PF19: Genetic Question 8

How should patients and families receive GENETIC TESTING COUNSELING

Chairs: Randall E. Brand MD, Balázs Németh MD PhD, TBN

Delegates: Katya Orlova MS CGC, Prof. Grzegorz Oracz MD, Ph.D, Katarzyna Wertheim-Tysarowska, Ph.D, Péter Hegyi MD PhD
and TBN

Considerations: What are appropriate roles for MDs, genetic counselors and others? How to translate genetic test results to clinically useful descriptors? How should pathogenic scores be generated for each patient and associate with level of risk?

References to consider: Shelton et al: PMID 26561988

10 Replies to “PF19: Genetic Question 8”

  1. There are a lot of important questions we need to discuss in this meeting regarding genetic counselling:
    1. What should we report exactly? (methods of genetic testing, found variants (including pathogenic, non-pathogenic and unknown)
    2. Who should report the results to the patients (geneticist, gastroenterologist, referring clinician or all of them)?
    3. What is the clinical signficance of the test results? Question 4 discussion could help us……. From personal experience: in Hungary we categorize variants as “causative” , “predisposing” , “harmless” and “unknown signficance”. It is based on reported Odds ratios from recent population-based studies. Ethnical differences and the mean age of the involved individuals might change the interpretation of a variant. Patients with multiple pathogenic variants could make this question more difficult.
    4. When should we test other family members?
    5. Should we recommend prenatal genetic testing? When? What about CFTR mutations?

    If you have anything that should be discussed on or before the meeting, please do not hesitate to add your comments.

  2. We (Katarzyna Wertheim-Tysarowska and Agnieszka Rygiel ) would like to respond to comments of Balázs and have the following suggestions.

    A. What should we report exactly? (methods of genetic testing, found variants (including pathogenic, non-pathogenic and unknown)
    – The general content of diagnostic report is well described in this recommendation.
    – Diagnostic results should be prepared according to national legislation and follow these recommendations.

    Following the guidelines mentioned above and also our experience as a diagnostic laboratory, the results should contain:

    1. Variant nomenclature.
    1.1 The names of the variants : should be reported according to HGVS (Human Genome Variation Society) recommendations ( and the used version of HGVS recommendation should be given (e.g. HGVS 2.00 or 15.11). The variants should be named on cDNA and protein level.

    1.2 The crucial point is to provide the reference sequence used (according to which the variants was named). Please note that both cDNA and protein names may differ with respect to the given transcript therefore this is crucial point. You can find RefSeq in NCBI or preferentially in LRG

    2. Variants classification:
    Here, we should classify each detected variant ( f.e pathogenic, likely pathogenic, benign , unknown significance.)
    Precise classification should be discussed in Question nr 4.

    3. Conclusions/interpretation of the result.
    3.1. Final genotype classification taking into account variants detected in all tested genes.
    3.2. Clinical relevance of the genotype and suggestions for further molecular diagnostics, if necessary. Please note that this part should be in line with the reasons for referral.
    3.3. Risk calculation of passing the variant into offspring.
    In case of CFTR pathogenic or likely pathogenic mutation it should be clearly stated that the patient is a carrier of the mutation and has an elevated risk of having CF/CFTR disorder affected child. Since CF is an inherited disease, a cascade screening for detected mutation in his/her relatives is also recommended after a genetic counseling consultation. It is also recommended to perform carrier screening in the patient partner.

    4. In all cases it should be clearly stated that consultation with genetic counselor is highly recommended.

    5. Scope of the analysis. Which regions f.e exones of particular genes were analyzed.

    6. Methodology and limitations: NGS (panel, WES, genome) or Sanger and other methods. Analysis platform (NGS e.g MiSeg Illumina, Sanger sequencer ).

    7. Sensitivity of the given test. If possible, mutation detection rate for certain population f.e in 56% of mutated Phe508del alleles in Polish population.

    In response to Balázs’s other questions.

    B. Who should report the results to the patients (geneticist, gastroenterologist, referring clinician or all of them)?

    Comment: In Poland, the general practice is that the report is send back to referring physician who gives the results to the patient. However, in each case we highly recommend genetic counseling with clinical geneticist as a separated consultation since the result may have implications for blood relatives of the given patient.

    C. When should we test other family members?

    Comment : This is to be decided by genetic counselor as different variants have different clinical impact (PRSS1 mutations vs SPINK1 mutations). We must remember however, that it is general practice in various hereditary disorders (eg. CF, EB etc) to confirm biparental inheritance of identified variants. This means that whenever possible parental samples should be analyzed (only for variants found in their index case offspring).

