clinical genetics and genetic counseling

Why is an accurate diagnosis important

-Appropriate screening for other disease odds

-Appropriate treatment

-Referral to correct specialist

-Counseling about recurrence risks

-Determines implications for other family members

-Referral to research studies

-Referral to support groups

Factors to consider for accurate diagnosis

- at least 3 generation pedigree

-Medical records

-Variability, penetrance, Age of onset

-Testing options

-Modes of inheritance

Reasons for a negative family history in genetic disorders

-Autosomal recessive disorders

-De novo mutations

-Chromosome abnormalities

-Variable expression

-Reduced penetrance

-Anticipation

-False paternity

What is dysmorphology/ morphogenesis

Abnormal physical development

What is teratology

Study of environmental causes of congenital anomalies

when do we see significant malformations in dysmorphology

Newborn period 2-3%

First year of life 3-4%

What are malformations due to

-Chromosome abnormalities

-Single gene disorders

-Teratogens

-Multifactorial

-Complications in pregnancy

What % of congenital defects are unknown

2/3 (known genetic component is identified in about 30% of cases)

What is a malformation

Primary defect of an organ or body part resulting from an abnormal developmental process

When does a malformation occur

Embryogenesis

What is dysplasia

Primary defect involving abnormal organization of cells into tissue

When does dysplasia occur

Embryogenesis

What is a sequence

Primary defect with secondary structural changes

What is Potter sequence?

Decreased amniotic, occurs due to renal/lung obstruction (causes clubbed feet, lung hyperplasia, cranial anomalies)

What is a syndrome

Pattern of multiple primary malformations with a single cause

What is a deformation

Alteration of form/shape/position of normally formed body part by mechanical forces

Is deformation primary or secondary alteration

Secondary alteration

What is a disruption

Defect in organ/region of the body resulting from secondary destructive force - interferes with original normal development

what is an example of a disruption

Amniotic Band Syndrome (ABS)

Occurs when inner membrane (amnion) is torn or ruptured

Can constrict fingers, limbs, and other body parts

What is the most important question when evaluating a child with a congenital malformation

Whether the defect is isolated or part of a syndrome pattern

What are teratogens

substances that cause birth defects when present in the environment of the developing fetus

Examples of teratogens

Alcohol

Tobacco

Drugs

Environmental chemicals (Hg, Pb, solvents)

Infections

Radiation

Therapeutic drugs

How do teratogens act on developing embryonic tissue

Directly and transiently - increases risk of birth defects for current pregnancy only

what does the effect of the teratogen depend on

time and level of exposure during pregnancy

When are organs most sensitive to teratogenic agents

Periods of rapid differentiation

What % of congenital anomalies are caused by environmental factors

7-10%

Can you predict individual thresholds for teratogens

NO

Will every exposure result in fetal malformation

NO

3 principles to consider in teratogen exposure

-Critical periods

-Dosage of drug/chemical

-Genotype of embryo

Most critical period for teratogen exposure

When cell differentiation, morphogenesis, and cell division are at its peak

Do all organs/tissues have the same critical period

NO they all have their own critical period

Critical period for brain

3-16 weeks, but continues to develop for 2 years after birth

First 2 weeks critical period

Teratogens can interfere with cleaving/implantation and cause death and SAB (no congenital abnormalities seen)

Weeks 3-8 critical period

major congenital anomalies result from exposure - can also see cognitive impairment

Weeks 9-38 critical period

Functional defects/ minor anomalies result from exposure

CNS critical period

5-8 weeks

Heart critical period

5-8 weeks

Arms/eyes/legs critical period

6-10 weeks

Teeth & Palate Critical Period

8-11 weeks

Gentalia critical period

9-12 weeks

Ear Critical Period

6-11 weeks

What is fetal alcohol spectrum disorder

physical, behavioral, and cognitive abnormalities seen as result of alcohol intake during pregnancy

