Biochemistry - Genetics Flashcards
Uniparental disomy
Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent
Hardy-Weinberg population genetics
If a population is in Hardy-Weinberg equilibrium and if p and q are the frequencies of separate alleles, then:
p-squared + 2pq + q-squared = 1 and p +q = 1
p-squared = frequency of homozygosity for allele p q-squared = fréquence of homozygosity for allele q 2pq = frequency of heterozygosity
What are the Hardy-Weinberg law assumptions?
- No mutation occurring at the locus
- Natural selection is not occurring
- Completely random mating
- No net migration
Imprinting
Imprinting/Inactivation by methylation
only one allele active and the other is inactive
With one allele inactivated, deletion of the active allele –> disease
What is the pathogenesis of Prader-Willi Syndrome?
maternal imprinting
mutation on chromosome 15 of PATERNAL gene
What are symptoms of Prader-Willi Syndrome?
hyperphagia obesity intellectual disability hypogonadism hypotonia
What is the pathogenesis of AngelMan Syndrome?
paternal imprinting
mutation on chromosome 15 of MATERNAL gene
What are symptoms of AngelMan Syndrome?
inappropriate laughter
seizures
ataxia
severe intellectual disability
What mode of inheritance affects both male and females in all generations?
What is the inheritance often due to?
autosomal dominant
due to structural genes
What mode of inheritance is usually only seen in 1 generation?
What is the inheritance often due to?
autosomal recessive
enzyme deficiencies
What mode of inheritance results in sons of heterozygous mothers having a 50% chance of being affected?
X-linked recessive
Can male-to-male transmission occur in X-linked recessive?
NO
Effects in a male from an X-linked recessive inheritance are more or less severe?
MORE
What is mitochondrial inheritance?
transmitted only through the mother
Who shows signs of disease in mitochondrial inheritance?
All offspring of affected females may show signs of disease
What diseases are associated with mitochondrial inheritance?
Mitochondrial myopathies (rare disorders)
often present with myopathy, lactic acidosis, and CNS
secondary to failure in oxidative phosphorylation
What can be seen on muscle biopsy of a mitochondrial myopathy?
“ragged red fibers”
What are autosomal dominant diseases (alphabetical order)?
Autosomal Dominant Polycystic Kidney Disease (ADPKD)- chrom 16 Familial Adenomatous Polyposis - chrom 5 Familial Hypercholesteremia Hereditary spherocytosis Huntington's Disease Marfan Syndrome Multiple Endocrine Neoplasias Neurofibromatosis Type 1 Neurofibromatosis Type 2 Tuberous sclerosis von Hippel-Lindau Disease
What are autosomal recessive diseases (alphabetical order)?
albinism ARPKD CF glycogen storage diseases hemochromatosis Kartagener Syndrome mucopolysaccharidoses PKU sickle cell anemia sphingolipidoses thalassemias Wilson Disease
What is the most common lethal genetic disease in Caucasian population?
Cystic fibrosis
What is the defect in CF?
defect in CFTR gene on chromosome 7
What are signs to diagnose CF?
- increased Cl- concentration in sweat = diagnostic!
- contraction alkalosis and hypokalemia (similar to a diuretic in that H2O/Na+ losses results in concomitant renal K+/H+ wasting)
What are complications of CF?
recurrent pulmonary infxns (e.g. Pseudomonas) chronic bronchitis and bronchiectasis --> reticulonodular pattern on CXR pancreatic insufficiency malabsorption and steatorrhea nasal polyps meconium ileus in newborns infertility in males Fat soluble vit. deficiencies (ADEK)
What is the treatment for CF?
N-acetylcysteine - loosens mucus plugs dornase alfa (DNAse) - clear leukocytic debris
What are X-linked Recessive diseases?
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 transcarbamylase deficiency
What is the pathogenesis of Duchenne Muscular Dystrophy?
X-linked frameshift mutation –> truncated dystrophin –> accelerated muscle breakdown
What tests are needed to confirm Duchenne Muscular Dystrophy?
Western blot and muscle biopsy
What lab findings will you see in Duchenne Muscular Dystrophy?
Increased CPK and aldolase
When do DMD symptoms begin?
Before age 5
What is the pathogenesis of Becker Disease?
X-linked POINT mutation –> defunct dystrophin protein –> less severe than Duchenne Muscular Dystrophy
When do Becker Disease symptoms begin?
adolescence or early adulthood
What is the pathogenesis of myotonic type 1 disease?
This is an example of muscular dystrophy.
CTG trinucleotide repeat expansion in the DMPK gene -> abnormal expression of myotonic protein kinase –> myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, and arrhythmia
What is the pathogenesis of Fragile X Syndrome?
X-linked defect affecting the methylation and expression of the FMR1 gene
What is a major finding of Fragile X Syndrome?
2nd most common cause of genetic intellectual disability (after Down syndrome)
What are physician findings of Fragile X Syndrome?
enlarged testes long face with a large jaw larged everted ears autism mitral valve prolapse
What are diseases with trinucleotide repeat expansions?
Huntington disease
Myotonic dystrophy
Friedrich ataxia
fragile X syndrome
Try Hunting for my fried eggs.
What is the MC cause of genetic intellectual disability?
Down Syndrome
What trisomy is associated with Down Syndrome?
Trisomy 21
What is the usual cause of Down Syndrome?
meiotic nondisjunction of homologous maternal age
What are the lab findings during pregnancy with a diagnosis of Down Syndrome?
1st trimester - increased nuchal translucency and hypo plastic nasal bone, serum PAPP-A is decrease and free beta-hCG is increased
2nd trimester - increased beta-hCG and estriol and decreased inhibin A and alpha-fetoprotein
What trisomy is associated with Edwards Syndrome?
Trisomy 18
What are some signs of Edwards Syndrome?
low set ears
micrognathia
intellectual disability
rocker bottom feet
What are the labs associated with Edwards Syndrome?
Decreased alpha-fetoprotein, estrial, beta-HCG, and inhibin-A
What trisomy is associated with Patau Syndrome?
Trisomy 13
What are some signs of Patau Syndrome?
rocker bottom feet polydactyly micropthalmia cleft lip/palate intellectual disability
What is a Robertsonian Translocation?
What can it result in?
nonreciprocal chromosomal translocation where long arms of acrocentric chromosomes fuse at the centromere and the 2 short arms are lost
results in miscarriage, stillbirth, and chromosomal imbalance (e.g. Down Syndrome)
What genetic abnormality is associated with Cri-du-chat Syndrome?
micro deletion of short arm of chromosome 5
What are some findings of Cri-du-chat Syndrome?
microcephay
mod-severe intellectual disability
high pitched crying/mewing* ("cry of the cat")
cardiac abnormalities (VSD)
epicanthal foldsWhat genetic abnormality is associated with Williams Syndrome?
micro deletion long arm of chromosome 7
What are some findings of Williams Syndrome?
"elfin" facies hypercalcemia extreme friendliness w/ strangers cardiac abnormalities well-developed verbal skills intellectual disablity
What are the syndromes associated with deletions at 22q11?
DiGeorge Syndrome and Velocardiofacial Syndrome
What is the pneumonic and findings associated with the 22q11 deletion diseases?
CATCH-22
Cleft palate Abnormal facies Thymic aplasia Cardiac abnormalities Hypocalcemia (d/t no parathyroids) Deletion at chrom. 22
What is the cause of DiGeorge Syndrome embryologically?
Failure of 3rd and 4th pharyngeal pouches to develop
