Lecture 20-Introduction to Clinical Genetics

Question 0

how much of the infant mortality rate can be attributed to birth defects and genetic etiologies?

Answer 0

1/3

Question 1

How many genes do we have on each chromosome?

Answer 1

100s-1000s

Question 2

How many newborns are born with some type of birth defect?

Answer 2

2-3%

Question 3

Birth defects/genetic disorders are major contributors to _______

Answer 3

developmental disabilities

Question 4

genetic disorders and consgential anomalies account for how many pediatric hospital admissions?

Answer 4

• 50%

Question 5

What is the prevalence for specific gene disorders?

Answer 5

• 1/500

Question 6

What is the prevalence for chromosome disorders? Chromosome disorders give rise to how many of the children with severe MR and multiple congenital anomalies (MCA)?

Answer 6

• 0.7%

- 10-15%

Question 7

Single gene disorders are also called______. What kind of inheritance do they exhibit?

Answer 7

• mendelian conditions

- characteristic

Question 8

The majority of single gene conditions are _____ but their combined effect is ______.

Answer 8

• rare

- significant

Question 9

Chromosome disorders

- Inheritance pattern?

Answer 9

• caused by a deficiency of a chromosome segment or entire chromosome
• not inherited usually

Question 10

Symptoms of chromosome disorders? (3)

Answer 10

• MR, physical retardation
• unique physical features
• congenital anomalies

Question 11

Symptoms of sex chromosome disorders?

Answer 11

• mild developmental/behavioral problems
• tall or short stature
• infertility

Question 12

pseudogenes

Answer 12

• may or may not be transcribed

- don’t lead to an end function

Question 13

how big is a mutation?

Answer 13

• single bp OR

- large segment of chromosome

Question 14

Inherited mutations

- also called _______

Answer 14

• mutations in a germ cell and is present throughout every cell in a persons body their entire life
• germline mutation

Question 15

what is a germline de novo mutation?

Answer 15

• a mutation not inherited from a parent but occurs in a fertilized egg

Question 16

Acquired mutations

• caused by what?
• also called _______

Answer 16

• mutations that occur during a person’s life in somatic cells. Usually caused by enviromental factors (UV), viruses, DNA replication mistake
• somatic mutations

Question 17

Can somatic mutations be inherited?

Answer 17

• no

Question 18

Polymorphism

Answer 18

allele sequence in 1% or more of the population

• considered a normal finding
• can contribute to multifactorial disorders

Question 19

Rare variant

Answer 19

• allele sequence in <1% of the population

Question 20

nonsense mutation

Answer 20

• stops protein from being transcribed

Question 21

missense mutation

Answer 21

• “misspelling” of the protein

Question 22

Give an ex of a loss of function mutation. What does this protein impact and what are the effects of having this gene mutated?

Answer 22

RB1–retinoblastoma

• tumor suppressor that regulates the cell cycle
• both copies must be mutated to have loss of function

Question 23

What are the different ways that a child can develop retinoblastoma from the loss of function mutation and what are the frequency and outcomes of each(2)?

Answer 23

• One mutated allele inherited an the other acquires the mutation (40%).
• bilateral, early onset Rb
• both alleles of Rb acquire the mutation somatically (60%)
• unilateral, late onset in childhood

Question 24

Give an ex of a gain of function mutation. What does this protein impact and what are the effects of having this gene mutated?

Answer 24

- FGFR3 (normally inhibits cartilage cell growth) - keeps FGFR3 on constitutively even without FGF so cartilage cells are constantly inhibited - achondroplasia

