Key Terms

Question 1

Dominant Negative Mutation

Answer 1

Mutation whose gene product adversely affects the normal, WT gene product within the same cell. This usually occurs if the product can still interact with the same elements as the WT product but block some aspect of its function.

Question 2

Positive predictive value

Answer 2

the probability that a patient with a positive (abnormal) test result actually has the disease.

Question 3

Heteroplasmy

Answer 3

Describes the situation in which two or more mtDNA variants exist within the same cell.

Question 4

iAMP21

Answer 4

Intrachromosomal amplification of chromosome 21

Eistinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), occurring in ~2-5% of patients

Associated with a poor outcome in patients treated by a standard protocol.

Question 5

BCR::ABL1-like disease

Question 6

Modifier genes

Question 7

Polygenic Risk Score

Answer 7

A mathematical score that is constructed to try to determine the risk of a condition or disorder. This score combines the contributions of multiple individual variants to estimate the chance of having the condition in question. Recently, polygenic risk scores of many conditions have been investigated and, in some cases, are being studied or implemented in clinical settings.

Question 8

Promoter

Answer 8

A type of DNA regulatory element. Typically, the promoter is located just upstream or next to the place where a gene will be transcribed

Question 9

Phenocopy

Answer 9

Term used to describe a person who does not have a particular genetic change, but who has clinical findings that would make it seem like they “should have” that genetic change. In the example in the question, the person with early-onset breast cancer might be anticipated to have the BRCA1 pathogenic variant found in the other family members, but does not; the person may have breast cancer due to causes other than the BRCA1 variant seen in other family members.

Question 10

Waardenburg syndrome

Answer 10

can involve hearing loss and pigmentary changes affecting the eyes, hair, and skin. Pigmentary findings can include areas of hypopigmentation or heterochromidia irides, where the eyes are different colors. There are multiple different types of Waardenburg syndrome, and certain types may also include other features, such as distinctive craniofacial features, congenital anomalies affecting organs such as the GI system, heart, kidneys, and skeletal system. Pathogenic variants (mutations) in multiple different genes can cause Waardenburg syndrome

Question 11

Pallister-Killian syndrome

Answer 11

Caused by mosaic tetrasomy of chromosome 12p (typically involving an additional isochromosome 12p). Manifestations are variable, but can include neurocognitive impairment, seizures, and distinctive features on physical examination, as well as other findings. Blood-based chromosomal testing will typically not detect the causative cytogenomic anomalies, but testing via buccal swab (which is easier to conduct, but involves some limitations) or skin biopsy can identify the cytogenomic cause

Question 12

Biotinidase deficiency

Answer 12

Inborn error of metabolism caused by bi-allelic pathogenic variants in BTD gene. Untreated, profound biotinidase deficiency leads to neurologic manifestations (ataxia, developmental delay, hypotonia, motor limb weakness, seizures, spastic paresis), vision problems, hearing loss, and skin abnormalities (alopecia, candidiasis, rash). Partial biotinidase deficiency may include hair loss, hypotonia, and rash, and hair loss. Infants identified by newborn screening should remain asymptomatic with early institution and lifelong therapy with biotin.

Question 13

Hereditary hemorrhagic telangiectasia

Answer 13

Het pathogenic variants in the genes ACVRL1, ENG, GDF2, or SMAD4

Clinical manifestations include nosebleeds (epistaxis) by early adulthood, telangiectases (found on the face, lips, tongue, chest, and fingers), and sequelae of AVMs in organs such as the lungs, liver, and brain.

Question 14

Approximately what percentage of the human genome consists of repetitive elements?

Answer 14

50%

Question 15

A “two-vessel cord” typically refers to what arrangement for the blood vessels in the umbilical cord?

Answer 15

One artery, one vein

Normally, the umbilical cord contains three vessels: two umbilical arteries and one umbilical vein. The umbilical arteries carry deoxygenated blood from the fetus to the placenta, while the umbilical vein carries oxygenated blood from the placenta to the fetus. A “two-vessel” cord (2VC) typically refers to a cord with a single umbilical artery (SUA) such that the umbilical cord contains one umbilical artery and one umbilical vein. The clinical significance of a SUA appears to depend on or at least be related to any accompanying structural anomalies, which may or may not be present. In addition to SUA, there are also other types of umbilical cord anomalies that involve missing blood vessels.

Question 16

Nystagmus

Answer 16

Repetitive, involuntary eye movements, can be congenital or acquired.

Many possible causes of nystagmus, including albinism, cataracts, and other optic nerve or retinal disorders, as well as a number of different neurological conditions. Nystagmus may occur in an apparently isolated or syndromic context

Question 17

During meiosis, when does recombination (crossing-over) occur?

Answer 17

Meiosis I

Question 18

Heterotopia

Answer 18

Collection of neurons that have not migrated to their normal position.

There are multiple types of heterotopias. Heterotopias can be associated with seizures, and may occur in the context of a known genetic disorder or syndrome, or in an apparently isolated context.

Question 19

Psuedogene

Answer 19

Sequence of DNA that closely resembles a gene, but which has become (apparently) inactive through evolution. The presence of pseudogenes can cause challenges in genetic testing processes; for example, it can be difficult to determine if a detected variant occurs in a gene or a related pseudogene.