Biochemistry First Aid- Genetics (pg 84-91) Flashcards
pgs 84-91 in First Aid 2014
define codominance
when both alleles contribute to the phenotype
list some common examples of codominance
AB blood groups, alpha1-antitrypsin deficiency
define variable expressivity
phenotype varies among individuals with the same genotype
name a good neuro example of variable expressivity
NF1 (two patients with neurofibromatosis 1 will have varying disease severity)
define incomplete penetrance
not all individuals with the mutant genotype show the mutant phenotype
what is a commonly known cancer gene that exhibits incomplete penetrance
BRCA1 gene mutations do not always result in breast or ovarian cancer
what is pleiotropy
one gene results in multiple phenotypic effects
name a common condition that exhibits pleiotropy
PKU (phenylketonuria) manifests with light skin, intellectual disability, and musty body odor
what is anticipation
increased severity or earlier onset of disease in succeeding generations
what kind of genetic conditions show anticipation
trinucleotide repeat diseases (i.e. Huntington’s, several spinocerebellar ataxias, Fragile X syndrome, Freidrich’s ataxia, juvenile myoclonic epilepsy, myotonic dystrophy)
explain the concept of loss of heterozygosity
if a patient develops a mutation in a tumor suppressor gene the other allele must be either mutated or deleted before cancer can develop (not true of oncogenes)
what is a dominant negative mutation
a heterozygote produces a nonfunctional altered protein that impairs function of the normal gene product
describe a key example of dominant negative mutation
mutation of a transcription factor in its allosteric site. The non-functioning protein can still bind DNA, preventing wild-type transcription factor from binding
what is linkage disequilibrium and what kind of sample is used to measure it
it is the tendency for certain alleles at 2 linked loci to occur together more often than expected by chance. It is measured in a population, not in a family, and it often varies in different populations.
what is mosaicism and how does it come about
the presence of genetically distinct cell lines in the same individual. It arises from mitotic errors after fertilization.
name and explain the two types of mosaicism
somatic (mutation propagates in different organs)
gonadal (mutation propagates through egg or sperm cells)
name a commonly-known mosaic condition
McCune-Albright syndrome (lethal is somatic, but survivable if mosaic)
what is locus heterogeneity
mutations at different loci can produce a similar phenotype
what kind of genetic heterogeneity does beta-thalassemia exhibit
allelic heterogeneity
what kind of genetic heterogeneity does albinism exhibit
locus heterogeneity
define allelic heterogeneity
different mutations at the same locus produce the same phenotype
what is heteroplasmy
presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease
what is uniparental disomy
the offspring receives two copies of a chromosome from one parent and none from the other
what are the two ways uniparental disomy can occur
heterodisomy: (heterozygous) indicates a meiosis I error
isodisomy: (homozygous) indicates a meiosis II error or postzygomatic duplication of one of the chromosomes with loss of the other
in what kind of pedigree can you be fairly certain that a child has been affected by uniparental disomy
a child affected by a recessive disorder for which only one parent is a carrier (and the other is unaffected)
name four assumptions required for Hardy-Weinberg population genetics
no mutation at the locus of interest no net migration random mating (no sexual selection) no natural selection
what are the two Hardy-Weinberg equations
p^2 + 2pq + q^2= 1
p + q = 1
what is imprinting
at some loci only one allele is active while the other is inactivated via methylation (imprinted). With one allele inactivated, deletion/ mutation of the other allele leads to disease.
