clinical genetics and genetic counseling

explain the importance of an accurate diagnosis*

appropriate screening for other disease manifestions and treatments/interventions

referral to appropriate specialist

counseling about recurrence risks

determine implication for fam members

refer to research studies and support groups

factors to consider accurate diagnosis

-3 generation pedigree for patterns of inheritance

-confirm diagnosis with med records

-use other specialist to evaluate symptoms

-understand variability, penetrance, and age of onset

-familiarity with clinical criteria and testing options

-understand mode of inheritance to understand recurrence risk

what is important to remember when collecting family history

it changes over time!

what fam history should you collect

sex

3 generations

ages

miscarriages and stillbirths

ethnicity

consanguinity

different reasons for a negative FH in genetic disorders

aut recessive

de novo mutations

chromosome abnormalities

variable expression

reduced penetrance

anticipation

sex-linked traits

false paternity

abnormal physical development is termed

dysmorphology/morphogenesis

the study of environmental causes of congenital anomalies is termed

teratology

% of malformations in the newborn period (dysmorphology)

2-3

% of malformations in the first year of life (dysmorphology)

3-4

causes of malformations (dysmorphology)

chromosome abnormalities

single gene disorders

teratogen

multifactorial

pregnancy complications

the cause of 2/3 of congenital defects are (etiology of congenital defects)

unknown or multifactorial

known genetic component in congenital defects are in __% of cases (etiology of congenital defects)

30

are well-established environmental causes of congenital malformations frequent (etiology of congenital defects)

no

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

malformation

when does malformation occur during 

embryogenesis

primary defect involving abnormal organization of cells into tissues

dysplasia

when does dysplasia occur during

embryogenesis

primary defect with secondary structural changes

sequence

what is potter sequence

decreased amniotic occurs due to renal disease or obstruction

fetus has clubbed feet, pulmonary hypoplasia, cranial anomalities

pattern of multiple primary malformation with a single cause

syndrome

alteration of the form, shape, or position of a normally formed body part by mechanical forces

secondary alteration

deformation

defect of an organ, part of an organ, or larger region of the body resulting from a secondary destructive force that interferes with an originally normal developmental process

disruption

what is the most important question to ask when evaluating a child with a congenital malformation

whether the defect is isolated or part of a syndrome pattern

agents that cause birth defects when present int he environment of the developing fetus

teratogens

examples of teratogens

alcohol

tobacco

weed, coke, LSD

mercury, lead, solvent

infections

radiation (xrays, cancer radiation, nuclear explosion)

therapeutic drugs (valium, antidepressants, anticonvulsants, lithium, accutane)

how do teratogens work

act directly on developing embryonic tissue

teratogens only inc risk birth defects on

current not subsequent pregnancies

what does teratogen risk depend on

time and level of exposure during pregnancy

what part and when is the embryo most sensitive to teratogens

organs and part of embryo during periods of rapid differentiation

will every critical exposure to teratogen result in fetal malformation

no

*individual threholds are not predictable

3 principles to consider when there is an exposure to a teratogen

critical periods

dosage

genotype of embryo

what is the critical period of the embryo

when cell division, differentiation and morphogenesis is at peak

does each tissue and organ have its own critical period

yes

*effects of teratogens depend on timing

when is the critical period for the brain

weeks 3-16 gestation and continues until 2 years after birth

*tooth and skeletal development continues after birth

effect of teratogens during first 2 weeks

interferes with cleavage and implantation or death

no congenital abnormalities

effect of teratogens during weeks 3-8

major congenital anomalies!

functional/cognitive impairment

effect of teratogens during weeks 9-38

functional defects! and minor anomalies

one of the most severe outcomes of alcohol use during pregnancy that causes physical, behavioral, and cognitive abnormalities

fetal alcohol spectrum disorder

when can birth defects associated with prenatal alcohol exposure occur

in first 3-8 weeks (before she knows shes pregnant)

