Hummel - The Genetic Evaluation

Question 1

Steps involved in?

• Collection of an appropriate history
• Examination of the patient
• Testing
• Establishment of a diagnosis
• Counseling for patient and family

Answer 1

Work up of the genetic patient

Question 2

What histories should you ask about?

1.

2..

3.

Answer 2

Family - 3 Generations

Pregnancy

Medical history of patient

Question 3

For the family history,

Generate a pedigree for family, with how many generations?

• Record miscarriages and causes of death
• Ask specifically about __________ (***for the parents, changes the probability)
• Inquire about ethnic origins

Answer 3

3

Consanguinity

Question 4

What type of trait?

Answer 4

Dominant trait

Question 5

Questions asked for what type of history?

• Timing of conception
• Illnesses during pregnancy
• Medication used before and during pregnancy
• Use of alcohol, tobacco or illicit drugs (more likely to tell you about illicit drugs than alcohol)
• Exposure to X-ray or other radiation

Answer 5

Pregnancy history

Question 6

Questions asked during what type of history?

• Weight gain during pregnancy
• Quality of fetal movement
• Testing prior or during pregnancy

–Ultrasound
–Maternal serum screening
–Free cell DNA
–Amniocentesis or CVS
–Carrier testing

Answer 6

Pregnancy history

Question 7

Questions asked for what type of history?

• Review labor and delivery - APGAR scores
• Feeding history - did baby need a special diet?
• Developmental milestone
  
  • Ask about regression (could be metabolic)
• Medical problems

Answer 7

Baby’s medical history

Question 8

Perfomed during what section of the patient visit?

• Observation
  
  • Estimation of developmental age
  • Look for asymmetry
• Measurements
  
  • Growth parameters - set statistics in handbook
  • Parental head size (also canthal measurements)
  • Anything else that looks abnormal - global developmental delays

Answer 8

Physical Examination

Question 9

What testing is usually performed first for children? (description below)

• **Routine (answer for boards)
• High resolution
• Microdeletion FISH
• Microarray CGH (unless geneticist recognizes the syndrome, would start with this type)

Answer 9

Chromosomal testing (Geneticists)

(If a neurologist - would probably do imaging of the brain)

Question 10

Fact:

Other possible tests done after patient visit

• Molecular/DNA testing
  
  • Disease specific testing
  • Whole genome/exome sequencing
• Metabolic studies
  
  • Amino acids
  • Organic acids
  • Others

Question 11

What type of analysis technique was used?

Answer 11

FISH - Fluorescence In situ hybridization

Shows deletion - second portion labelled with red fluorescence is missing

Question 12

Examples of microdeletion syndromes

• Williams
• Langer-Giedion
• WAGR
• Prader-Willi
• Angelman
• Smith Magines
• Miller Dieker
• Retinoblastoma
• DiGeorge
• VeloCardioFacial

Question 13

Which microdeletion syndromes?

Same deleted region - but depends on whether it is missing from the father’s chromosome 15 or the mother’s chromosome 15

–> Called uniparental disomy, need to look at the methylation patterns

Answer 13

Prader Willi Syndrome - dad’s chromosome missing

Angelman Syndrome - mom’s chromosome missing

Question 14

What Syndrome?

• See regression, course facial features, clouding of cornea
• Storage of glycosaminoglycans in eyes, bones, soft tissue, brain, gums
• Global problem
• Recessive trait, die before reach 10 years of age

Answer 14

Hurler’s Syndrome

Question 15

What syndrome?

• Chest is too small for the baby to breathe outside of the womb
• Short limbs, relatively big head
• Femurs are bowed
• New mutation, dominant - can’t have this and survive, and pass it on
• Allelic to achondroplasia - same protein that creates the receptor for the FGF, but mutated differently (if mutated at transmembrane section - have achondroplasia, if mutated in tyrosine kinase domain - hypochondroplasia)
• FGFR3 are involved with cellular signaling

Answer 15

Thanatophoric dwarfism

Question 16

Facts: Establishing a Diagnosis

• Development of an overall gestalt
  
  • This takes practice
• Use standard references
  
  • Text books
  • Data bases - face-to-gene database, good for exclusion
  • Online
• Follow over time and patient may grow into their diagnosis

Question 17

Establishing a Diagnosis

For single defects try to categorize the anomaly into what 3 categories?

*Makes a difference in recurrence, risk, and counseling as well

Answer 17

–Malformation

–Deformation

–Disruption

Question 18

Fact: Patients with multiple malformations

–Up to 60% will have a diagnosis

–The Human Genome Project is generating better diagnostic tools.

–Even if no formal diagnosis is established, genetic counseling may be helpful.

–If possible whole genome/exon sequencing (expensive)

Question 19

What is the communication process which deals with the human problems associated with the occurrence or risk of occurrence of a genetic disease in a family?

*Opportunity to give the family options to make an informed decision

*Provided by: Family Doctor, Specialist for a Specific Condition (Hemophilia, Cystic Fibrosis), Genetic Professionals (MD, PhD or MA in clinical genetics)

Answer 19

Genetic Counseling

Question 20

Who?

• Masters or PhD program with board certification
• Trained to collect and assess information pertinent to potential genetic disease
• Can provide patient education
• Furnishes psychosocial support
• Determine risk assessment.
• Generally works under a physician guidance

Answer 20

Genetic Counselors

Question 21

Name some patients who can benefit from genetic counseling.