Question 25

``` Dominant negative (2) - example? ```

Answer 25

- a mutation in one allele disrupts or antagonizes the function or product of the other allele - usually related to structural proteins - mutation in Type I collagen resulting in inability to form collagen and therefore osteogenesis imperfecta

Question 26

Clinical/phenotypic heterogeneity

Answer 26

- mutations in the same GENE (can be in different places on the gene) give rise to different phenotypes

Question 27

Types of genetic heterogeneity?

Answer 27

- allelic | - locus

Question 28

allelic heterogeneity

Answer 28

- different mutations/alleles give rise to similar phenotype

Question 29

locus heterogeneity

Answer 29

- different genes (and therefore loci) give rise to a similar phenotype

Question 30

Give an example of clinical heterogeneity.

Answer 30

- RET gene - MEN2B (thyroid carcinoma, neuromas of the lips and tongue, etc.) and Hirschsprung Disease (congenital aganglionic megacolon)

Question 31

Give an example of allelic heterogeneity.

Answer 31

CFTR (cystic fibrosis transmembrane conductance regulator) mutations can block different steps within the pathway leading to the same phenotype

Question 32

Give an example of locus heterogeneity.

Answer 32

- retinitis pigmentosa - 339 genetic syndromes have this as a feature - varied inheritance (AD, AR, XL)

Question 33

Phenocopy | - example?

Answer 33

an environmentally induced condition that mimics/is very similar to a phenotype caused by a specific genotype - 22q11 deletion/DiGeorge syndrome and retinoic acid embryopathy

Question 34

teratogens (3)

Answer 34

- agents that cross the placental barrier - cause structural and functional malformations, growth deficiency - account for a SMALL percentage of congenital malformations

Question 35

What are the categories of teratogens (5)

Answer 35

- Rx drugs (thalidomide, Fetal hydantoin syndrome) - illicit substances (FAS) - chemical/physical agents - maternal metabolic/genetic factors (maternal diabetes) - infectious agents

Question 36

Pleiotropy | - example?

Answer 36

- multiple phenotypic effects of a single gene | - Stickler syndrome causing collagen 2A1 mutations

Question 37

What's the difference between penetrance and expressivity?

Answer 37

- penetrance: an individual who has the genotype for disease may or may not have signs/symptoms of the disease (on/off switch) - expressivity: the extent to which the genetic defect is expressed but is NEVER unexpressed in those who have the genotype (dimmer switch)

Question 38

How do you calculate penetrance?

Answer 38

- # who have disease associated with mutation/# who have mutation

Question 39

Example of a gene that shows varied penetrance when mutated?

Answer 39

- BRCA

Question 40

Example of a disorder that shows varied expressivity?

Answer 40

- achondroplasia: every person with mutation effected by have variable presentations

Question 41

Malformation | - frequencies

Answer 41

- localized abnormalities in organogenesis that are intrinsic to the embryo/fetus - can be major (3%) or minor (17%)

Question 42

Dysplasia

Answer 42

- abnormal organization of cells, abnormal tissue development intrinsic to embryo/fetus - all components are present but disorganized

Question 43

Deformation | - example?

Answer 43

- extrinsic mechanical force impairs normal ongoing fetal development and can change the shape, form and position of the body - oligohydramnios--low amniotic fluid

Question 44

Disruption | - example?

Answer 44

- extrinsic force destroys tissues or organ that had already developed normally - 2º limb defect from vascular event

Question 45

Syndrome | - example?

Answer 45

- pattern of anomalies from one single etiology | - Downs

Question 46

Association | - Example?

Answer 46

- grouping of congenital anomalies that are found together more than statistically expected with no known common etiology - VACTERL associate

Question 47

Sequence | - Example?

Answer 47

- congenital anomalies from one defect that causes secondary structural changes - Robin sequence (mandibular hypoplasia resulting in tongue displacement then cleft palate

Question 48

Finding areas with increased incidence of consanguinity you are more likely to find a higher rate of _______ diseases

Answer 48

- autosomal recessive

Question 49

What are the 3 types of referrals for genetic diagnosis? What are the indications for each?

Answer 49

- prenatal: family history of a disease/disorder; abnormal maternal screening/ultrasound - Pediatric: suspected physical external/internal anomalies; growth problems, developmental delays, intellectual disability - Adult: suspicion that they may have a genetic disorder based on behavior, mental deterioration, specific medical problems; personal/family history of cancer

Question 50

Successful genetic counseling is contingent upon _______

Answer 50

accurate diagnoses!!!