime Risk of CRC

General Population 6%

Personal history of CRC 15-20%

Inflammatory Bowel Disease 15-40%

Hereditary Nonpolyposis Colon Cancer (HNPCC)

60-80%

Familial Adenomatous Polyposis >95%

Kohlmann & Gruber, GeneReviews 2006

HNPCC (Lynch syndrome)

� Gx: AD� Mismatch repair gene mutations� MLH1, MSH2, MSH6, PMS2

� Dx: FH� Colon, uterus, ovarian, GI CA� Skin lesions� MSI, IHC of tumor� Gene sequencing

� Tx: � Colonoscopy yearly from age 20� TVUS w/bx & CA125 yearly from 30� ?Upper endoscopy & urine cytology

� Px: � 80% colon, 20-60% endometrial , 10% ovarian cancer lifetime risk� Patients tend to do well, surviving multiple bouts with cancer

Another pedigree

Colorectal cancer screening

� Colonoscopy every 10 years

� Flex sig or CTC q5 years

� gFOBT or FIT yearly

� Starting at age 50

� Colonoscopy

� Every 1-2 years

� Starting at age 20-25 or 10 years younger than earliest cancer in family

General populationGeneral population HNPCCHNPCC

Gastroenterology 2010; 138:2115-2126 NCCN Practice Guidelines in Oncology – v.1.2011

HNPCC Surveillance—gene carriers or at-risk relatives

� Women—Endometrial & Ovarian� Patient education & prompt response to symptoms

� TV US with endometrial sampling yearly, CA-125 q 6-12 months

� Start age 30-35, or 5-10 years before earliest gyne cancer diagnosis

� Consider prophylactic hysterectomy, BSO, and chemoprevention

� Extra-colonic� Gastric/duodenal: Consider upper GI endoscopy at age 25-30, repeat every 1-3 years

� Urothelial: Consider annual UA and renal collecting system imaging

� CNS: Annual physical exam

� Pancreatic: No recommendations

NCCN Practice Guidelines in Oncology – v.1.2009

Tumors with >10% genetic causes

� Review of genetics & testing issues

� Cancer syndromes

� Genetic diagnoses commonly encountered in IM

� Managing adults with “congenital” disorders

� Resources

1. BREAST/OVARIAN CANCER SYNDROME

2. HNPCC

3. HUNTINGTON DISEASE

4. CYSTIC FIBROSIS

5. CARDIAC CHANNELOPATHIES

6. MARFAN SYNDROME

7. POLYCYSTIC KIDNEY DISEASE

8. HEMOCHROMATOSIS

9. THROMBOPHILIA

10. NEUROFIBROMATOSIS TYPE1

11. DOWN SYNDROME

Top 11 Genetic Diagnoses for the Internist

42 y/o male established patient

� PMH: HTN, depression

� FH: Adopted

� CC: I just met with my birth mother, and she says my father died of Huntington Disease. I would like to be tested for HD!

What is the most appropriate response?

a) Sure, I’ll give you an order and

send a post-card with your results.

b) Why would you want to know that?

You can’t treat HD anyways.

c) I’d like you to see a genetic counselor to discuss

this diagnosis and the implications of testing.

Points to consider about genetic testing

Pre-test counseling

Health Insurance Portability and Accountability Act

Health Insurance Portability and Accountability Act

Genetic Information Nondiscrimination Act

Genetic Information Nondiscrimination Act

� HIPAA, enacted 2003

� Genetic Information may fall under Protected Health Information (PHI)

� Insurance plan may not exclude someone from group coverage� Plan may request genetic results

� Plan may charge higher premiums to an individual

� Plan may not require test results in order to reimburse cost of test

� GINA, enacted 2008

� Prohibits discrimination in health coverage or employment based on genetic information

� Insurers may not request, require, or use genetic information for deciding on coverage, rates, or pre-existing conditions

� Employers may not use genetic information for hiring, firing, or promotion decisions

Current Protections for Genetic Information

3. Huntington’s Disease

� Gx: � Autosomal dominant, with anticipation

� Trinucleotide repeats in the Huntingtin gene

� Dx: Clinical� Choreiform movements, dysarthria

� Cognitive dysfunction

� Psychiatric distubrance

� FH—especially FH of “mental problems”

� Molecular testing (PCR for >36 CAG repeats)

� Tx: Supportive, symptom-targeted

� Px: Progressive, unremitting, death in 15-18 years

� How do you feel about the results? � Suicidal?

� Guilty about passing on a disease gene?

� Relieved?

� Guilty NOT to be affected while siblings/parents are?

� Who else needs to be notified of the result?

� Who else should be tested?

