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Flashcards in CBCL2 Quiz Review Deck (40):

The term “heritability” refers to what?

That component of a multifactorial disease due to genetics - This term refers to the component of a multifactorial disease that is inherited. It can be seen in twin studies where if there is 100% concordance between monozygotic twins, there is a very strong heritability, whereas if there is lower concordance, but still more than in dizygotic twins, there is a smaller impact, or heritability, on the disease. What is not due to heritability is due to environmental factors.


As a newly graduated and board-eligible pediatrician, you are covering for the newborn nursery service at the local University Hospital. It is a rather slow day, being slightly before the fall baby season, and you have time to discuss issues of importance with your gaggle of third-year medical students. One of the nursing staff obtains a heel-stick on an eighteen-hour-old infant for the state Newborn Screening Program. You kindly and professionally remind the nurse that it is not advised to collect the sample before twenty-four hours of age. The nurse apologizes and states that she never knew that. One of your medical students asks you why the timing is so important for newborn screening. How do you respond?

  1. The code for insurance billing is different on the second day of life and will result in higher reimbursement.
  2. Babies have a more difficult time with temperature regulation over the first day of life and this can alter the results of newborn screening and increase the false positive rate.
  3. There is no scientific reason for this rule and it exists only as tradition.
  4. Determination of the cut-off point for each analyte is an age-related phenomenon and is always a compromise between values which rise with age and those which lower with age.
  5. In all states, the examination for phenylketonuria is performed with capillary electrophoresis and performing this test prior to 24 hours will result in falsely low phenylalanine levels.

4 - Determination of the cut-off point for each analyte is indeed age-dependent, with some analytes decreasing after birth and others increasing after birth. Standardized age of testing ensures a minimum of both false-positive and false-negative results. Generally speaking, newborn testing is provided by individual states (within the United States) or similar arrangements in other countries, so insurance coding is not altered by the newborn screening. Although it is true that neonates not infrequently have temperature regulation difficulties in the first 24 hours of life, this is not the deciding factor in the integrity of newborn screening. The supposition that there is no scientific consensus for this rule is incorrect for the reasons stated above, although “received wisdom” in medicine sometimes does exist in the absence of evidence. Lastly, virtually all modern newborn screening tests are performed with tandem mass spectrometry, not with capillary electrophoresis.


Some inherited conditions can be caused by multiple genetic mechanisms. What is a condition that displays both autosomal dominant and autosomal recessive inheritance?

Long QT syndrome - Long QT syndrome is caused by mutations in five different genes encoding various subunits of potassium or sodium channels. Mutations in two of these genes, KCNQ1 and KCNE1 can be either dominant or recessive. This is an example of locus heterogeneity.


Evidence that “typical” type 2 diabetes (NIDDM) has a genetic predisposition includes?

different concordance in mono vs dizygotic twins - The concordance would be a measure of the genetic contribution. If there is greater concordance in monozygotic twins, it’s because they are genetically identical. But just because they are genetically identical doesn’t mean that they will be 100% concordant if there is a significant environmental influence.


Patients with heterozygous FH mutations have a highly penetrant autosomal dominant disease, familial hypercholesterolemia, the severity of which can be affected by which of the following?

Modifier genes and diet - There is evidence for modifier genes and of course diet.


Type 2 diabetes (NIDDM) can be caused by mutation in any one of these three genes.

PPARG, HNF4A, GCK -  But it reinforces the fact that NIDDM like other multifactorial diseases can have single-gene causes as well as being multigenic.


Bisphenol A (BPA) is a chemical produced at high volumes and is a main component in polycarbonate plastics, other plastics, and resins.  BPA use is widespread and is found in many common items (baby bottles, canned goods, food containers, receipts, etc.). Humans are exposed to BPA through ingestion of contaminated food and beverages and even through air, water, and soil.   Due to its chemical structure, BPA is weakly estrogenic and has endocrine disrupting activities.  Exposure to low-dose, environmentally relevant levels of BPA has been shown to disrupt meiotic prophase (synaptic defects, altered crossover number/positions) in several species (mouse, nonhuman primate, human). 

Which of these individuals would be most vulnerable to the described potential meiotic recombination errors induced by BPA exposure?

  1. A female fetus at 12 weeks of gestation
  2. A male fetus at 12 weeks of of gestation
  3. A 12-year old pre-pubertal boy
  4. A 12-year old pre-pubertal girl
  5. A 50-year old menopausal woman



A female fetus at 12 weeks of gestation - Meiotic recombination occurs during fetal development in the female, so this marks a significant window of vulnerability.  In contrast, meiotic recombination does not begin until puberty in the male.  Females are also born with a finite, non-renewable pool of oocytes, whereas males are continuously producing sperm.


