New Genomics

Question 1

What is the coefficient of inbreeding (F)?

Answer 1

average proportion of the autosomal genome that is IBD (identical by descent) in the offspring of related parents (CMA can tell you exactly what this is, which can give you a better idea of how the parents are related)

Question 2

What should you think about when ROH on a single chromosome is found on CMA?

Answer 2

UPD
Accurate Dx of UPD requires further testing with microsatellite markers of methylation (63% yield for cases when large ROH, telomeric region, and/or impacts a chromosome with a known imprinting disorder)

Question 3

What should you think about when ROH is found on multiple chromosomes is found on CMA?

Answer 3

IBD (identical by descent)
Recommend repeat testing with sequence and/or targeted CNV detection (7% diagnostic yield when known parental consanguinity)
Increases risk of AR conditions in homozygous regions

Question 4

What are the “risks” of WES?

Answer 4

undisclosed paternity/family relationships
incidental/secondary findings
many VUS (may be left with ambiguous results)
results may have implications for other family members
identifying a novel suspected pathogenic gene with little/no clinical data
future insurance (GINA)

Question 5

Describe the difference between “incidental findings” and “secondary findings”.

Answer 5

Incidental- findings unrelated to the indication for ordering testing, but of medical value or utility to the ordering physician and patient
Secondary- variants that are actively sought in genes that are part of a defined list, as opposed to genomic variants found incidentally or accidentally

Question 6

What are the categories of secondary findings?

Answer 6

Cancer genes (e.g. APC, BRCA1/2)
Cardiovascular genes (e.g. FBN1, LDLR)
Inborn Errors of Metabolism (e.g. BTD, GAA)
Miscellaneous (e.g. RYR1, HFE)

Question 7

What is important to include in the WES pretest counseling session?

Answer 7

background of genetics/exomes
assess patient/family perception of testing and correct missunderstandings
likelihood of finding dx is about 20-50% (depending on the pt’s ethnic background, availability of relatives for testing, and phenotypic presentation fit)
possible results (positive/negative/VUS, secondary findings)
other unexpected results (undisclosed family relationships, non-paternity, consanguinity, implications for other relatives)
results are NOT static (new interpretations of VUS, new gene discoveries, new symptoms change interpretations)
choices (opt in/out of carrier status or pharmacogenetic testing- this is lab specific)
what is NOT covered (common, multifactorial conditions; adult onset disease with no known treatment or cure, limited information on parents’ genetic status)

Question 8

List the genes commonly used for pharmacogenomics.

Answer 8

Dosing:
CYP2D6- SSRIs
CYP2D9/VKPRC1- warfarin
Adverse events:
HLA-B5701- abacavir (HIV drug- this polymorphism reduces risk of hypersensitivity to this drug)
HLA-B1502- carbamazepine (epilepsy, bipolar disorder)
Efficacy:
CYP2C19- clopidogrel (coronary artery disease, peripheral vascular disease)
IL28B- pegylated interferon/ribavirin (HCV infection)

Question 9

Describe the categorization of patients with CYP2D6 genotypes.

Answer 9

Ultra Metabolizers (UM)- greater than normal CYP2D6 function due to multiple gene copies
Extensive Metabolizers (EM)- normal CYP2D6 function
Intermediate Metabolizers (IM)- reduced CYP2D6 function
Poor Metabolizers (PM)- little to no CYP2D6 function