Result disclosure must involve post-test counseling

4. Cystic fibrosis

� Gx: AR, CFTR gene mutations� ∆F508 common; 1/20 NW Europeans is a carrier� Compound heterozygotes

� Dx: � Clinical:

� Classic� Lung infections, thick secretions, bronchiectasis, fibrosis, parasinusitis

� Pancreatic insufficiency, DM, Salt loss, Infertility (male)� Non-classic

� CBAVD or pancreatitis, or chronic bronchiectasis

� Sweat chloride testing� Molecular testing

� Tx: Abx, mucolytic enzymes, pancreatic enzymes, insulin� ART if fertility is desired

� Px: Classic live into 30’s (M>F); non-classic >60

Jervell & Lange-Nielson

Romano-Ward

Jervell & Lange-Nielson

Romano-Ward Brugada SyndromeBrugada Syndrome

� Gx:

� AD—long QT

� AR—long QT & deafness

� Dx:

� FH sudden death, deafness

� EKG with long QT

� Tx: ICD, B-blockers

� No drugs, stress, exercise

� Cochlear implants

� Px:

� JLNS:½ of untreated die by 15

� RWS: events in teens-20’s

� May be responsible for some SIDS

� Gx:

� AD—SCN5A

� Dx:

� ST abnormalities in V1-V3

� Tx: ICD, quinidine

� Avoid drugs that worsen

� Care with anesthetics

� Px: Death at ~40, w/o tx

5. Cardiac channelopathies

6. Marfan syndrome

Marfan syndrome

� Gx: AD� Fibrillin gene mutation

� Disrupts connective tissue structure

� Dx: Clinical (>2 organ systems)� Aortic dilation� Lens dislocation� Long limbs & digits, joint hypermobility � Dural ectasia, striae or herniae, spontaneous PTX or apical blebs� Molecular testing available

� Tx: � ARB, β-blocker to slow aortic dilation

� Inhibit TGF-beta pathway� Decrease pulse pressure (???)

� Aortic root replacement at >4-5 cm

� Px: Nearly-normal lifespan with good management

7. Polycystic kidney disease

� Gx: AD (although there is an early onset AR form)� PKD1 & PKD2 mutations� 2 loci on different chromosomes

� Dx: Clinical� Cysts in kidney, pancreas, liver, seminal vesicles, arachnoid membrane

� Age-related increase in number (age-related penetrance)

� Molecular testing available

� Tx: � ACE/ARB, diet� Avoid nephrotoxic agents, caffeine, estrogens (for liver cysts), smoking� Tx infection aggressively, cyst excision for pain control if conservative tx fails� MRI monitoring for intracranial lesions (if have FH of same)

� Px: � 50% have ESRD by age 60� 25% with MVP� 22% risk of subarachnoid hemorrhage if FH (6% w/o FH)

Age-related penetrance of ADPKD

In a person at 50% risk, dx can be made with:

•At least two unilateral or bilateral cysts in

individuals younger than age 30 years

•Two cysts in each kidney in individuals ages 30 to

59 years

•Four cysts in each kidney in individuals age 60

years or older

8. Hemochromatosis

� Gx: AR, incomplete penetrance� HFE gene mutation

� Increases GI iron absorption� 1/9 NW Europeans is carrier

� Dx: Clinical suspicion� Liver failure, skin bronzing, pancreatic failure/DM, joint pain,hypogonadism, cardiomyopathy

1. Test for iron overload—transferrin-iron saturation >45%2. Molecular confirmation for C282Y or H63D mutations3. Liver biopsy

� Tx: Phlebotomy to keep serum ferritin at <50 ng/mL� Px:

� Most people homozygous for HME mutations never develop Sx!� Males develop symptoms between ages 40-60� Females after menopause

9. Thrombophilias

� Gx: Incomplete dominance� Factor V Leiden

� Prothrombin gene mutation 20210G>A

� Dx:� Factor levels/activity, molecular genetic testing

� Recurrent or unprovoked vte, pregnancy loss

� Tx:� Use clinical judgement

� Genetic predisposition pushes toward long-term α-coag

� Px:� Het’s generally do well

� Homozygotes, mixed gene, or gene & acquired risk factors do poorly

� Review of genetics & testing issues

� Cancer syndromes

� Genetic diagnoses commonly encountered in IM

� Managing adults with “congenital” disorders

� Resources

1. BREAST/OVARIAN CANCER SYNDROME

2. HNPCC

3. HUNTINGTON DISEASE

4. CYSTIC FIBROSIS

5. CARDIAC CHANNELOPATHIES

6. MARFAN SYNDROME

7. POLYCYSTIC KIDNEY DISEASE

8. HEMOCHROMATOSIS

9. THROMBOPHILIA

10. NEUROFIBROMATOSIS TYPE1

11. DOWN SYNDROME

Top 11 Genetic Diagnoses for the Internist

10. Neurofibromatosis I

Variable expressivity

Neurofibromatosis Type I

� Gx: AD—NF1 gene mutation

� Tumor suppressor

� 50% new mutation; No role for molecular testing (>500 mutations)