*one of the most severe outcomes of alcohol use during pregnancy

When do birth defects for fetal alcohol syndrome occur

first 3-8 weeks of pregnancy

Frequency of FASD

1-2/1000

Facial features in FASD

Small palpebral fissure

Thin upper lip

Microcephaly

Low nasal bridge

Ear anomalies

Epicanthal folds

Where do we see a flattened face and railroad track ear

FASD

Are doctors able to diagnose a pattern of postnatal malformations

YES, some

Can we test if a malformation is due to an exposure

NO

Can genotype interfere with effects of hazardous materials

YES

what percent of malformations are due to antiepileptic drugs

6-7%

what is the effect of valproate (antiepileptic)

spectrum is broad

increased NTDs, characteristic craniofacial appearance, 1-2% risk of lumbar meningomyelocele, heart defects

Characteristics of fetal valproate

Limb defects

Heart defects

Spina bifida

Hypospadias

Decreased fetal growth

What can warfarin (Coumadin) cause

Syndrome identical to severe chondrodysplasia punctata (High fetal/perinatal death)

Defects in use of warfarin (Coumadin)

Nasal hypoplasia

Stippled epiphyses

CNS defects

Hearing/vision loss

IUGR

Heart disease

What % risk of prematurity do wee see in use of warfarin (Coumadin)

20%

What % risk of stillbirth do wee see in use of warfarin (Coumadin)

12-15%

What defects does retinoic acid cause

Microtia

Cardiac malformations

Thymus/Parathyroid abnormal

Neural crest abnormalities

Posterior fossa malformation

what can be used to prevent neural tube defects such as spina bifida

folic acid (folate) 400mcg daily

When do dural tube defects occur

14-28 days gestation (before you know you are pregnant)

When did genetic counseling arise

1990s

Who made the term genetic counseling

Sheldon Reed in 1947

What does genetic counseling help family with

-Comprehend diagnosis/medical facts

-Appreciate how heredity contributes to disorder

-Alternatives for recurring risk

-Choose course of action

-Make best possible adjustment

What is genetic counseling 3 principles

-Interprets family and medical histories

-Education about inheritance

-Counseling to promote choices

What 4 things happen in genetic counseling

-Personal and family history

-Education/risk assessment

-Discussion of options for genetic testing

-Follow up (provide support and test family members)

5 decisions in genetic counseling

-To get genetic testing or not

-Whether to have More children

-To continue or terminate prgenancy

-Who to tell about condition

-When to have testing done

What does non directive genetic counseling enable

Patients to make independent, informed decisions without coercion

When should genetic counselors be directive

-Testing minors for adult conditions (no no)

-Predictive testing if patient is unstable

-Encourage patient to share results with family

-Discuss about screening/management

what is GINA

federal law that protects people from discrimination based on their genetic information in health insurance and employment

who does GINA not apply to

-members of US military

-veterans obtaining healthcare through the VA

-individuals using Indian Health Service

-Federal employees enrolled in health benefits program

-other insurance policies

-employers with less than 15 employees

What does information giving inform patients of

-Risks

-Related medical info

-Possible options

-Medical outcomes

Factors that influence decision making

-Medical constraints

-Financial constraints

-Legal values

-Family values

-Patient motivation

-Patient values

-Patient personality

-Counselor constraints

What is Bayes' Theorem?

Overall probability of an outcome by considering all initial possibilities then modifying with additional information

What is proper probability

Baseline likelihood of having or not having a mutation

Conditional probability

Probability of not developing disease, based on having or not having a mutation

Joint probability

Probability of having a mutation and not developing disease

Posterior probability

standardize the probabilities

What was the eugenics movement based on

Theory of improvement of the human race through application of genetic theories, filter out undesirable traits

4 effects of eugenics

-Laws restricting immigration

-Laws against inter-racial marriage

-Mandatory involuntary sterilization

-Ethnic cleansing in Germany

What is eugenics?

the science of improving a human population by controlled breeding to increase the occurrence of desirable heritable characteristics

Why eugenics could not be effective

-Complex traits

-Multifactorial inheritance

-Heterozygote advantage

-Chromosomal disjunction

-De novo mutation

Ethical issues to consider for eugenics

-Prenatal diagnosis

-Carrier/presymptomatic testing

-Genetic discrimination

-CRISPR

-Cloning/ stem cell research

-Implications for family members