Answer 21

• Known hereditary disease in family (carrier or presymptomatic testing)
• Individual with suspected genetic disease
• Individual with birth defects
• Individual with unexplained mental retardation
• At risk individual because of ethnic background
• Advanced maternal age
• Family history of early onset cancer
• Recurrent pregnancy loss (3 or more)
• Teratogen exposure
• Consanguinity
• Individual with abnormal sexual development
• Interpretation of abnormal prenatal tests
• Couples seeking preconceptual counseling

Question 22

When should a family or individual be referred for genetic counseling?

Answer 22

• Prior to conception, when there is a family history or other risk factor which increases the chance for an abnormal offspring
• As soon as possible for newly diagnosed patients

Question 23

What is necessary to provide genetic counseling?

Answer 23

• An accurate diagnosis
• A complete family history (3 generations if possible, more if indicated)
• Current information on the condition
• An unbiased approach to the family - patients shouldn’t know what you would personally do in these situations

Question 24

Fact: Information covered in a genetic counseling session:

• Basic information on the condition or disease in question
• How the condition is inherited
• The risk for others in the family
• Options available to deal with the risk of occurrence ‑prenatal testing, IVF, donor sperm, etc.
• The prognosis for an individual with the disease and treatment options

Question 25

Communication of risk:

______________ ‑ calculated risk

______________ ‑ can look up empiric risk (observed, in handbooks)

______________ ‑ use of both calculated risk with observed data to modify the first

Answer 25

• Mendelian Trait
• Polygenic/Multifactorial Traits
• Bayes Theorem

Question 26

What risk?

Answer 26

Mendelian risk - if this is a known dominant condition risk would be 50%

Question 27

What risk?

Answer 27

Empiric Risk

If this family has a history of clefting with multifactorial inheritance, the recurrence risk would be 5-10%

Question 28

If a woman has a 50% chance of being a carrier for an X-linked trait (2 brothers are affected) - she has one daughter, 3 healthy boys, and is pregnant. 25% chance of passing it on.

Chance of baby being a boy and affected?

• With Bayes Theorem, do we need to take into account that her previous boys are not affected?

Answer 28

12.5% risk

We do have to take this into account - the more boys that she has that are normal, the lower her risk for being a carrier.

Question 29

Facts: Educational Components for genetic counseling

• Use of visual aids (pictures of karyotype, pedigrees ,etc.)
• Avoid jargon and technical terms
• Elicit feedback to measure understanding
• Be sensitive to cultural, religious, and ethnic background of family –> esp. to those who are hearing impaired
• Give both sides of the statistics

Question 30

Fact: Some components of the genetic counseling session.

• Discuss all reproductive options
• Avoid terms that are judgmental (example: many individuals who are deaf do not consider themselves as abnormal or to have a disease)
• Provide the family with a written report which reviews information covered during the counseling
• If possible give family information on parent support groups

Question 31

For couple at risk for offspring with genetic condition.

Prior to pregnancy:

• Elect to have no children or adopt
• Take risk - testing after birth (fewer than 25% are terminated)
• Donor gamete to avoid defective genes
  
  • ______ or __________ (for men - recessive or dominant traits or chromosome abnormality)
  • _________ (requires in vitro fertilization) (for women - recessive, dominant or X‑linked traits or chromosome abnormality)

Answer 31

• Donor sperm or artificial fertilization
• Donor egg

Question 32

What are some reproductive options for couples?

Answer 32

• Establish pregnancy then have prenatal testing
• Preimplantation testing (requires in vitro fertilization)
• Surrogate with father’s sperm or donor’s sperm

Question 33

Example of a counseling session:

A 37 year old woman has recently married and considering starting a family. She is referred to genetics to discuss the potential genetic risks for older mothers.

What is the first step? - what should we ask about?

Answer 33

Obtain a family history

–Ask about both sides of the family

–Ideally send request for family history prior to the clinic visit

–Include ethnic origins

–Reproductive problems

–Things that run in the family

–Ask about consanguinity

Question 34

Genetic counseling issue

Maternal Age:

• Pregnancy for women ______ increases risk of Down syndrome as well as other aneuploidy disorders in fetus.
• Counseling to explain chromosomes and their disorders ‑ quote risk for age of 37 to be ~1 in 190 births.
• Review prenatal screening & diagnostic testing available, discuss both risk and benefit of each procedure.

Answer 34

> 35 years old

Question 35

Genetic counseling issue

Family history of cystic fibrosis

• Husband’s risk of being a ________ and calculated risk for pregnancy.
• Review carrier testing and its limitations
• Discuss options open to couple if both are found to be carriers

Answer 35

Carrier

In this example - 50/50 chance likely

Question 36

Genetic Counseling Issue

Family history of neural tube defect

• 3rd degree relative with open neural tube defect
• Quote ~ 1% risk for this couple’s offspring (empiric risk)
• Discuss use of _______ supplements prior to conception
• Review prenatal diagnostic/screening tests

Answer 36

Folic Acid

Question 37

Genetic Counseling Issues

Jewish ancestry on both sides of family

• At risk for certain autosomal recessive conditions including _________ and ________.
• Offer carrier testing for the at risk conditions
• Review reproductive option if both are determined to be carriers.

Answer 37

Tay Sachs disease and Gaucher.

Question 38

Fact: Ashkenazi Jewish carrier screening by molecular analysis for the following disorders:

• Tay-Sachs disease (1 in 25)
• Canavan disease (1 in 40)
• Familial dysautonomia (1 in 30)
• Fanconi anemia type C (1 in 89)
• Niemann-Pick disease type A (1 in 90)
• Bloom syndrome (1 in 100)
• Mucolipidosis IV (1 in 125)
• Gaucher disease (non-neuronopathic type) (1 in 14)
• Cystic fibrosis (1 in 25)