� Dx: Clinical—2 or more:

>2 neurofibromas/1 plexiform NF >6 café au lait >15 mm

Inguinal/axillary freckling Optic glioma

>2 Lisch nodule (iris hamartoma) Family history of NF1

Osseous lesion (sphenoid dysplasia, tibial pseudarthrosis)

� Tx: Monitor eyes, growths, development, bp

� Remove transformed, painful lesions; tx with chemo, no radiation

� Px: 15-year reduction in life expectancy

� 50% with learning disabilities

� 10% lifetime rate of malignant transformation

Monitoring for patients with NFI

Medical problem Onset Screening

Hypertension Teens +Yearly blood pressure

screening

Pheochromocytoma 10+Yearly bp and symptom

screening

Breast cancer <50Mammogram starting at

40

Malignant nerve sheath

tumor5-75 years

Symptom-based

monitoring

Osteopenia/osteoporosis Teens +Symptom awareness,

DEXA from 40?

11. Down syndrome

� Gx: Trisomy 21, occasionally translocation or other

� Dx: Karyotype, characteristic facial features

� Tx: Supportive� Watch for hypothyroid, DMII, hearing loss, MVP, cataracts

� Leukemia & testicular cancer

� Spinal cord compression atlantoaxial instability

� May need special dental care, screen for OSA

� Mental health—depression, OCD, abuse, conduct d/o

� Alzheimers develops by age 40 (presinilin is on Chr 21)

� Parents must prepare for child to outlive them

� Px: Live into >50’s� Am Fam Physician 2001;64:1031-8,1039-40

Screening for patients with Down syndrome

Medical problem Onset Screening

Cardiac disease (mitral

valve)Congenital or acquired

Yearly auscultation, may

need echo

Hypothyroidism Childhood + Yearly TSH

Diabetes Teens +Yearly blood sugar

monitoring

Mental health disorders Teens +Screen for depression,

OCD, abuse,

Obesity & low muscle tone Childhood + Obstructive sleep apnea

Atlanto-axial instability Childhood +Symptoms of spinal cord

compression

Peridontal decay Teens + Twice-yearly dental visits

Alzheimer’s disease 40-50Anticipatory guidance,

estate planning

DD, NOS

� Age-specific screening� BP, cholesterol, DM

� Don’t assume the patient is not sexually active!

� By choice or by force

� Do the pap, if possible

�May need to coordinate numerous procedures to be done under a single sedation

� Look up disorder & med-specific concerns� Increased renal cell cancer risk in tuberous sclerosis

� Anti-seizure med’s require early DEXA

� Anti-psychotic med’s increase DM risk

� Use your resources� Genetic counselors

� High-risk providers

� Think about the entire family� When possible, test an affected person first

� Do others need testing/screening?

� Be prepared for the unexpected� Variants of uncertain significance

� Incomplete or mis-reported family history

� Diagnoses different than reported

� Patient response to test results

Summary

� Review of genetics & testing issues

� Cancer syndromes

� Genetic diagnoses commonly encountered in IM

� Managing adults with “congenital” disorders

� Resources

Local resources

� Adult genetics� Zoe Powis, MS, CGC

� Gail Martino, MS, CGC

� Christina Laukaitis, MD, PhD

� High-risk cancer genetics clinic� 694-CURE

� Gail Martino, MS, CGC; Zoe Powis, MS, CGC

� 694-0800

� Joanne Jeter, MD; Setsuko Chambers, MD; Marlon Guerrero, MD

General resources

� Breast cancer risk calculator (Gail model): http://www.cancer.gov/bcrisktool/

� Genetic diseases (including cancer syndromes): www.genereviews.org

� Cancer genetics and genetic counseling: http://www.cancer.gov/cancertopics/pdq/genetics/

� Information about other genetic disorders: http://www.ncbi.nlm.nih.gov/omim/

Acknowledgements

� Clinical colleagues� Joanne Jeter, MD

� Setsuko Chambers, MD

� Dave Alberts, MD

� Zoe Powis, MS, CGC

� Gail Martino, MS, CGC

� Research colleagues & lab support� Bob Karn, PhD

� Corina Fuentes

� Department of Medicine Chair Support

� UA GI SPORE Career Development Funding

� NACP Support