What steps should laboratories take to try and resolve clinically relevant genes affected by segmental duplication and pseudogenes? Why is it important? While our ability to accurately detect disease-causing variants in the human genome is continuously improving, there are certain genomic regions that remain a challenge to validate, analyze, and interpret.
A number of clinically important variants are located in regions that are not covered with standard next-generation sequencing (NGS) strategies or Sanger sequencing. By developing custom solutions, we can resolve difficult-to-sequence regions and structural variants that have highly homologous genomic regions or consist of longer stretches of repetitive sequences.
Provide an overview of difficult-to-sequence genetic regions
Explain why it is important to be aware of possible limitations in tackling pseudogenes when ordering genetic testing
Review the clinical importance of resolving these regions
Demonstrate the need for customized methods to detect and confirm disease-causing variants in challenging regions
Review case examples including PKD1 associated with polycystic kidney disease, RPGR (ORF15) associated with X-linked retinitis pigmentosa, and novel disease-causing transposable element insertions
No, we are not here to talk about a movie. But honestly, isn’t this the kind of question a patient comes with when visiting a genetic counselor? Well, at least in most cases, yes!!
Now, Imagine the intensity of this question in case of WGS and WES, where Secondary/Incidental findings are behind this DOOR.
Know The Basics
Patients and families can have varied responses to receiving genomic testing results, specially in case of WGS or WES whether positive, negative, uncertain or unexpected.
Collaboration in patient management between the referring provider and genetic counselor will lead to optimum patient care. The genetic counselor typically provides support and guidance in developing a management plan based on results. Even before we get to this management stage, what are these different results:
Positive result: A mutation was found that is known to be associated with your medical concerns. The response to this result can often be complex as some families may experience stigma or shame surrounding the fact of genetic or congenital disease or linked findings. Inherited conditions impact the whole family and result in feelings of parental guilt. On other hand, many families that undergo testing have already been through exhaustive journey of search for diagnosis and finding a pathogenic variant may provide relief and an end to long diagnosis odyssey.
Negative Result: Contradictory to above, receiving a negative result meaning no casual variant is identified, the patient and family can be feeling a sense of disappointment or a lack of diagnosis feeling as they had already made a strong mindset expecting or suspecting a syndrome. Here, it is the role of Genetic counselor to provide management plan based on clinical presentation and family history, discuss further testing if needed now or in future and mainly provide counseling to help patient/family cope with these feelings of lack of diagnosis and address psychological concerns.
VUS Results: Variants of Uncertain significance(VUS) may be reported in many tests and can be likely many in tests such as multi-gene panel, exome and WGS. Patient reactions can be very similar to that of negative results and involves regular follow up on VUS classification with the genetic provider.
Of all the above, today’s major highlight is on SECONDARY FINDINGS:The findings you weren’t looking for!!
When Exome sequencing is done, there is an option to learn about other genetic mutations. these are mutations that are not related to your primary reason of diagnosis. If these other mutations are found, these are then called secondary findings. These secondary findings although unrelated to primary reason for testing, yet can be a cause for some serious disease or heart condition which can lead to sudden death. Secondary finding can also recognize mutations which might show that patient might be risk at severe response to certain type of medications. Paradoxically, while these variants are ubiquitous in the genome, their presence must be actively sought from among the vast number of other genomic variants in order to be identifiable and reportable.
Impact of such diagnosis:
Whether a diagnosis was desired or unexpected, coming to such diagnosis often raises additional questions for the family around medical arrangement, life expectancy and social issues. There may also be healthy or reproductive risks for family members such as siblings.
Role of Genetic counseling in this aspect:
Genetic Counselling as we all know is a profession focused around the central element of non- directive approach and “patient choice.” This element plays a key role in the process of addressing secondary findings. There is a huge room for flexibility in approach and workflow to follow in genetic counseling setups and the common view from many research studies have suggested that dealing with secondary findings and whether to get secondary findings, whether to disclose or not; all these aspects lie inside the circle of the patient case you are dealing with, pre-counseling and setting expectations, providing clear information on test options, what these tests can mean to the patient and their family, their rights to informed consent and choice to not know these results and alternatives.