name two conditions that are commonly known to result from imprinting
Prader-Willi syndrome and Angelman syndrome
what is the clinical manifestation of Prader-Willi syndrome
hyperphagia, obesity, intellectual disability, hypogonadism, hypotonia
what kind of imprinting does Prader-Willi result from
materal imprinting (maternal gene is normally silent/imprinted and paternal gene gets mutated/deleted)
25% of Prader-Willi cases are due to this genetic phenomenon rather than imprinting
maternal uniparental disomy
what is the clinical manifestation of Angelman syndrome
inappropriate laughter, seizures, ataxia, severe intellectual disability
what kind of imprinting does Angelman syndrome result from
paternal imprinting (paternal gene is normally silent/imprinted and maternal gene is mutated/ deleted)
5% of cases of Angelman syndrome result from this genetic phenomenon rather than from imprinting
paternal uniparental disomy
name 5 modes of inheritance
autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, mitochondrial
what is the mode of inheritance of hypophosphatemic rickets
X-linked dominant
what is the inheritance pattern of mitochondrial myopathies and how do they present
mitochondrial inheritance;
present with myopathy, lactic acidosis, CNS disease, all as a result of failure in oxidative phosphorylation
(on biopsy: ragged red fibers)
name as many autosomal dominant diseases as you can
ADPKD, familial hypercholesterolemia, familial adenomatous polyposis, hereditary hemorrhagic telangiectasia, hereditary spherocytosis, Huntington’s, Marfan’s, MEN, NF1, NF2, tuberous sclerosis, VHL
85% of cases of ADPKD are due to what mutation and on what chromosome
15% of cases of ADPKD are due to what mutation and on what chromosome
85% of cases from gene PKD1 on chromosome 16
15% of cases from gene PKD2 on chromosome 4
what is the clinical manifestation of familial adenomatous polyposis
adenomatous polyps in the colon that develop post-puberty and can progress to colon cancer if not resected
what gene and on what chromosome is the mutation for familial adenomatous polyposis
APC “adenomatous polyposis of colon”
on chromosome 5
what is the defect in familial hypercholesterolemia
defective or absent LDL receptor leading to elevated LDL and eventual severe atherosclerotic disease early in life (xanthomas such as Achilles tendon xanthoma)
what is the clinical manifestation of hereditary hemorrhagic telangiectasia (aka Osler-Weber-Rendu syndrome)
telengiectasias, recurrent epistaxis, skin discolorations, AVMs, GI bleeding, hematuria
what is the defect in hereditary spherocytosis
defective ankyrin or spectrin –>spheroid erythrocytes and hemolytic anemia
what is the mutation in Huntington’s disease and on what chromosome
CAG trinucleotide repeats in the huntingtin gene on chromosome 4
what is the defective gene product in Marfan syndrome and what organs are affected as a result
fibrillin-1 gene –> defective connective tissue –> defects in skeleton (long extremities, pectus excavatum, hypermobile joints, arachnodactyly), heart/vessels (medial calcific necrosis of aorta, floppy mitral valve) and eyes (subluxation of lens)
what gene are MEN2A and MEN2B associated with
ret
on what chromosome is the NF1 gene
chromosome 17
what are the most common findings for neurofibromatosis type 1 on physical exam
cafe au-lait spots, neurofibromas, Lisch nodules
how much penetrance does neurofibromatosis type 1 show
100% penetrance
what gene and chromosome is mutated in neurofibromatosis type 2
NF2 gene on chromosome 22
what are the characteristic findings of neurofibromatosis type 2
bilateral acoustic neuromas, meningiomas, ependymomas, juvenile cataracts
what kind of tissue pathology characterizes tuberous sclerosis
hammartomas
how much penetrance does tuberous sclerosis show
incomplete penetrance
what gene and what chromosome is mutate in von Hippel Lindau
VHL gene on chromosome 3
name as many autosomal recessive disorders as you can
albinism, ARPKD, cystic fibrosis, glycogen storage diseases, hemochromatosis, Kartagener’s syndrome, mucopolysaccharidoses (except Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoses (except Fabry disease), thalassemias, Wilson disease
in what gene and on what chromosme is the mutation that causes cystic fibrosis
CFTR gene on chromosome 7
what is the gene product that is defective in cystic fibrosis
ATP-gates Cl- channel that secretes Cl into lungs and GI tract and reabsorbs Cl in sweat glands
–> Cl retained in cells –> Na and H2O retained in cells –> thick secretions
how is cystic fibrosis diagnosed
> 60mEq/L of Na in sweat
what are common complications of cystic fibrosis
Pseudomonas infection, chronic bronchitis and bronchiectasis, pancreatic insufficiency, malabsorption, steatorrhea, nasal polyps, infertility in males, fat soluble vitamin deficiencies
name to pharmacologic treatments for cystic fibrosis
N-acetylcysteine (breaks disulfide bonds in mucus glycoproteins) dornase alpha (clears leukocytic debris)
name as many X-linked recessive disorders as possible
Bruton agammaglobulinemia, Wiskott-Aldrich syndrome, Fabry disease, G6PD deficiency, ocular albinism, Lesch-Nyhan syndrome, Duchenne and Becker muscular dystrophy, Hunter syndrome, Hemophilia A and B, Ornithine transcarbamoylase deficiency
Duchenne muscular dystrophy is caused by what kind of mutation and to what protein? what inheritance?
