Exam 3

Question 1

rules of medelian genetics

Answer 1

Principle of Segregation

• Genes occur in pairs and only one member of the pair is transmitted to the offspring

Principle of Independent Assortment

• Genes at different loci are

Question 2

“black urine disease”

Answer 2

Alkaptonuria

Question 3

Major Types of Genetic diseases

Answer 3

Major Types of Genetic diseases

1: Chromosomal
2: Single gene

• mutation in a single gene
• 95% located in autosomes: dom or recessive
• Follow Mendelian patterns of inheritance
• 5% located in sex chromosomes (X and Y): X or Y linked

3: Multifactorial disorders/complex diseases
* Caused by interactions of multiple genes and the environment
4: Mitochondrial disorders
* Caused by alterations in mitochondrial genome

Question 4

Answer 4

Autosomal Dominant Inheritance Pattern

• at least 1 affected parent - abnormal phenotype appears every gen
• affects and can be transmitted by EITHER sex
  
  • Male-to-male transmission can occur and affected males can have unaffected daughters

ONE copy = expression

• 50% child disease is affected x unaffected

Question 5

Examples of Diseases with Autosomal Dominant Inheritance Pattern (10)

Answer 5

Huntington Disease (HTT)

Familial hypercholesterolemia (LDLR)

HNPCC (MSH2, MLH1,PMS1/2)

Acute Intermittent Porphyria (PBGD)

Postaxial Polydactyly (GLI3)

Achondroplasia (FGFR3)

Marfan syndrome (FBN1)

Osteogenesis imperfecta type 1 (COL1A1/2)

Retinoblastoma (RB1)

Neurofibromatosis Type 1 (NF1)

Question 6

Huntington Disease

Answer 6

tri-nt repeat (CAG) in chr 4

• signal, txp, protection from apop
• larger number of repeats correlated with earlier age of onset (anticipation)

late-onset neurodegen (35-44 y/o)

• dmg corpus straitum
• chorea (abnorm, invol, writhing mvmt)
• loss motor control
• behav/mood/personality chnages

Question 7

Penetrance

Answer 7

proportion of individuals carrying a variant (mutation) of a gene that also expresses the associated phenotype

Question 8

Tendency for greater repeat expansion when disease of _______ origin

Answer 8

paternal

Question 9

Answer 9

Pedigree of an American Huntington’s Disease Family

Question 10

Pedigree of family with HD

Individual II-1 is 50 years old, and currently does not manifest any signs of HD.

Question: Do you think II-1 will develop the disease later in life?

Answer 10

yes

Question 11

Familial Hypercholesterolemia

Answer 11

mutations in LDLR in chr19:

• elevated LDL –> CAD @ young age
• hetero = reduced fxtional LDLRs

most ommon autosomal dominant disorder

• thickened Achilles tendon
• cholesterol deposits in soft tissues:
  
  • xanthelasmas
  • xanthomas
  • arcus cornealis

Question 12

HNPCC

Answer 12

“lynch syndrome” - mismatch repair genes

• MSH2 (Chr. 2)
• MLH1 (Chr. 3)
• PMS1 (Chr. 2)
• PMS2 (Chr. 7)
• locus heterogeneity: mutations in different genes –> same phenotype

incr freq of colon/colorectal and endomet ca

Question 13

Postaxial Polydactyly

Answer 13

Primary genetic defect: Extra fingers or toes

• Mutations in GLI3 gene in Chr. 7
• Ts: patterning of many organs and tissues during development

May exhibit reduced penetrance, variable expressivity

• extra digit may vary from a small skin tag to a fully formed digit

Question 14

Achondroplasia

Answer 14

FGFR3 gene in Chr. 4:

• txmemb TK receptor that binds fibroblast GF

most cases = NEW MUTATIONS

• less inherited from affected parent: Gly380Arg

bone growth disturbances

• Short limbs relative to trunk length (normal-sized torso)
• Prominent forehead, flattened nasal bridge; and redundant skin folds in arms and legs

Question 15

Answer 15

mating of 2 pts with achondroplastic dwarfism

Question 16

Marfan Syndrome

Answer 16

FBM1: chr15

• encodes fibrilin –> affects elastin deposit

mutations:

