Lec 68: Clinical Genetics Flashcards
Hereditary
Familial
Congenital
- derived from parents
- passed in gametes through generations
- present at birth (not all are genetic)
Point Mutation
Missense …
Nonsense…
Frameshift…
- single nucleotide substitution
- point mutation that alters genetic code
- changes a codon to a stop codon
- alters reading frame with insertions or deletions
Sickle Cell Anemia
missense mutation - changes glutamate to valine in RBC
hydrophobic interactions worse when oxygen is not bound at active site
Trinucleotide repeat mutations
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
DNA polymorphisms
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)
miRNA
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
siRNA
small interfering RNA
like miRNA, but introduced by investigators to cell
Mendelian disorders
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)
codominance
both alleles contribute to phenotype
pleiotropism
one gene –> many effects
genetic heterogeneity
many genetic loci –> same trait
incomplete penetrance
some who have gene done express the phenotypic trait
variable expressivity
all who carry mutant gene express trait but to different degrees
Marfan Syndrome
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
Ehlers Danros Syndromes
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
familial hypercholesteremia
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)
cystic fibrosis
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
phenylketonuria
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
galactosemia
inherited lack of GALT enzyme
galactose 1 phosphate and its metabolites increased in tissues
jaundice, liver damage, cataracts, neural damage, vomiting diarrhea, ecoli sepsis
tay-sachs disease
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
glycogen storage diseases
- 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
cytogenetic disorders
alterations in number or structure of chromosomes
euploid
aneuploid
exact multiples of haploid n
not exact multiple, nondisjunction, failure of chromatids to separate
robertsonian translocation
long arms attached on acrocentric chromosomes–> 1 long chromosome and 1 short
short pieces usually don’t contain vital info
trisomy 21
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
digeorge syndrome
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
trisomy 13
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
trisomy 18
Edwards syndrome
prominent occiput, mental retardation, micrognathia, low ears, short neck, overlapping fingers, limited hip abduction, horseshoe kidney, rocker bottom feet
use CGH array
klinefelter syndrome
XXY nondisjunction of sex chromosomes
testicular atrophy, male sterility, decreased body hair, gynecomastia
turner syndrome
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)
fragile x
uniparental disomy, 15q12 maternal deletion
mental retardation, ataxia, seizures, inappropriate laughing,
