Hummel - The Genetic Evaluation Flashcards by Ellen Petryna

Steps involved in?

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

Work up of the genetic patient

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What histories should you ask about?

2..

Family - 3 Generations

Pregnancy

Medical history of patient

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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

Consanguinity

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What type of trait?

Dominant trait

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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

Pregnancy history

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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

Pregnancy history

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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

Baby’s medical history

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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

Physical Examination

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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)

Chromosomal testing (Geneticists)

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

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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

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What type of analysis technique was used?

FISH - Fluorescence In situ hybridization

Shows deletion - second portion labelled with red fluorescence is missing

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Examples of microdeletion syndromes

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

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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

Prader Willi Syndrome - dad’s chromosome missing

Angelman Syndrome - mom’s chromosome missing

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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

Hurler’s Syndrome

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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

Thanatophoric dwarfism

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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

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

–Malformation

–Deformation

–Disruption

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)

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)

Genetic Counseling

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

Genetic Counselors

Name some patients who can benefit from genetic counseling.

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

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

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

What is necessary to provide genetic counseling?

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

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

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

* Mendelian Trait * Polygenic/Multifactorial Traits * Bayes Theorem

What risk?

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

What risk?

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

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?

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.

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

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**

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)

* Donor sperm or artificial fertilization * Donor egg

What are some **reproductive options for couples?**

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

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?

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

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.

**\> 35 years old**

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

Carrier In this example - 50/50 chance likely

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

Folic Acid

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.

**Tay Sachs disease and Gaucher.**

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)