Genetic/Mendelian D/O P1 Flashcards
For the following syndrome, detail the:
- incidence
- parental age effect
- principal clinical and morphological features including survival data
- basis(es) of chromosome abnormality
- karyotypic patterns
Down Syndrome
Incidence: most common, 1:700
Survival: ~47 years
Abnormality: [95% true trisomy, 4% Robertsonian (meiotic NDJ)], 1% mosaic, mitotic NDJ
Parental age: correlation w/ increased age
Clinical features: palm crease, big toes widely spaced apart, cong. Heart disease, macroglossus, epicanthic eyefold, broad flat face, short nose; brush field spots - cataracts
For the following syndrome, detail the:
- incidence
- parental age effect
- principal clinical and morphological features including survival data
- basis(es) of chromosome abnormality
- karyotypic patterns
Trisomy 18; Edwards Syndrome
Incidence: 1:6000-8000
Parental age: positive correlation w/ age
Karyotype: meiotic NDJ; 5% mosaics, Chromosome 18 does not participate in Robertsonian translocation
Clinical features: intellectual disability, Cong. Heart defects, horseshoe kidney, rocker bottom feet
For the following syndrome, detail the:
- incidence
- parental age effect
- principal clinical and morphological features including survival data
- basis(es) of chromosome abnormality
- karyotypic patterns
Trisomy 13; Patau syndrome
Incidence: 1:12-15,000
Parental age effect: positive correlation
Karyotype: can participate in Robertsonian translocation, can be mosaic
Clinical features: intellectual disability, cong. Heart defects, polycystic kidneys, holoprosencephaly, polydactyly, rocker feet, cleft lip
For the following syndrome, detail the:
- incidence
- parental age effect
- principal clinical and morphological features including survival data
- basis(es) of chromosome abnormality
- karyotypic patterns
Chromosome 22qII.2 deletion syndrome
Incidence: 1:4000
Chromosome abnormality: band 11.2 deletion on long arm (q) of chromosome 22
Clinical features: failure of 3rd/4th pharyngeal arches - failure of thyroid/parathyroid structures, facial abnormalities, eye abnormalities, cardiac malformations, learning disabilities.
Due to the Human Genome Project, we know that there are ~3.2 billion nucleotide base pairs and ~20,000 protein-encoding genes (1.5% of the genome). What makes up the remaining portion of the nucleotide base pairs?
About 98.5% of the genome that doesn’t encode for proteins instead encodes for regulators of gene expression, including microRNAs, long non-coding RNAs, promotes, enhancers, and transposons
Therefore, most of the genetic variations associated with diseases are located in the non-protein coding regions.
Humans share >99.5% of DNA. What are the two types of DNA that are not identical in all humans. Where are these forms most located?
- SNPs- Single Nucleotide Polymorphisms
- CNVs- Copy Number Variations - large stretches of DNA from 1000 to millions bp
- Epigenetics
Recall that less than 1% of SNPs occur in coding regions; however, up to ~50% of CNVs are located in coding regions. Thus, it is more likely that human variations are due to CNVs.
What are the three stop codons?
TAA, TAG, TGA.
Describe the genetic mutation that occurs to produce sickle cell.
In the beta globulin gene, a cytosine is switched to uracil, forming a missense mutation that is non-conserved.
Does a frame shift mutation occur in order to produce Cystic Fibrosis? Also, what is the gene deletion that causes Cystic Fibrosis?
No, because 3 bp are deleted, the frame shift does not change, there is simply a deletion of an amino acid, which may produce a truncated and/or defunct protein. Cystic fibrosis is caused by a 3 bp deletion of (delta)F508, which cleaves out a phenylalanine.
What type of mutation produces Tay Sachs?
Tay Sachs is produced by a 4 bp insertion, which alters the reading frame (frame shift mutation), producing an altered protein- inhibition of storage of GM2 gangliosides, causing their over accumulation and neurotoxicity in glucocerbrosidase. Recall key features for Tay Sachs is a cherry-red spot on the macula, and neurodegenerative symptoms.
Differentiate between Euploid and Aneuploid
Euploid- a chromosome number that is 23 or a multiple of 23
Aneuploid - a chromosome number that is not 23 or a multiple of 23
Explain mechanism of NDJ (nondisjunction) in meiosis I vs. meiosis II:
NDJ in meiosis I: Chromosomes fail to separate in Anaphase I of meiosis I. All possible results are mutated (trisomic- 2n+1, and monosomic- 2n-1, after fertilization.
NDJ in meiosis II: Sister chromatid fails to separate in Anaphase II or meiosis II. Half are normal, half are mutated after fertilization (trisomic, monosomic, disomic)
What determines the phenotype for a person with mosaicism (ie Turner syndrome)?
Phenotype is determined by the percentage of cells with the abnormal chromosome. If more cells (usually somatic cells since germ cells tolerate mosaicism less) are with an abnormal chromosome # (ie monosomic/trisomic) then the abnormal phenotype is more evident.
Normally, autosomal dominant disorders can be seen in families members of all generations. What can explain the presence of 2+ children born with an autosomal dominant/x-linked disorder, which is not present in the parents?
This may be a case of gonadal mosaicism, or mosaicism that occurs with germ line cells early on in the zygote, affecting cells that leads to gonadal formation. Mosaicism is mostly seen with sex chromosomes, and less common with autosomes.
Note, gonadal mosaicism can be passed down to offspring if the mutated egg/sperm participates in fertilization.
Examples: Osteogenesis imperfecta, familial achondroplasia, duchenne muscular dystrophy
Differentiate balanced reciprocal and Robertsonian translocation.
Balanced reciprocal is a translocation wherein the two chromosomes have breaks and switches genetic material. However, no material is “lost” so pt. Is phenotypically normal. But they can still pass along unbalanced/abnormal gametes to children.
With Robertsonian translocation, genetic material is usually lost, and abnormal phenotypes are observed. Chromosomes 13, 14, 15, 21, 22 are acrocentric and can be implemented in Robertsonian translocations. Results in one chromosome with a large amount of material and a second, minute chromosome that is usually lost. Similar to balanced reciprocal translocation, the person carrying this translocation is typically phenotypically normal. Problems arise if the Robertsonian translocation chromosome is inherited.