frameshift mutation to dystrophin protein (anchors muscle fibers by connecting actin to transmembrane proteins called alpha and beta dystroglycan)
X-linked recessive
what are some clinical signs and symptoms you would see in a Duchenne Muscular Dystrophy patient
pseudohypertrophy of calf muscles (fibrous fatty replacement of muscle), Gower maneuver (using UE to help stand up), muscle weakness that begins in the pelvic girdle and ascends
when is the typical onset of Duchenne Muscular Dystrophy
before 5 years old
what is the most common cause of death in Duchenne Muscular Dystrophy
dilated cardiomyopathy
what enzyme levels would be increased in Duchenne Muscular Dystrophy
creatinine phosphokinase (CPK) and aldolase
how is diagnosis of Duchenne Muscular Dystrophy confirmed
Western blot and muscle biopsy
what is unique about the dystrophin gene (DMD)
has the longest coding region of any human gene
what’s the difference between the mutation in Duchenne vs. Becker Muscular Dystrophy
Duchenne= X-linked recessive frameshift Becker= X-linked recessive in frame deletion
what’s the difference between Duchenne vs. Becker Muscular Dystrophy in terms of onset and severity
Duchenne’s has earlier onset (s is less severe and onset occurs in adolescence or early adulthood
what causes Myotonic type I Muscular Dystrophy
CTG trinucleotide repeat expansion in DMPK gene
what protein is affected in Myotonic type I Muscular Dystrophy
abnormal expression of myotonin protein kinase
what are the clinical manifestations of Myotonic type I Muscular Dystrophy
myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, arrhythmia
what gene is affected in Fragile X syndrome
FMR1 (fragile X mental retardation) gene, which is responsible for normal neural development
what is the heredity of Fragile X syndrome
X-linked (due to X inactivation in females no distinction is made between dominant vs. recessive)
what are the clinical manifestations of Fragile X syndrome
intellectual disability (2nd most common genetic cause after Down’s), macroochidism (opposite of Myotonic type 1 MD), long face with large jaw and forehead, large everted ears, autism, mitral valve prolapse, arched palate
what is the trinucleotide repeat in Fragile X syndrome
CGG
name 4 major trinucleotide repeat expansion diseases and what the associated codons are
Huntington’s (CAG), Friedrich’s ataxia (GAA), Fragile X syndrome (CGG), Myotonic type 1 MD (CTG)
what are the clinical manifestations of Down’s syndrome (include disease risks associated with Down’s)
intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, space between toe 1 and 2, duodenal atresia, Hirschsprung’s, ASD, Brushfield spots (light spots around periphery of iris);
increased risk of ALL, AML, Alzheimer’s
95% of Down syndrome cases are due to what meiotic abnormality
meiotic nondisjunction of homologous chromosomes
4% of Down syndrome cases are due to what meiotic abnormality
Robertsonian translocation
1% of Down syndrome cases are due to what defect/ abnormal process
mosaicism (no maternal association); post-fertilization mitotic error
what would be seen in first trimester and in second trimester that would suggest Down syndrome
1st trimester: increased nuchal translucency, hypoplastic nasal bone, low serum PAPP-A, high free beta-hCG
2nd trimester: low alpha-fetoprotein, high beta-hCG, low estriol, high inhibin A
what genetic defect causes Edward syndrome
trisomy 18
what are the clinical manifestations of Edward syndrome
rocker bottom feet, severe intellectual disability, micrognathia (small jaw), low-set ears, clenched hands, prominent occiput (occipital bone), congenital heart disease, death within 1st year of life
what prenatal labs values are suggestive of Edward syndrome
decreased beta-hCG and PAPP-A (pregnancy associated plasma protein A) in 1st trimester
quad screen shows: decreased alpha-fetoprotein, beta-hCG, estriol, and low or normal inhibin A
what does a quad screen test for and when is it done
quad screen is a blood screen that tests for alpha-fetoprotein, beta-hCG, estriol and inhibin A
done at 16-18 weeks (2nd trimester)
what genetic abnormality causes Patau syndrome
trisomy 13
what are the clinical manifestations of Patau syndrome
severe intellectual disability, rocker bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, congenital heart disease, death within 1 year of birth
what abnormalities would be seen on first trimester screen
decreased free beta-hCG, decreased PAPP-A, increased nuchal translucency
define Robertsonian translocation
a common type of translocation that occurs when the long arms of two acrocentric chromosomes fuse at their centromeres, losing the 2 short arms
what chromosomes typically experience Robertsonian translocation
13, 14, 15, 21, 22
which diseases can be caused by unbalanced Robertsonian translocation
Down syndrome, Patau syndrome
what causes cri-du-chat syndrome
microdeletion of short (p) arm of chromosome 5
what are the clinical manifestations of cri-du-chat
microcephaly, moderate to severe intellectual disability, high-pitched crying, epicanthal folds, cardiac abnormalities (VSD)
what causes Williams syndrome and what specific important gene is deleted
congenital microdeletion of long (q) arm of chromosome 7;
elastin gene is deleted
what are the clinical manifestations of Williams syndrome
elfin facies, intellectual disability, hypercalcemia (decreased sensitivity to vit D), well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems
what two syndromes are caused by deletion of 22q11 and what are their symptoms
Di George (thymic aplasia=> T cell def., hypocalcemia, cardiac defects) and Velocardiofacial (cleft palate, abnormal facies, cardiac defects) syndromes