*in 1-2 infants per 1000 births

key feature of FASD

flattened facial profile unusual ear cartilage

*railroad track ear

-also microcephaly, low nasal bridge, epicanthal folds, ear abnormalities, thin upper lip

do teratogenic effects well known and documented

some but some malformations may be a result of exposure but the pattern is not well documented

*some drugs dont have well documented dose response

*genotype can interfere with effects

is there a way to test if a malformation was due to exposure

not postnatally

effect of antiepileptic prescription drugs (valproate)

spectrum of defects is broad

including congenital heart disease, clefting, risk could be dose related

6-7% risk for malformations

what drugs may cause this signs of: limb and heart defects, spina bifida, hypospadias, dec fetal growth

fetal valproate (antiepileptic drug)

what are these signs of: looks like severe form of chondrodysplasia punctata, high fetal and perinatal loss, skeletal defects like nasal hypoplasia, stipped ephiphyses

12-15% risk of still births; 20% risk of prematurity

effect of warfarin

what are these signs of: microtia, conotruncal cardiac malformations, posterior fossa malformation, thymus and parathyroid abnormalities, neural crest and branchial arch derived structures

effect of retinoic acid

what can folate/folic acid be used for

to prevent neural tube defects like spina bifida and anencephaly

take 400 mcg of women of reproductive age

when do neural tube defects occur

14-28 days gestation (may not know they are pregnant)

explain the purpose of genetic counseling

see facts, diagnosis, course of disorder, available management

see how heredity contributes to disorder and risk of recurrence

understand alternatives for recurrence risk

find appropriate course of action

make possible adjustments

process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions of disease

genetic counseling

genetic counseling includes interpreting family and med history to assess

the chance of disease occurrence or recurrence

genetic counseling includes education about

inheritance, testing, management, prevention, resources, and research

genetic counseling including counseling to promote

informed choices and adaptation to the risk of the condition

preconception, prenatal, pediatrics, cancer, cardiology, neurology, opthalmology, metabolic, research, advocacy groups, public health departments

places genetic counselors work

what occurs during genetic counseling

collect history

education and risk assessment

discuss options for genetic testing and medical management

follow up (support and test family members)

these are indications for...

someone with developmental delay, malformations, inherited metabolic disease, single-gene disorder, chromosomal disorder, risk for genetic condition, history of recurrent miscarriages, consanguinity, teratogen exposure

genetic referral

different types of decisions in genetic counseling

should u genetic test? continue or terminate pregnancy? have further children? what/who to tell about a condition? should u have predictive testing?

what is nondirective genetic counseling

patient can make independent, informed decisions without coercion by having set goals for session, provide info in unbiased manner, aiding in decision aside from personal beliefs

when should genetic counseling be directive

testing of minors for adult onset conditions

predictive testing if an individual seems unstable

encourage patients to share results with family

discuss screening for a conditions that was already diagnosed

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

GINA (genetic information non-discrimination act)

who does GINA not apply to

members of military

veterans getting healthcare through VA

individials using indian health service

federal employees enrolled in federal employees health benefits program

inform patients as much as possible regarding

- Risks

- Related medical information

- Possible options

- Medical outcomes

bayes theorem

calculates the overall probability of an outcome by considering all initial possibilities and then modifying these with additional information

prior probability

baseline likelihood of having of 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

movement based on the theory of improvement of the human race through application of genetic theories

eugenics

4 main effects of eugenics

laws restricting immigration, inter-racial marriages, involuntary sterilization, ethnic cleansing in germany

issues with eugenics

complex traits

multifactorial inheritance

heterozygote advantage

chromosomal disjuction

de novo mutations

ethical issues to consider

prenatal diagnosis, carrier testing, pre-symptomatic testing, genetic discrimination, non-paternity, implications for family members, preimplantation genetics, incidental findings, cloning and stem cell research, CRISPER gene editting