    D. Should we recommend prenatal genetic testing? When? What about CFTR mutations?

    Comment : This is definitely in the scope of clinical genetic counseling and is probably regulated by national legislations in each country. Please note, that the prenatal test cannot be recommended but can be only considered as each invasive parental test includes the risk of spontaneous miscarriage.
    Regarding CFTR mutations and risk of CF/CFTR-related disorders please see above (point 3 : Conclusions/interpretation of the result) and CF guidelines (


    By whom the genetic test should be performed ?
    Ideally, molecular diagnostics should be performed in laboratory which has documented expertise in diagnostics. It is also recommended or even obligatory in some countries (f,e in Poland) that diagnostic laboratory must participate in external quality assessments schemes for certain disorders f.e CF or in methodological schemes eg. NGS or Sanger (e.g EMQN. European Molecular Genetics Quality Network). Of note is that currently there is no quality program measurements for CP but experience in the other schemes is always of value.

    1. Dear Katarzyna and Agnieszka,
      Thank you for your highly valuable comments. You already answered some of the most important questions of this topic. I definitely agree that we should follow actual guidelines in case of reporting any variant. Local law (of different countries) however might change the practice of reporting any genetic data.
      I also agree that a molecular laboratory which has documented expertise in diagnostics should perform genetic testing. It seems evident for me, but of course we should recommend it. The role of external quality assesment is more interesting. Clinical diagnostic laboratories usually has to have external quality supervision otherwise they cannot operate. This is not always the case however in a “non-clinical” research laboratory.

  3. One statement we might make is that we only report variants of known significance. With the advent of exome seq, the number of unknown variants is just too high to report. An interesting exception might be reporting new variants in known high-impact risk genes, e.g. a novel PRSS1 variant found in a case.
    Another issue to tackle is whether we should report low-effect variants such as those described in GWAS studies.
    Another statement we can make is that reporting should be based on local or regional data if available when risk assessment is performed.

    1. In my point of view reporting variants with unknown significance is an ethical question. I think we should report variants with unknown signficance, but have to be sure that the variant can be surely found in the patient’s genome. If we find an unknown variant by using at least 2 different methods, we should report it. What if it turns out later that the earlier unknown variant has significant effect for developing a disease? Once we reported sg, practically nobody will go back and check wether a certain variant was reported in a patient or not. In a genetic report we need to highlight however which variants are pathogenic, non-pathogenic and harmless and which variants have unknown significance.
      Since pancreatitis is considered a multifactorial and polygenic disease I would report low-effect variants as well. Accomulation of susceptibility factors (genetic and non-genetic) might lead to the development of the disease.
      I absolutely agree that reporting should be based on local or regional data if they are available.

  4. Regarding the Methods of genetic testing, it is important to address which exons/introns were analyzed exactly (as not always the whole gene is sequenced) and also whether copy number variants analysis was performed or not (especially in case of PRSS1).
    I agree with Balazs on reporting VUS.

  5. Many excellent comments.
    We have been doing it for many years in Hungary.
    We must make a difference between
    – what should be on a detailed genetic report
    – what should be on the patients’ report
    They are lay readers. Too many information would not be beneficial in the patients report.
    We must:
    – briefly describe the disease development (genetic and environmental)
    – make a statement concerning from both genetic and environmental
    – tell them the current epidemiological evidence. What they can expect.
    – discuss the lifestyle factors they should be incorporated in their life.
    – discuss the necessary of future visits.

  6. Miklos and I prepared some preliminary statements for “Question 8”. Please review them and let us know whether you would like to add or change something.

    1. Patients should be referred for genetic testing by a gastroenterologist or pediatric gastroenterologist. Genetic testing has to be performed by a laboratory with documented expertise in molecular genetics. Diagnostic procedure should be supervised by a clinical geneticist. Patients should be informed about their genetic test results by the referring medical doctor or clinical geneticist, however consultation with a clinical geneticist regarding the test results is highly recommended.

    2. Genetic test report must include at least the following:
    (1) uniqe identifier of the sample
    (2) name and date of birth of the patient,
    (3) name and contact details of the laboratory where the genetic test was performed,
    (4) purpose of genetic testing,
    (5) accession number of the reference sequence(s),
    (6) description of methods,
    (7) description of the analyzed regions of the genome,
    (8) results of genetic testing as defined in statement “3”.

    3. Description of genetic test results should meet the following criteria:
    (1) variants should be named according to the recommendation of the Human Genome Variation Society,
    (2) Exonic variants should be described on cDNA and protein level,
    (3) carrier status (e.g. homozygous, heterozygous) of each detected variant has to be reported,
    (4) All variants with known clincal signficance have to be reported,
    (5) Reporting variants with unknown clinical signficance found in known susceptibility genes is suggested.

    4. Genetic variants, regardless of effect size, should be categorized and reported based on their clinical significance as follows: pathogenic, likely-pathogenic, likely-benign, benign, protective and unknown significance.
    It is recommended to report high risk pathogenic genotypes (e.g. PRSS1 p.R122H heterozygous, SPINK1 p.N34S homozygous, CPA1 p.S282P heterozygous) as causative.
    For other pathogenic variants it is recommended to report effect size as approximate Odds ratios as a measure of risk. Effect size should be based on local or regional data if available.

    5. Genetic counseling of family members is recommended in the case of hereditary pancreatitis or a pathogenic CFTR mutation is detected.

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