Multifactorial inheritance shows familial patterns primarily because of which of the following?

  1. The environments of close family members are usually very similar
  2. More DNA is shared among family members than in the general population
  3. Family members have similar diets, nutrition, and lifestyle
  4. Gene-environment interaction largely governs phenotypic expression
  5. The environments of close family members are usually very similar
  6. The disease-causing mutation is the same among affected family members

More DNA is shared among family members than in the general population - Familial patterns seen in multifactorial inheritance are often due to groups of genes that together give rise to the phenotype, including modifier loci. More of these genes would be shared by close family members.


A 12-year boy comes into your clinic with cognitive defects. He’s been to numerous doctors who cannot find a cause for the symptoms.  He’s had mRNA sequencing and has reduced expression of the TSPYL gene; however, genomic sequencing shows no mutations in or around the gene.  Being a diligent doctor, you order bisulfite sequencing for DNA methylation.  Methylation of CpG islands in gene promoters generally causes what?

  1. Euchromatic regions
  2. Histone deacetylation
  3. Repression of gene expression
  4. Histone acetylation
  5. Activation of gene expression

Repression of gene expression

Methylation of promoters prompts condensation and repression of promoter activity. Histone deacetylation is associated with the process, but is not caused by CpG methylation.


Sporadic forms of Alzheimer disease may be associated with somatic mutations that occur by what mechanism?

Somatic mutations caused by dinucleotide deletion in microsatellite regions of APP have been reported, according to Westman. These disrupt the mRNA and ability to code the protein, leading to protein aggregation.


Monozygotic twins with cystic fibrosis can have different severities of pulmonary disease. As such, cystic fibrosis is best described as being?

an autosomal recessive condition affected by modifier genes - CF is also affected by the environment, in


The genetic basis for long QT syndrome is best described as having?

 Locus heterogeneity means that the same disease can be caused by mutation of different genes (loci).


The Pima Native American population in Arizona is noted for having a high incidence of?

Type II NIDDM - Type 2 diabetes is common in the Pima population, due in part to their shared genetics and environmental factors.


Genetic conditions have typical patterns of inheritance and recurrence risk. What would be the mode of inheritance for this pattern?



With appropriate genetic counseling, clinical DNA testing is available for Alzheimer disease. What is the most prevalent mutated gene in inherited early onset autosomal dominant Alzheimer’s?

PSEN1 encodes presenilin-1, the catalytic subunit of the γ-secretase complex. This gene is mutated in ~30-70% (or 18-50% depending on the source) of early-onset cases.


Loss of function LDL receptor mutations cause which of the following diseases?

  1. Alzheimer disease
  2. Type 2 NIDDM
  3. Maturity-onset diabetes of the young
  4. Insulin-dependent diabetes mellitus
  5. Coronary artery disease

Coronary Artery Disease - Coronary artery disease results from the elevated circulating LDL, which results from an inability of the liver to take up LDL and metabolize it.


The following table indicates what about the inherited condition?

stronger genetic component in females - This is Table 8-10 in Thompson & Thompson “Risk for Coronary Artery Disease in Relatives of a Proband” which shows that when the proband is female or young, there is likely to be a greater genetic contribution to MI to others in the family, thereby increasing the risk for disease in the proband's relatives. This is because females, otherwise, are somewhat protected.


Radiation embryopathy is a rarely described condition, and very little modern literature exists on the subject. However, it is clear that the central nervous system is strikingly radiosensitive and as such the critical period is between the 8th and 15th weeks gestational age. Fetal exposure in excess of 100 rads has been associated with microcephaly, microphthalmia, optic atrophy, and cataracts. If we presume that radiation acts to destroy developing tissue that is inherently normal, it would be an example of what kind of event?

  1. Malformation
  2. Deformation
  3. Convocation
  4. Elocution
  5. Disruption

Disruption - A malformation concerns inherently abnormal tissue, whereas a deformation concerns normal tissue which is affected by external or internal forces that act on it. Radiation embryopathy is a classic example of disruption.


What is syntelic?

sister chromatid pairs attach to the same spindle pole


An infant is born with an isolated congenital heart defect, a ventricular septal defect. What term best describes the cause of this anomaly?

A malformation would describe a developmental abnormality, in this case in the heart during fetal development.


What is amphitelic?

sister chromatid pairs attach to opposite spindle poles


What is merotelic

individual sister chromatids of a pair attach to opposite spindle pole


Monogenic forms of multifactorial diseases often reveal key biochemical pathways affected by other gene mutations. Which of the following is an example?

