Question

General guidelines for completing the Assignment-1

1. You are required to work independently on one of the two cases listed for the assignment.

2. You may choose to search for the information online or in standard text books, research journals, online resources of biomedical research, pharmacogenomics knowledge base, etc.

3. You are required to list items of literature referred to at the end of the narrative under the subheading ‘References’. You are encouraged to refer to the original research publications where applicable and cite in the text. Citations in the narrative should be numeric as per the list of references.

4. Please Be Independently Dependent on the resources.

5. Expectations in regards to the required key points of information, are provided for individual cases.

6. Limit the entire narrative to not more than two pages including references.

Two year-old Sasha is brought into ER with high fever and high respiratory rate. Upon thorough check-up sepsis was suspected. Blood cultures and laboratory studies are obtained and the child is moved to the intermediate care unit for i.v. antibiotics. After realizing the recommendation, the mother tells the care team that she has hearing loss that had occurred when she received antibiotics during her elementary school years though she doesn’t remember what the medication was. Vaguely recalls something ‘sounds like mycin’. She is very concerned that this could happen to her child and requests that the baby be checked out. Care team immediately looks into the possible gene-drug interaction and to choose a right antibiotic for Sasha.

Investigate and synthesize pharmacogenomics of this case? Your narrative should contain but not limited to the following information:

1. What is the most relevant gene to be tested for variants in the child? How many genetic variants for this particular gene are reported? What are the major variants? 2 points

2. What is the prevalence of major variants in different ethnic groups? 2 points

3. Describe the molecular and phenotypic characteristics of the mutations (nucleotide or amino acid switch) in the major variants? Answer should include but not limited to the following: cellular localization of the variant of interest is located, how does it interact with antibiotics, how does this interaction lead to hearing loss. 3 points

4. Comment on the pattern of inheritance of the variant. 1 point

5. Given the fact that the genetic information is not available for the patient, who is in need of immediate therapy, what would be a right choice of antibiotic that would not cause deafness.

Answer 1

Some antibiotics like streptomycin, neomycin, amikacin,gentamicin, tobramycin, and kanamycin used in the treatment of serious infections caused by bacteria. Complication of their clinical use are nephrotoxicity and ototoxicity.These anitibiotics belong to aminoglycoside group which treats gram negative bacteria. Some studies suggest that prenatal exposure of aminoglycosides may lead to sensorineural hearing loss. MT-RNR 1 variant mutation is found to be associated with prenatal aminoglycoside exposure.

Pharmacogenomic testing can be informative and can help caregivers and patients make safer decisions when choosing between medications

1.MTHFR (methylenetetrahydrofolate reductase)gene is the most relevant to be tested for variants in the child.Two genetic variants of MTHFR gene are present .They are  C677T and A1298C.There is no major variant ,both are common forms. This gene may lead to serious genetic disorders such as homocystinuria, anencephaly, spina bifida,etc.

Cytochrome P450 2D6 (CYP2D6) gene is also one of the variants in children

2. Prevalance of both genes are found in

C677T: Hispanics – 5%,European,Caucasians – 35% ,African Americans – 12%

A1298C:European Caucasians – 31% ,African Americans – 15%

4. Pattern of inheritance is autosomal recessive.

Ref:

1. Anne Marie Tharpe, Richard Seewald,Comprehensive Handbook of Pediatric Audiology, Second Edition,2016. Page no:186-187