Questions & explanations
1. A person has a family history of colon cancer and polyps. How does genetic counseling help distinguish Lynch syndrome from familial adenomatous polyposis (FAP)?
The counselor explains that Lynch syndrome is caused by mutations in DNA repair genes and leads to few polyps but early colon cancer. FAP is caused by mutations in the APC gene and causes hundreds of polyps starting in the teens. In Lynch, colon cancer occurs around age 45 on average, while in FAP, cancer often appears by age 40 if untreated. The counselor reviews the family history: how many family members had cancer, at what ages, and if they had many polyps. Genetic testing can confirm which syndrome it is. The management is different: Lynch requires frequent colonoscopies, while FAP often needs preventive colectomy (removal of the colon). The counselor helps the family understand the specific risks and screening plan.
2. A couple has a child with spinal muscular atrophy (SMA). They want to know the chance their next child will be affected. Both parents are carriers. The mother has a negative carrier test for the common SMN1 deletion. How does Bayesian analysis change the risk?
SMA is autosomal recessive. The mother is a carrier because she had an affected child, but her negative test suggests she might have a rare mutation not detected. The test detects about 95% of carriers. Using Bayesian analysis, the prior probability that the mother is a carrier is 1 (since she had an affected child). The conditional probability of a negative test if she is a carrier is 0.05 (false negative rate). The probability of a negative test if she is not a carrier is 1. So posterior probability she is a carrier = (1 × 0.05) / (1 × 0.05 + 0 × 1) = 1, meaning she is still definitely a carrier. The test result does not change her carrier status because she already has an affected child.
3. What is clonal evolution in cancer cytogenetics?
Clonal evolution refers to the process by which cancer cells acquire new genetic changes over time, leading to the emergence of subclones with different chromosome abnormalities. A tumor often starts with a single abnormal cell (the founder clone) that gains a growth advantage. As the tumor grows, additional mutations occur, creating diverse cell populations. These changes can be seen as new chromosome rearrangements or copy number alterations. Clonal evolution is important because it can lead to more aggressive disease or resistance to therapy. For example, in chronic myeloid leukemia, the appearance of additional abnormalities like an extra chromosome 8 signals disease progression.
4. Compare IC deletions in Prader-Willi and Angelman syndromes: how are they different?
In Prader-Willi syndrome, the IC deletion is on the father's chromosome 15, causing loss of paternal gene expression. In Angelman syndrome, the IC deletion is on the mother's chromosome 15, causing loss of maternal gene expression. Both deletions disrupt the imprinting center, but the parent of origin determines the syndrome. The IC controls a region of genes that are imprinted differently. So, a deletion on the father's chromosome leads to Prader-Willi, while on the mother's leads to Angelman. The syndromes have different symptoms: Prader-Willi includes obesity and intellectual disability, Angelman includes severe intellectual disability, seizures, and happy demeanor.
5. How do secondary chromosome changes differ from primary changes in cancer?
Primary chromosome changes are the first abnormalities that drive the initial development of cancer, such as the Philadelphia chromosome in chronic myeloid leukemia. They are often specific to the cancer type and are present in all tumor cells. Secondary changes occur later during tumor progression and are additional abnormalities that accumulate in some cells. They are less specific and can vary between patients. Secondary changes often confer additional growth advantages or resistance to treatment. For example, in acute lymphoblastic leukemia, a primary change might be a translocation, while secondary changes include deletions of tumor suppressor genes.
6. A person tests positive for a gene that causes a late-onset condition but has no symptoms. Should they tell their insurance company?
In many places, laws like GINA (Genetic Information Nondiscrimination Act) in the US protect against health insurance discrimination based on genetic test results. However, life insurance, disability insurance, and long-term care insurance may still use genetic information. It is important to check local laws. Genetic counselors advise thinking carefully before disclosing results to insurers. Some people choose not to tell to avoid potential discrimination. The decision is personal and should be discussed with a counselor. In India, the Insurance Regulatory and Development Authority (IRDAI) has guidelines but no specific genetic nondiscrimination law.
7. How can cytogenetic analysis distinguish between a primary and a secondary chromosome change in a cancer sample?
Cytogenetic analysis, such as karyotyping or FISH, can identify all chromosome abnormalities present in a sample. Primary changes are usually found in all or most cells, while secondary changes are present in a subset of cells (subclones). By examining multiple metaphases, the proportion of cells with each abnormality can be determined. If an abnormality is present in all cells, it is likely primary; if only in some, it is secondary. Also, primary changes are often recurrent in a given cancer type, whereas secondary changes are more variable. For example, in acute promyelocytic leukemia, the t(15;17) is primary, and additional trisomy 8 is secondary.
8. How does the genetic testing process for Huntington disease differ from testing for Alzheimer disease?
For Huntington disease (HD), genetic testing is predictive: a positive test means the person will develop HD if they live long enough, because the mutation has nearly 100% penetrance. For Alzheimer disease (AD), only a small fraction of cases are caused by single-gene mutations (familial AD), which also have high penetrance but are rare. Most AD is sporadic, with the APOE gene increasing risk but not guaranteeing the disease. Therefore, predictive testing for AD is less common and less definitive. In HD, testing is often done with pre-test counseling, while for AD, testing is mainly used in research or for families with clear dominant inheritance.
9. How does mitochondrial inheritance differ from autosomal dominant inheritance?
In autosomal dominant inheritance, a mutation in a gene on a non-sex chromosome (autosome) causes disease when one copy is changed. Both males and females can inherit and pass it on equally. In mitochondrial inheritance, only females pass the mutation, and all their children inherit it. Autosomal dominant conditions show a 50% chance for each child of an affected parent, regardless of sex. Mitochondrial diseases are always inherited from the mother, and both sons and daughters are affected. Also, mitochondrial mutations can vary in amount (heteroplasmy), leading to different symptoms, which is less common in autosomal dominant disorders.
10. A woman has a BRCA1 mutation. What are her options to reduce her cancer risk?
The counselor explains that a BRCA1 mutation greatly increases the risk of breast and ovarian cancer. Options include increased screening: breast MRI and mammogram every year starting at age 25. Some women choose preventive mastectomy (removing breasts) to lower breast cancer risk by over 90%. Preventive removal of the ovaries and fallopian tubes is often recommended after age 35 to reduce ovarian cancer risk. There are also medicines like tamoxifen that can lower risk. The counselor discusses the pros and cons of each option, including effects on fertility and menopause. The woman can decide based on her personal values and health.
11. How does variable expressivity differ from incomplete penetrance?
Variable expressivity means the symptoms differ among people with the same mutation, but all have some signs. Incomplete penetrance means some people with the mutation have no symptoms at all. For example, in hereditary breast and ovarian cancer (BRCA1 mutation), some women develop cancer (expressivity varies), but some never get cancer (incomplete penetrance). Both concepts are important in genetic counseling because they affect risk assessment. A person with a mutation may have a mild form or no symptoms, but their child could have a severe form. Counselors explain that not everyone with the mutation will be affected the same way.
12. How does Klinefelter syndrome increase the risk of type 2 diabetes?
Type 2 diabetes is a condition where the body cannot use insulin properly, leading to high blood sugar. In Klinefelter syndrome, the risk is higher because of obesity and low testosterone. Belly fat makes the body less sensitive to insulin, a condition called insulin resistance. Also, low testosterone directly reduces the body's ability to handle sugar. Studies show that men with Klinefelter syndrome are two to three times more likely to develop diabetes than other men. Early detection through blood sugar tests is important. Treatment includes lifestyle changes, diabetes medicines, and sometimes testosterone replacement therapy.