  1. LDLR and non-insulin dependent diabetes mellitus
  2. APP and coronary artery disease
  3. HNF4A and maturity-onset diabetes of the young
  4. GCK and Alzheimer disease
  5. PSEN1 and insulin-dependent diabetes mellitus
  6. LDLR and non-insulin dependent diabetes 

HNF4A and maturity-onset diabetes of the young - HNF4A mutations cause a single-gene form of diabetes that mimics other forms of type 2 diabetes that are largely multifactorial. The value in identifying these monogenic forms of complex diseases is that they provide insight into what biochemical pathways are potential targets for therapy.


This clinical characteristic is a significant diagnostic feature of

Down Syndrome - This is a single transverse palmar crease found in ~50% of people with Down syndrome and ~10% of the general population.


Genes that do not cause genetic disease but affect the phenotypic expression of the disease are called?

Modifier Genes - According to Westman, “Modifier genes are not associated with disease origin, but once disease susceptibility is present or the disease has developed, these genes modify the severity of phenotypic expression of the disease.”


Older individuals with Down syndrome are at high risk of Alzheimer disease for what reason?

The APP gene is located on chromosome 21 - Down syndrome is caused by trisomy 21. Thus, there is an extra copy of the APP gene which is located on chromosome 21. This results in overexpression and promotes aggregation of Aβ and its toxic effects on neurons.


A female child is born with an atrial septal defect and thumb anomalies as a reflection of an underlying syndrome. Predictably, a heterozygous mutation in the TBX5 gene (located on chromosome 12q24) is found and the diagnosis of Holt-Oram syndrome is confirmed. Aside from repair of the patient’s congenital anomalies, as the genetics professional you also offer counseling for recurrence. You note that neither parent has similar thumb anomalies, nor do they have a history of atrial septal defect. Based on this information, what can you say about the likely inheritance pattern in this case?

  1.  Autosomal dominant, present due to de novo mutation
  2. Autosomal recessive
  3. Mitochondrial
  4. X-linked recessive
  5. Autosomal dominant, inherited from the parents

1 -  Autosomal dominant, present due to de novo mutation


The severity of pancreatic insufficiency in cystic fibrosis is due largely to?

CFTR allelic heterogeneity - Of the various pathologies seen in CF, exocrine insufficiency is largely determined by the CFTR genotype.


A congenital condition caused by mutation of a number of partially interdependent genes in the RET signaling pathway, causing a loss of neural crest cells is?

Hirschsprung disease is caused by a defect in the innervation of the intestine.


You are on weekend call for your pediatrics group and are woken up from a deep slumber early on a Saturday morning (as these things tend to go) by the coordinator for the state Newborn Screening Program. They tell you that a three-day old male infant who was recently discharged from the hospital by one of your partners has an abnormal newborn screen showing significant elevation in C8 suggesting that the patient has a diagnosis of Medium-chain Acyl-CoA dehydrogenase deficiency (MCADD). What is the most appropriate next step to take in the evaluation and management of the patient?

  1. Alert the family of the results of testing immediately and enquire as to the wellbeing of the patient.
  2. Make a note to call the patient the next morning and suggest follow up on Monday morning.
  3. Reference the American College of Medical Genetics ACT Sheet for MCADD and follow the algorithm.
  4. Refer the patient to a metabolist when you get back to the clinic on Monday.
  5. Both A and C should be done.


5 - The American College of Medical Genetics publishes ACT sheets, which serve as a guide for the diagnosis and immediate management of patients in whom an abnormal newborn screening result has been found. Certainly in a patient who has suspected MCADD, reference to the ACT sheets absolutely must be coupled with immediate discussion with family, which concerns avoidance of fasting and what to do if the infant were to fall ill. Waiting until light of day would be inappropriate, as MCADD can be a cause of Sudden Infant Death Syndrome (SIDS). Additionally, while referral to a metabolist would be appropriate, it would be terribly cavalier to forgo any meaningful immediate discussion with the family.


A polymorphism in the gene for methylenetetrahydrofolate reductase (MTHFR) is involved in which two diseases?

Neural Tube Defects and Coronary Artery Disease - Mutations in this gene, which is involved in folate metabolism, can contribute to both neural tube defects, e.g. spinal bifida, and coronary artery disease. Individuals and/or their mothers who are homozygous for the C677T polymorphism are at higher risk of these diseases, especially if they have low folate levels.


For Alzheimer’s, 20-30% of cases show early or late-onset familial patterns. Among these cases?

some are autosomal dominant, some are multifactorial - For Alzheimer’s early onset is due to autosomal dominant mutations; late onset are more likely due to multifactorial causes.


The effects of a common polymorphism in a gene involved in methionine metabolism causing a multifactorial condition in the homozygous state can be effectively treated by dietary or nutritional supplementation with?

Folic acid - The MTHFR C677T polymorphism, which causes a single amino acid substitution, is common in the U.S. population (30% of whites, 10% of African Americans). As such, it is recommended that all women of childbearing age take a folic acid supplements to prevent neural tube defects.


