11/18- Interpretation of Genetic Testing (small groups) Flashcards
Case 1)
- Your pt, Mr. Richards, is a 52 yo male with colon cancer. He had R sided hemicolectomy and his tumor was resected and sent for IHC staining for MLH1, MSH2, MSH6, and PMS2
- IHC studies for Mismatch Repair Proteins (from tumor):
- MLH1: Intact nuclear positivity, tumor cells
- MSH2: Intact nuclear positivity, tumor cells
- MSH6: Loss of nuclear psotivity, tumor cells
- PMS2: Intact nuclear positivity, tumor cells
- IHC studies now being done (some places) for everyone with CRC < 70 yo
What’s abnormal. What is the next step in testing for this pt to confirm diagnosis?
Here loss of MSH6 is indicative of Lynch syndrome
- Confirm diagnosis with single gene test for MSH6
- Sequencing
- Deletion/duplication
- Loss of MSH2 could be reflective of mutn in MSH2 or MSH6
How would you manage Mr. Richards now that you know he has Lynch syndrome? What guidelines would you follow?
- Mr. Richards had part of his colon removed already, but the rest is still at risk
Colonscopies:
- Start at age 25 (20s-30s) every 1-2 yrs
- Annual colonoscopies > 40 yo
Also screen for other at-risk cancers:
- Bladder cancer
- (If woman: endometrial, but can’t screen for ovarian)
Which other family members should and should not be tested for Lynch syndrome? Why? How would you test other family members?
- Test first degree relatives (kids for sure)
- Each of his kids (3) has 50% chance of inheriting gene
- Adult kids are at age to start colonscopies
- Test his siblings
- Work your way upwards; maybe test Mr. Richard’s mom (that side has history of cancer) and if she was positive, test her siblings and such
So basics: work your way down (test affected’s kids) and up (test parents). Based on parent results decide to go up/over further into the tree
What screening recommendations are in place for asymptomatic family members that are identified as harboring a Lynch syndrome mutation?
Since confirmed the mutation, start screening and such
- Colonscopies every 1-2 yrs in 20s-30s and then annually > 40 yo
- Endometrial and bladder cancer screening
(Total colectomy typically isn’t indicated as it may be in APC/FAP)
So recap, what cancers are associated with Lynch syndrome?
- CRC!
- Endometrial
- Ovarian
- Skin
- Bladder
- Biliary tract
Case 2)
- Jacob is a 12 yo boy affected with a devastating neurological disorder of unkown etiology. He has severe neurological impairment and is unable to sit without support or communicate with words or manual signs. Completely dependent on others for ADLs
- Medical hx began soon after birth when physicians noted heart murmur, mildy dysmorphic features, and cutaneous syndactyly of his toes. Though he was discharged home soon after his birth, neurological impairment was evident early in infancy
- Jacobs clinical features include: acquired microcephaly, growth failure, dysmorphic features (abnormal hair whorl, bilateral cutaneous syndactyly, bilateral fifth finger clinodactyly), and hypogonadism. He has several seizures each day (even on max meds), cortical blindness, and spastic quadriparesis.
- Multiple studies hav ebeen performed, including MRI of the brain which revealed a lack of myelination fo the CNS with progressive atrophy of the cerebrum, cerebellum, and brainstem. No results from past genetic testing (microarray, metabolic, single gene tests, enzyme analysis).
- After discussion with geneticist, the parents consent to whole exome sequencing (WES) in their son. Five months following blood draw, test discussed. WES did not reveal an underlying cause for Jacob’s neurodevelopmental problems; however, a deleterious mutation in BRCA1 was identified. This was reported to the parents as a “medically actionable result”
What categories of DNA changes are reported on BCM WES focused report? Describe each category in 1-2 sentences
What types of genetic changes are not detected with WES?
1. Deleterious mutations in disease genes related to clinical phenotype: based on the change (e.g. stop codon, frameshift, etc.) or history/previously reported
2. Variants of unknown significance in disease related to clinical phenotype
3. Medically actionable deleterious mutations in disease genes unrelated to clinical phenotype: set by different entities; genes that include: cancer susceptibility (Lynch, BRCA), heart-affecting genes (long QT, cardiomyopathy)
4. Carrier Status for Recessive Mendelian Disorders
5. Pharmacogenetic results (not that useful…)
6. Mitochondrial (not anymore; only in past)
Information provided:
- Name of condition
- Inheritance pattern
- Gene name
- Chromosome/position
- Nucleotide and protein changes
- If it’s been seen before
Why did we do a CMA in this individual?
In what % of patients does WES arrive at a definitive etiologic diagnosis
- CMA can see deletions and duplications not seen on whole exome sequencing
- CMA can find definitive diagnosis in 5-10% of conditions that have intellectual disabilities and multiple congenital anomalies (?)
- In about 30% of cases, WES can arrive at definitive etiologic diagnosis (?)
What is a VUS?
Describe how parental results can be used to interpret variants of unceratin significance that are related to the clinical phenotype
VUS- Variant of Uncertain Significance
- Should see if either of the parents carry the gene
- If parents carry same gene without the kid’s health problems, we’re no that worried
What is a medically actionable mutation?
What organization(s) have published documents regarding these findigns on WES?
Medically actionable mutation = decided upon by a group of people that certain measures/managment/screening should be done
- Cancer genes
- Genes with late adulthood presentation
- Genes aftecting the heart (cardiomyopathy, long QT)
People should be told if they have these genes
ACMG is typically the authority followed (American College of Medical Genetics), but here at Baylor some extras are included