• missense mutations
• dominate neg effect: mutation fibrillions bind and disable normal fibrillins

Question 17

FMB1 mutations can also lead to defects in…

Answer 17

ocular: myopia, dispalced lens (ectopic lentis)
skeletal: tall stature, unusually long & slender, scoliosis, hypermobility of joints

CV: MVP, dilatation of ascending aorta

pleiotropism: multiple phenotypic effects of a single gene

Question 18

Answer 18

Autosomal Recessive Inheritance Pattern:

• affected usual born to unaffected parents (usually asymp - hetero)
  
  • 2 MUTATED copies –> homozygote recessive
  • 25% chance of being affected
• increased in indicdence of parental consanguinity
• affects EITHER sex:

Question 19

proband

Answer 19

affected individual who got genetic testing

Question 20

Summary: Comparison of Major Characteristics of Autosomal Dominant and Autosomal Recessive Inheritance Patterns

Question 21

Examples of Diseases with Autosomal Recessive Inheritance Pattern

Answer 21

*CF (CFTR)

*PKU (PAH)

Albinism (TYR)

*Sickle cell anemia

Thalassemia

Alkaptonuria (HGD)

Niemann-Pick Disease (SMPD1)

Tay-Sachs Disease (HEXA)

Xeroderma pigmentosum (XP)

Ataxia telangiectasia (ATM)

Question 22

CF

Answer 22

CFTR: chr7

• delta-F508 is most common mutation
• Cl channel for salt/h20 balance

Question 23

Cystic Fibrosis

if you analyze III-3 and determine that he has the DF508 mutation, what would be the expected PCR product/s for II-4, II-5, III-4, III-5 and III-6?

Answer 23

Question 24

classic PKU

Answer 24

PAH: chr 12

• complete or almost complete deficiency in enz activity
• most commonly clinc encountered inborn error of aa metab

​hypopig if due to lab of tyr

SCREENING for newborns mandatory –> can cause mental-retard

tx:

• limit phe in diet
• supplement with tyr, trp, BCAA (val, leu, ile)

Question 25

Factors that may complicate inheritance patterns

Answer 25

1. New mutation * affected person may be first person in the family with the condition * achondroplasia 2. Delayed onset * Huntington disease mean age of onset between 35-44 years of age; 25% after 50 3. Variable Expressivity * Considerable variation in the severity or types of abnormalities present although the genetic effect is the same 4. Incomplete/reduced Penetrance * Some people who have the gene mutation do not show symptoms or phenotype of the disease 5. Pleiotrophy * Mutations in a single gene results in defects in several organ systems (multiple phenotypes) * Marfan syndrome (FBN1 mutation) * Phenylketonuria (PAH mutation) 6. Locus heterogeneity * same phenotype caused by many different genes * Hereditary Nonpolyposis Colorectal Cancer (HNPCC) * Mutations in mismatch repair genes MSH2, MLH1, PMS1 and PMS2 confer predisposition to HNPCC

Question 26

Answer 26

a

Question 27

Answer 27

b

Question 28

Answer 28

b

Question 29

Answer 29

b

Question 30

Question 31

x chromosome

Answer 31

Composed of 155 x 106 base pairs Contains about 1,100 genes * 800 protein-coding * 300 RNA genes

Question 32

Lyon Hypothesis: X inactivation

Answer 32

one of x chr in females randomly inactivated early in rmb dev

Question 33

Dosage compensation

Answer 33

ensures that equal amounts of X-linked gene products produced in males and females

Question 34

Characteristics of X-linked Recessive Disorders

Answer 34

mutations on x chr * males = 1 copy --\> affected * females = 2 copies --\> can be carrier, **possible** manifesting heterzyg **No male-to-male transmission in the pedigree**

Question 35

Examples of X-linked Recessive Diseases (9)

Answer 35

Duchenne muscular dystrophy (DMD) G6PD Deficiency (G6PD) Fabry Disease (GLA) Hunter Syndrome (IDS) Lesch-Nyhan syndrome (HPRT) Ornithine Transcarbamoylase Deficiency (OTC) Menkes syndrome (ATP7A) Hemophilia A (F8) Red-Green Color blindness (OPN1LW, OPN1MW)