There are numerous risk factors for Alzheimer disease. Which of the following would represent the highest risk group for the development of sporadic Alzheimer’s?

  1. female gender, APOE deletion, advanced age
  2. advanced age, male gender, APOEe2/e3
  3. APOE deletion, male gender, middle age
  4. female gender, advanced age, APOEe4/e4
  5. APOE deletion, advanced age, male gender

female gender, advanced age, APOEe4/e4 - While none of the three, female gender, advanced age, or APOE status, is a direct cause, this combination increases the risk of whatever is the underlying cause triggering the disease.


Sycp3 encodes a component of the synaptonemal complex (SC), and is conserved in mouse and human.  A man had his genome sequenced, and it was determined that he had a 1 base pair deletion at position 643 in the Sycp3 gene which results in a premature stop codon and truncation of the protein. This change is predicted to interfere with the ability of this protein to form fibers of the SC. 

You may expect that when this man tries to conceive a child, he is likely to experience:

  1. Normal fertility because of stringent meiotic checkpoints
  2. Normal fertility because of weak meiotic checkpoints
  3. Decreased fertility because of stringent meiotic checkpoints
  4. Decreased fertility because of weak meiotic checkpoints
  5. Increased fertility because of stringent meiotic checkpoints

Decreased fertility because of stringent meiotic checkpoints -  Defects in Sycp3 impair SC formation, which induces meiotic arrest and thereby activates checkpoint pathways that lead to germ cell death.  This ultimately results in azoospermia (lack of sperm in the testis) and results in infertility. Such phenotypes have been observed in both mice and human.  This finding highlights the concepts that meiosis is highly linked to gamete formation and that meiotic checkpoints are very stringent in males (i.e. defects in meiosis often result in germ cell death).


Meiosis I is unique because it is a reductional division that results in the separation of homologous chromosomes (sister chromatid pairs; bivalent).  This is accomplished because each sister chromatid pair is held in close proximity by cohesin proteins, which allows them to act as a functional unit and segregate together.  With advanced maternal age, however, there is a loss of chromosome cohesion which allows each sister chromatid pair more flexibility so that each individual sister chromatid can function independently (see image). 

  1. Amphitelic (sister chromatid pairs attach to opposite spindle poles)
  2. Syntelic (sister chromatid pairs attach to the same spindle pole)
  3. Merotelic (individual sister chromatids of a pair attach to opposite spindle pole)
  4. No attachments are made

Merotelic (individual sister chromatids of a pair attach to opposite spindle pole) - Cohesin loss during aging weakens sister chromatid cohesion and predisposes the individual sister chromatids of a pair to bi-orient (instead of mono-orient) and attach to opposite spindle poles.   This is referred to as a merotelic attachment and results in premature separation of sister chromatids and aneuploidy.


The common form of IDDM (type 1 diabetes) is thought to be largely caused by which interaction between genes and the environment? 

HLA locus and viral infection - Type 1 diabetes is thought to be caused by an autoimmune reaction, and to have a genetic susceptibility component, due to polymorphisms at the HLA locus, in addition to an environmental trigger such as a viral infection.


Which of the following has NOT been documented as an epigenetic change associated with the development of cancer?

  • Hypomethylation
  • Oncogene promoter methylation
  • Hypermethylation
  • Aberrant histone acetylation
  • Loss of imprinting

Oncogene promoter methylation - While all of these processes, methylation, acetylation, imprinting, are epigenetic, you would not expect to see oncogene promoter methylation because this would repress oncogene activity, exactly the opposite expected.


While all of these processes, methylation, acetylation, imprinting, are epigenetic, you would not expect to see oncogene promoter methylation because this would repress oncogene activity, exactly the opposite expected.

  • a reciprocal translocation
  • a methylation event
  • an epigenetic change
  • euchromatinization
  • uniparental disomy

an epigenetic change - This is the succinct definition of epigenetics. It is due to methylation but the term "methylation event" is too general and could mean many things. A translocation affects the DNA per se, and like uniparental disomy, is not "a change in gene expression." Euchromatinization occurs without a change in DNA sequence, but is not heritable. An important point about epigenetics is that the changes are indeed heritable from cell to daughter cell.


An autosomal dominant condition that affects a grandfather and a grandson, but no other family members is most likely due to?

 Incomplete penetrance - For a dominant condition, skipping a generation is due to non-penetrance in that individual who carries the mutation but does not express the phenotype. The term “incomplete penetrance” refers to the general phenomenon for mutations in that gene and the expression of the phenotype in the population. Most dominant mutations lie in a spectrum from virtually complete penetrance to weak penetrance such that the condition would not even look inherited.