Question #1:

A child has a hearing loss.You do not know how this hearing lossoccurred.What are threecharacteristics of the condition, the family history, or in the population that would suggest this condition is:
a) Dominant?
b) Recessive?
c) X-linked recessive?
d) Multifactorial?

Question #2:

Explain the differences between random and non-random X-inactivation, and how each can cause a female to manifest an X-linked disease.

Question #3:

Part 1: The frequency of sickle cell disease in African Americans is approximately 1:400 and in Hispanic-Americans about 1:16,000. A couple consisting of an African-American woman and a Hispanic man ask what is their risk of having a child with sickle cell disease. Before any DNA or carrier testing is done, what is their risk of having an affected child?

Part 2: Genetic diversity (e.g., numbers of single nucleotide variants) tends to be greater in African populations than in populations elsewhere in the world, such as Europe. Given that populations are believed to have derived from an ancestral African population, how would you explain this difference in genetic diversity?

Question #4:

Peripheral blood G-banded chromosome analysis of a girl demonstrates that she carries a deletion in the terminal end of the short (p) arm of chromosome 4.

a) What is the name of the clinical syndrome that you would expect?

b) What additional cytogenetic tests are recommended to confirm that this is a terminal deletion and not an interstitial deletion or an unbalanced translocation? Explain how these tests can be used to differentiate between the three possibilities.

c) After further testing, this abnormality turns out to be due to an unbalanced translocation between the p arms of chromosomes 4 and 11, resulting in the formation of a derivative chromosome 4 [der(4)t(4;11)(p15.3;p15.4)], which was inherited from the father who carries the balanced version of this translocation. Please draw a diagram of the derivative chromosome 4, indicating the cytogenetic bands from the 4 and11.

d) What additional information can you provide to the family regarding the diagnosis of this girl?

Question #5:

In studying a rare disease phenotype, you need to identify the causative mutation. You have two initial experiments you could do to accomplish this, arrays and sequencing. Compare and contrast array based methods v. sequencing based methods for causative variant detection. What follow up experiments would need to be done to validate the variant is indeed causative?

Question #6:

Your clinician friend is part of an Undiagnosed Disease Program. They have sequenced the total genome of few patients and found two patients with mutations in genes coding for mitochondrial proteins: one patient harbors a mutation in SDHB gene and the other in MT-ND6 gene.
a) Would you expect any differences in the disease manifestation and genetics of these two undiagnosed diseases?
b) If so, why?
c) Would you have any recommendation to your friend to help diagnose and treat the patients?

Question #7:

A substantial subset of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases is caused by expansion of hexanucleotide 5' GGGGCC 3' /5' GGCCCC 3' repeats in the C9orf72 gene.Please answer the following questions using class material and additional published material, if needed:

1. Based on the attached model, name 5 possible modes of pathogenesis (A - E) that can be induced by expanded hexanucleotide repeats in the C9orf72 gene.
a)
b)
c)
d)
e)

2. For each of the 5 modes of pathogenesis, describe in 1 - 2 sentences the pathogenic biomolecules that can be involved in the molecular processes of disease development (e.g. "pathogenic polyglutamine tract").
a)
b)
c)
d)
e)

3. Based on your literature search, please name an example of a repeat expansion disease that is (or is postulated to be) caused by each of the 5 identified above molecular modes of pathogenesis. One example per category is sufficient (excluding ALS/FTD).
a)
b)
c)
d)
e)