An example of one such workflow:
Tips for supporting families with genomic test results:
Being aware of factors that can influence understanding of or coping with results:
a. Potential emotional reactions to results
b. Existing experiences and underlying pyschosocial issues
c. Health Literacy level and baseline understanding of genomic testing
2. Elicit knowledge and validate unique feelings that arise from genomic results.
3. Think ahead about the kinds of pyschosocial referrals that might be appropriate and have support resources specific to diagnosis available to provide.
4. Create a plan for next steps with family, specific to their results.
Recommendations by many different boards of Genetic Counseling:
Include awareness of results to expect in pre-test counseling and informed consent discussion.
Make them aware of their rights and choice to receive or not receive such variant or secondary findings results and what could be the implications of their choice and the results itself. That being said, enabling a patient to make an informed decision remains the responsibility of the clinical provider, a role that has not changed with the expansion of testing from single gene tests to whole-genome sequencing.
The responsibility as to how, when, and, if results should be communicated is on a medical professional’s judgment. This patient-centric approach demands a robust informed consent process prior to clinical sequencing. It prompts questions of which information should be included and how it should be tailored to promote patient understanding.
Ongoing Follow- up: Regardless of result, the genetic counselor may recommend follow up with patient every 1-2 year.
Provide References to external support or to a clinical specialist and other support groups to help deal with psychological feelings.
Finding the balance between the appropriate degree of professional guidance and individual choice will require more than vigorous commentary and the reporting of subjective data on hypothetical preferences, but will require empiric data on actual decisions and their outcomes. There is a growing need to evolve and advance the traditional models of informed consent and disclosure. There is also a demanding need to develop educational strategies to enhance the way people make informed decisions that streamline, yet complement, the genetic counseling process. The most crucial aspect though still relies on interpersonal dialog of a genetic counselor to help people understand and reach complex decisions and information into a healthier choice for their individual self and family life. Educational strategies that touch both the cognitive and the emotional chords in the decision-making process by helping patients forecast their short- and long-term emotional responses to their decisions will help keep genetic counseling relevant regardless of what genomic testing looks like in the future.
Interesting videos and resources for further reference:
Are you anxious/nervous/lost looking for resources and not sure where to begin from?
Are you interested to speak with a current grad student and also listen to their journey on getting into grad program? This is your chance to register for Part 1 session on Journey of applying to universities and journey up-to the stage of interview.
We will be conducting part 2 session of interview process, rank and match day hopefully in the next 1-2 weeks and registration will open soon.
Topics that will be covered in the Part 1 session:
GC students introduction and their journey to grad school in brief.
Overall Application Timeline
Cost of Application process
Preparation for application
Helpful resources and tips to share
Pre-requisites and how he met the requirement, extra curricular and any recommended experiences to have for strengthening application.
Finding Genetic Counselor to shadow or alternative options due to Covid19
Writing personal statement and LOR’s – how many to take and who to ask?
Deciding schools to apply – Factors considered for shortlisting options.
A 20- 25 mins discussion round for any questions on application process. Please bring through any doubts or questions you may have. Please also register only if you think you will be able to block your calendar to make it, so that all the students have an opportunity to join. Only 20 seats available.
When: 5th February 2021 EST / 6th February 2021 IST/AEDT
Time: 8.30 PM EST
Please make sure to convert time and date as per your time zone. Link to the meeting will be sent after registration. Please come in your comfy PJ’s and a cup of coffee/tea or snacks 🙂
Please register below and I will send through the journal article 48 hours before our meetup.Journal meetup will be on 8th January 9.00 PM Eastern Standard Time/ 9th January 7.30 AM Indian Standard Time