Genetics (Hersh) Flashcards
What is Mendelian Inheritance?
a.k.a. single gene or monogenic. Disorder or traits in which single genes are altered. Mendelian inheritance can be autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant.
What is compound heterozygote? Give an example.
Alleles are different, but both are abnormal. This may modify the phenotype in contrast to a disease resulting from 2 copies of the same mutation. ex. Sickle cell disease with Hgb S gene on one #11 and Hgb C gene on other #11 chromosome = milder form of disease.
Hemizygous
Refers to males affected with X-linked recessive trait = XaY
What is the risk of an autosomal dominant gene being passed from affected parent to offspring? What does the transmission look like in a pedigree?
Every offspring has 50% risk of being affected. Will see vertical transmission in pedigree with male-to-male transmission. *Won’t see male-to-male transmission in recessive disorders.
Define penetrance. What is incomplete penetrance? Give an example.
Penetrance: probability that an abnormal gene will have any phenotypic expression (likelihood of expressing it clinically). Incomplete penetrance: person carries the mutation, but does not exhibit the disease phenotype. ex. Split hand mutation in grandmother and grandson, but not in father. Dad has the mutation, just isn’t expressing it.
If you know that split hand is an autosomal dominant trait that is 70% penetrant, what is an offspring’s risk for inheriting the disease AND having physical abnormalities?
0.5 x 0.7 = 0.35. Thus, 35% risk for inheriting disease and expressing physical abnormalities. (Offspring’s risk for inheriting autosomal dominant mutation = 50%)
Define variable expressivity. Give an example.
quantitative and qualitative differences in phenotype between individuals having the same allele. Ex. Treacher Collins syndrome (affects development of bones and other tissues of face), expression ranges from mild to severe.
Define pleiotropism. Give an example.
multiple phenotypic effects coming from a single gene. ex. Marfan syndrome is an autosomal dominant fibrillinopathy (FBN1) resulting in: -musculoskeletal abnormalities (long fingers, scoliosis) -cardiovascular lesions -ocular defects (dislocated lens, myopia)
What is Neurofibromatosis 1? What mendelian pattern does it exemplify?
Neurofibromatosis 1 is a progressive, clinically variable autosomal dominant disorder characterized by: cafe-au-lait spots, neurofibromas, Lisch nodules, optic pathway gliomas, and tibial hypoplasia. It is an example of Pleiotropism.
What is genetic (locus) heterogeneity? Give an example.
Different genes contribute to one phenotype. Ex = Adult polycystic kidney disease. Mutations on chrom 16 and 14 result in same phenotype.
What is tuberous sclerosis complex (TSC)? What type of heterogeneity does it exemplify?
An autosomal dominant neurocutaneous syndrome. Locus heterogeneity because two genes have been identified to cause TSC, but do not result in a difference phenotypically. Both act as tumor suppressors. -TSC affects CNS, eye, heart, lungs, kidney, and skin (hypopigmented macules)
What is phenotypic (clinical) heterogeneity v. locus heterogeneity?
Clinical heterogeneity: one gene has different phenotypes. Locus heterogeneity: different genes contribute to one phenotype.
What is the risk of an autosomal recessive gene being passed from affected parent to offspring? What is the chance of being a carrier of an autosomal recessive gene? What does the transmission look like in a pedigree?
25% (1 in 4) risk of being affected. 2/3 chance of being a carrier. Will see a horizontal pattern in pedigree.
What is Spinal Muscular Atrophy?
an autosomal recessive disorder, whose infantile form presents in early life as a floppy infant. Usually results in death before 24 months of age.
In autosomal recessive disorders, what is the chance that a first degree relative is a carrier?
1/2 risk for being a carrier
In autosomal recessive disorders, what is the chance that an unaffected sibling is a carrier?
2/3 risk that an unaffected sibling of an infected individual is a carrier
For an affected individual of an autosomal recessive disorder, what does that mean for the parents?
