Lec 68: Clinical Genetics

Question 1

Hereditary
Familial
Congenital

Answer 1

• derived from parents
• passed in gametes through generations
• present at birth (not all are genetic)

Question 2

Point Mutation
Missense …
Nonsense…
Frameshift…

Answer 2

• single nucleotide substitution
• point mutation that alters genetic code
• changes a codon to a stop codon
• alters reading frame with insertions or deletions

Question 3

Sickle Cell Anemia

Answer 3

missense mutation - changes glutamate to valine in RBC

hydrophobic interactions worse when oxygen is not bound at active site

Question 4

Trinucleotide repeat mutations

Answer 4

amplification of a three nucleotide sequence (all with C and G)
Example: Fragile X - 200 to 4000 tandem CGG repeats in FMR1 gene (29 usually)
dynamic in gametogenesis (can increase)
causes mental retardation

Question 5

DNA polymorphisms

Answer 5

DNA variations

SNP- single nucleotide polymorphism - two choices at single position; coinherited with disease related gene so can act as marker; about 1 % in coding regions

CNV - copy number variation - different numbers of large DNA stretches; duplicated or deleted or rearranged; about 50% in coding regions ( account for some phenotypic diversity)

Question 6

miRNA

Answer 6

micro RNA, don’t encode proten
inhibit translation of target mRNAs into proteins –> post transcriptional silencing of gene expression

doublestranded, 1 per RISC (rna induced silencing complex); base pairing to target mRNA causes cleavage or repression

Question 7

siRNA

Answer 7

small interfering RNA

like miRNA, but introduced by investigators to cell

Question 8

Mendelian disorders

Answer 8

caused by single gene defect
follow medelian inheritance
1) autosomal dominant (delayed onset, doesn’t affect enzymes)
2) autosomal recessive (early onset; enzymes)
3) x linked (recessive)

Question 9

codominance

Answer 9

both alleles contribute to phenotype

Question 10

pleiotropism

Answer 10

one gene –> many effects

Question 11

genetic heterogeneity

Answer 11

many genetic loci –> same trait

Question 12

incomplete penetrance

Answer 12

some who have gene done express the phenotypic trait

Question 13

variable expressivity

Answer 13

all who carry mutant gene express trait but to different degrees

Question 14

Marfan Syndrome

Answer 14

pleiotropy
autosomal dominant
Connective tissue disorder
missense defect in glycoprotein fibrillin 1 (FBN1) - 15q21

2 effects - - inhibits polymerization so structural support is decreased in microfibril rich CT AND excessive TGFB activation (since microfibrils usually sequester it)

Physical characteristics: arachnodactyly, tall, doublejointed, ectopia lentis(eyes up and out), CV lesions (mitral valve), scoliosis, cystic medionecrosis, depressed sternum, pigeon breast

treat w beta blockers

Question 15

Ehlers Danros Syndromes

Answer 15

6 variants, all characterized with defects in collagen synthesis or assembly

mutation in one of several collagen genes or genes that encode ECM protein like tenascin x

fragile hyperextensible skin vulnerable to trauma and ruptures (colon, cornea, arteries), poor wound healing, joint contorsion

Question 16

familial hypercholesteremia

Answer 16

autosomal dominant
LDLR receptor disease
loss of feedback control and excess cholesterol –>premature atherosclerosis (MI risk)
increase in serum cholesterol
impaired transport of LDL into cells
cholesterol deposits along tendon sheaths (xanthomas on eyes and Achilles tendon)

treat: statins suppress intracellular cholesterol by inhibiting HMGCoA reductase ( increase LDL receptors)

Question 17

cystic fibrosis

Answer 17

autosomal recessive
epithelial transport disorder affecting fluid secretion
abnormal chloride channel protein function (CFTR gene - cystic fibrosis transmembrane regulator)
decreased chloride reabsorption
thick mucus –> pulmonary infection
high NACl in sweat
bronchioles distended in mucus –> hyperplasia/hypertrophy of secretory cells
hepatic cirrhosis

Question 18

phenylketonuria

Answer 18

PKU
autosomal recessive
lack of phenylalanine hydroxylase (PAH) so cant convert to tyrosine
hyperphenylalaninemia
accompanied by decreased pigmentation (tyrosine is melanin precursor), seizures and eczema

maternal pku - must initiate restriction meds before getting pregrnant so fetal organs aren’t affected

Question 19

galactosemia

Answer 19

inherited lack of GALT enzyme
galactose 1 phosphate and its metabolites increased in tissues
jaundice, liver damage, cataracts, neural damage, vomiting diarrhea, ecoli sepsis

Question 20

tay-sachs disease

Answer 20

lysosomal storage disease
ganglisoside accumulation
hexosaminidase A
foamy/swollen cells
cherry red spot on macula

severe mental retardation, blindness, motor weakness, death by 2 or 3 usually

Question 21

glycogen storage diseases

Answer 21

• von Glerke (hepatic) - enlarged liver cells store excess glycogen; lack of hepatic G6P (hypoglycemia)
• mcardle disease(myopathic) - lack of muscle phosphorylase; storage in skeletal muscle –> cramps
• pompe disease (myopathic) - lack of lysosolmal acid maltase and all organs are affected but mostly heart –> cardiomegaly

Question 22

cytogenetic disorders

Answer 22

alterations in number or structure of chromosomes

Question 23

euploid

aneuploid

Answer 23

exact multiples of haploid n

not exact multiple, nondisjunction, failure of chromatids to separate

Question 24

robertsonian translocation

Answer 24

long arms attached on acrocentric chromosomes–> 1 long chromosome and 1 short
short pieces usually don’t contain vital info

Question 25

trisomy 21

Answer 25

down syndrome
47,xx,+21
meiotic nondisjunction
more likely as mother is older
flat face, epicanthic folds (upper eyelids cover lower), simian creases on palms, risk of acute megakaryoblastic leukemia
endocardial cushion defects (atroventricular septums)
mental retardation

Question 26

digeorge syndrome

Answer 26

developmental failure of the 3rd and 4th pharyngeal pouches due to 22q11 microdeletion

t cell deficiency (lack of thymus)
hypocalcemia (lack of parathyroids)
abnormalities of heart, vessels,and lower face

Question 27

trisomy 13

Answer 27

patau syndrome
microcephaly, mental retardation, polydactyly (extra digits)
cleft lip/palate, cardiac defects, umbilical hernia, small head/eyes, rocker bottom feet

use FISH –>see chromosome 13 x3 centromeres in metaphase spread

Question 28

trisomy 18

Answer 28

Edwards syndrome

prominent occiput, mental retardation, micrognathia, low ears, short neck, overlapping fingers, limited hip abduction, horseshoe kidney, rocker bottom feet

use CGH array

Question 29

klinefelter syndrome

Answer 29

XXY nondisjunction of sex chromosomes

testicular atrophy, male sterility, decreased body hair, gynecomastia

Question 30

turner syndrome

Answer 30

45, x
loss of short arm on x
short, neck webbing, aortic coarctation, broad chest, wide nipples, streak ovaries, lymphedema, cystic hydroma (dilated lymphatic mass on neck)

Question 31

fragile x

Answer 31

uniparental disomy, 15q12 maternal deletion

mental retardation, ataxia, seizures, inappropriate laughing,