Problem Set 4

How do treatments for a genetic deficiency and a positively harmful effect differ?

Deficiency- treated by supplementing with missing factor or adding normal gene

Positively harmful effect- treated by targeting harmful protein or gene

If it is suggested that an individual avoid going outside in the spring because they have severe seasonal allergies, how would this “treatment” be classified

Preventative

What is Graft-versus-Host disease (GVHD)

potentially fatal complication where the donor cells attack the patient’s normal tissues

Is GVHD more likely to result from allogeneic or autologous transplant and why

allogenic transplant because the cells are more different

What is the major advantage of using CRISPR for gene editing?

does not cause insertional oncogenesis

Is CRISPR considered an RNA therapeutic

No because it doesn’t alter RNA

How might a patient with Duchenne muscular dystrophy be effectively treated using an RNA therapeutic?

Use antisense oligonucleotide to block exon 51 acceptor site, skipping exon 51, and restoring transcript reading frame → shorted but functional dystrophin protein

Precision medicine

Using an individual’s genomic, environmental, and lifestyle info to guide decisions related to their medical management

What is the primary symptom of ornithine transcarbamylase (OTC) deficiency?

Hyperammonemia

What is the mode of OTC disease inheritance

X-linked recessive

What are four ways in which OTC can be treated long-term?

1. Protein restriction

2. Ammonia scavengers

3. Avoidance of stressors / catabolism

4. Liver transplantation

What percent of female OTC carriers are “manifesting females?”

15%

What is the reason that some carrier females exhibit a moderate to severe OTC phenotype?

Skewed x-linked inactivation

What is the risk of a carrier female giving birth to an affected male?

25%

Patients with disorders of somatic mosaicism (e.g. PIK3CA-related overgrowth spectrum and vascular malformations) often present diagnostic challenges for standard clinical genetic testing. Why?

The genetic variant is only in certain cells, so if the affected tissue isn’t tested the variant isn’t detected

What specific genetic mechanism accounts for mosaic disease development?

somatic mosaicism- post-zygotic mutation

What is the term used to define a genetic disorder in which a mutation or variant disrupts a specific metabolic pathway?

Inborn error of metabolism

Phenylketonuria (PKU)

inborn error of metabolism in which you cannot breakdown phenylalanine (usually issue with phenylalanine hydroxylase)

What is clinical variant analysis and interpretation?

Process of analyzing an individual’s gene variants and determination of if they are associated with a disease

What are three major considerations when assessing a potential disease-causal variant that was inherited from a parent?

1. Inheritance pattern

2. Parental phenotype/penetrance

3. Variant segregation with disease