It means both parents are silent carriers for the autosomal recessive disease
Name (4) principles of X-linked recessive inheritance patterns
-50% carrier risk for daughters of carrier mother -All daughters of affected father are carriers -Lyonization (random X-inactivation) impacts phenotype in female carriers -NO male-to-male transmission (on pedigree, see it going from infected males to carrier females to infected grandsons)
Duchenne Muscular Dystrophy (DMD)
Lethal X-linked recessive dystrophinopathy, where muscle tissue is replaced by fibrous tissue. Mother is carrier and 2/3 of these women have elevated CPK levels.
What is germline mosaicism?
Where a portion of the mother’s eggs carry the mutation and a portion do not. Seen in the transmission of DMD from mother to son.
If mother is a carrier of a recessive X-linked disorder, what is the risk of having an effected male? What is the risk of having a carrier female offspring?
50% for both
What offspring predominantly affected in recessive v. dominant X-linked diseases?
Recessive X-linked: almost all instances, males only Dominant X-linked: usually only females; because lethal gene in males.
What is the offspring risk of inheriting a dominant X-linked disease from an infected mother?
1/3. Since only a female can be effected, and affected male pregnancy usually results in fetal loss.
Amniocentesis
procedure done (usually in 2nd trimester) that takes small amount of amniotic fluid with fetal cells. The fetal cells are cultured in lab and then do chromosome analysis on them.
Transcervical chorionic villus sampling
procedure where remove cells from fetal portion of placenta and perform chromosomal analysis as early as 10-11 weeks gestation. This is a better option for couples, so they can avoid talking about the pregnancy before getting the result (and deciding if want to terminate)
Preimplantation genetic diagnosis (of Down’s Syndrome)
procedure done by in vitro fertilization. You remove the egg and fertilize it with the sperm. At the blastocyst stage, you can microscopically remove one of the cells without damaging the embryo and do a fluorescent probe study for chromosome 21 to determine if there are 2 or 3 signals for chrom 21. If result is normal, implant that embryo into the woman.
Prader-Willi Syndrome
a UPD 15 = uniparental disomy of chromosome 15. Means there are 2 chromosome 15s contributed by one parent with no contribution of that chromosome from other parent.
Phenylketonuria (PKU)
a disorder of phenylalanine metabolism. High levels of phenylalanine in blood can result in severe brain damage. By modifying the amount of phenylalanine in diet, the result can be autism spectrum disorder.
Epigenetic changes
individual has normal genetic makeup, but that gene does not work properly. Non-genetic factors cause genes to express themselves differently. ex. DNA methylation suppresses gene expression w/out altering the sequence of silenced genes (e.g. cancer)
Ornithine Transcarbmylase Deficiency (OTC)
an X-linked recessive urea cycle defect. So several females carry the mutation and transmit it to affected males. Ex. where infant died on day 4 and mother had 2 maternal uncles who were well at birth and died of progressive encephalopathic process at 3 days old.
Define metacentric, submetacentric, and acrocentric.
metacentric: have an equal amount of genetic material above and below the centromere. Lower #’s, such as 2.
submetacentric: as move up in chromosome #s, p arm gets smaller than long arm
acrocentric = 13, 14, 15, 21, and 22. These don’t have any functional material above the centromere. ALL important material is on the long arm of these five chromosomes.
Which 5 chromosomes are acrocentric?
13, 14, 15, 21, and 22. These chromosomes don’t have any functional material above the centromere. Means all important material is on the long arm (q)
Dx of this newborn
Trisomy 18. Note overlapping of 5th over 4th digits.
What are the (3) possibilities for the offspring when one of the partners has a balanced translocation?
Off spring has:
- normal chromosomes
- balanced translocation, like the parent
- unbalanced translocation: occurs more frequently than the other 2
Mutations of what gene (on which chromosome) leads to familiar adenomatous polyposis (FAP)?
mutations of the APC gene, locatd on the long arm of chromosome 5, leads to FAP.
