X-linked Inheritance Flashcards
Describe the sex chromosomes
1095 genes are annotated on the X chromosome (this is the current estimation; maybe there are more)
- Female have two copies of all genes on the X-chromosome
- Males are said to be hemizygous fir the X chromosome (males only have one copy)
What are the pseudo autosomal regions?
Regions of X and Y chromosomes that match. It is necessary to line up chromosomes correctly during meiotic recombination
About 148 genes mapped to the Y chromosome (mostly related to spermatogenesis )
Give the main examples of X-linked disirders
- Dystrophin associated muscular dystrophy
- Duchenne muscular dystrophy (severe)
- Becker muscular dystrophy (milder form)
- both are due to mutations of the same gene (DMD, dystrophin )
- Glucose 6-phosphate dehydrogenase (G6PD) deficiency
- hemolytic anemia on ingestion of primaquine, sulfa drugs
-Hemophilia A and B result in bleeding tendencies
- Lesch-Nyhan syndrome [Hypoxanthine Guanine Phosohoribosyl transferase (HGPRT) deficiency]
- causes hyperuricemia, gout, & self mutilation
- Red-green color blindness /deficiency (non-lethal)
- X-linked SCID (defect in the SCIDX1 gene)
Briefly describe X-linked recessive disorders in males
- Males require only one copy of the mutation (hemizygous) to express the disease
- Disirders are more common and more severe in males than in females
- Skipped generations common
- Affected father transmits the mutation to all his daughters who are typically NOT affected but they are carriers . A carrier daughter may transmit the mutation to her sons who would then be affected.
- Make to male transmission not seen
Summarize the X-linked dominant disirders
- Skipping of generations not common
- Preponderance of females compared to males
- No male to male transmission
- Affected make transmits the disease to all his daughters, but none of his sons would be affected
Variable expressivity in females: Due to the phenomena of X-inactivation
If a disirder, males are often very severely affected (often lethal)
Briefly describe Y-linked inheritance
-Only males will show the trait
- Genes on Y are primarily genes involved in spermatogenesis and, therefore, mutations in these usually causes sterility and are not passed on
- Genetic lethality (the person may be relatively unaffected but unable to procreate
Examples of Y traits
-Variations mutations in the SRY genes
- H-Y histocompatibility antigen
- Hairy ears
What is Y-linked inheritance?
Males only
- males transmit the trait all if their sons but none of their daughters
- Main point: If a trait is controlled by an allele from the Y chromosome , it has to have come from the father, as the mother is XX
What is reduced penetrance ?
Incomplete or reduced penetrance May complicate an autosomal dominant pedigree
A disorder is said to be fully penetrant, if all the people carrying the mutation, express the phenotypic manifestations of the disorder
Explain locus heterogeneity
Mutations at different loci (meaning different genes ) that cause the same phenotype
- Osteogenesis imperfecta: Defect in collagen
- Mutations of chromosome 17 (COL1A1 gene) or chromosome 7 (COL1A2 gene) will both lead to disease manifestations (phenotype) of osteogenesis imperfecta
What are the examples of locus heterogeneity?
Many other disorders that demonstrate locus heterogeneity.
Examples:
- Sensorinueral hearing impairment (many types)
- Retinitis Pigmentosa
- Charcot Marie Tooth disease (AD, AR, or X-linked)
- SCID (many forms are known, so far, we have discussed AR and X-linked forms)
Describe variable expression
-In individuals who have inherited the same mutant allele, some individuals are severely affected, and others are mildly affected
- three reasons:
1. Other genetic factors (modifier loci) or sex influence
2. Environmental exposure
3. Random chance
Explain hemochromatosis as an example of variable expression
Hemochromatosis- is an iron overload disorder(autosomal recessive disorder)
- Hemochromatosis is more severe in males, less severe in females. Premenopausal females will menstruate and lose iron - Variable expression due to sex differences
Explain Xeroderma Pigmentosum as an example of variable expressivity
Autosomal recessive- more severe individuals exposed more frequently to environmental UV radiation
-first child would be expected to be more severely affected than the second child
- Parents might know to keep the second child out of the sun; variable expression due to environment
Explain cystic fibrosis as an example of variable expression
Two patients with the same exact mutation profile might present with very different clinical pictures. Could be different genetic modifiers/background, or different environment exposure
-Some embryonic development disorders (syndromic cleft lip), might be severe in one child than in another, but caused by the same mutation- some of this might be due to random chance
What are the main exampkes of variable expressivity?
- hemochromatosis
- Xeroderma Pigmentosa
- Cystic fibrosis
New autosomal dominant tend to occur more often in…
Older fathers. Particularly men she can have a long reproductive life.
Remember this mutation is occurring during gamete formation. It is spontaneous, (that is it is new), not in the parents original genome
Explain the effect of paternal age
The average age for fathers with children which have new Autosomal Dominant mutations is greater than the average age of the father in the general population
True for number of conditions
- Average age for father in population: 30-31 years
- Average age of father of Achondroplasia: 36.1 years
- Average age of father of Marfan syndrome: 36.6 years
-About 1/2 of all NF1 cases are de-novo, and risk increases with age of the father
Genetic advice is difficult to give for this because there is nothing specific to advise on.
Genetic basis: spermatogonia continually divide & sperm cells from older fathers may contain replication error mutations. (Point mutations)
Describe germline Mosaicism
A healthy man had two children affected with osteogenesis imperfecta with different partners. The father also has another child that is normal
Genetic testing shows the same mutation in both affected children, but all parents test normal
-No parent has the mutation in their peripheral cells (blood cells)
Maybe due to Mosaicism in the germline (gonadal) in the father
The mutation is present in a proportion of the germline cells
-Presence of two affected children suggests germline Mosaicism ( compare to new mutation, where there is a single child with a disorder and NK family history of the disorder
Give examples of delayed age of onset
Disease causing variants can be given at birt, but don’t manifest until later in life
Huntington disease
Hemochromatosis
Familial breast cancer (BRCA-1 or BCRA-2 mutation)
Describe pleiotropy
A disease-causing mutation affects multiple organ systems
Marfan syndrome (autosomal dominant)
- mutation in the FBN-1 gene (fibrillin-1)
- skeletal abnormalities (arachnodactyly, long limbs, percussion excavatum)
- Hypermobile joints
- Ocular abnormalities (myopia, lens dislocation)
- Cardiovascular disease (mitral valve prolapse, aortic aneurysm)
Osteogenesis imperfecta (brittle bones, peridintal weakness, blue sclera) is due to a mutation in a gene encid8ng pro-collagen
What are the requirements of translation?
- mRNA
- ribosomes
- CHARGED tRNA
- initiation factors
- GTP
