Evidence-based consensus guidelines for ALS genetic testing and counseling

Genetic Testing

• What are the implications for me and my family?

  ✓Supports this

  “Adult relatives who do not have ALS/MND may be able to have predictive testing to find out whether they carry a genetic change, and it is usually only available where a gene change is already known in the family.”

  The consensus guideline says adult relatives are candidates for testing before any symptoms, that it is their own choice, and that it should be done with proper genetic counselling.

  Adult relatives are candidates for presymptomatic testing, which is a personal choice and should be performed with appropriate genetic counseling.

  Recommendation 22

• What are the implications for me and my family?

  !Qualifies this

  “If a genetic change is found in you, relatives may carry the same change.”

  Adds a limit the sentence does not carry. Many ALS gene changes are incompletely penetrant, so a relative who has inherited one will not necessarily develop the condition, and the guideline says counselling should convey how variable and uncertain that is.

  Many ALS variants are incompletely penetrant, meaning that not all carriers of the variant will develop disease.

  Recommendation 15

• What is genetic testing in ALS/MND, and is MND inherited?

  ✓Supports this

  “Genetic counselling alongside testing is a core part of the process rather than an optional extra.”

  The consensus guideline makes counselling a recommendation in its own right, offered to everyone with ALS regardless of family history, and says it should cover the nature of inheritance, the testing options and what a result would mean for relatives.

  All persons with ALS should be offered genetic counseling, irrespective of the presence or absence of a family history of ALS.

  Recommendation 8

• What is genetic testing in ALS/MND, and is MND inherited?

  ✓Supports this

  “A genetic change is sometimes found in people with no family history, and sometimes no known cause is found in families where the condition recurs.”

  The consensus guideline says current testing still fails to find a cause in a large share of families, and separately recommends counselling for everyone with ALS whether or not there is a family history, because variants are found in a meaningful minority of people who have none.

  Current genetic testing fails to identify a genetic etiology in a significant proportion of familial cases, indicating that additional, unknown genetic mechanisms contribute to the etiology of ALS.

  Recommendation 24

• Why is genetic counselling so important?

  ✓Supports this

  “Counselling after testing is where the result is explained and worked through with you, rather than left with you alone.”

  The consensus guideline recommends that everyone with ALS who is tested has counselling afterwards, and that it covers an uncertain result in particular, explaining that such a change may or may not be contributing to their condition.

  Posttest counseling provides persons with ALS the opportunity to discuss their result and understand the implications in the context of their specific personal and family circumstances.

  Recommendation 20

• Why is genetic counselling so important?

  ✓Supports this

  “Counselling before testing is what makes the decision an informed one and prepares you for the possible results.”

  The consensus guideline recommends that counselling comes before testing is even offered, so a person can weigh the benefits, risks and limits and anticipate the effect on themselves and their relatives. It also lists harms that can follow from testing without it. This is one of its weaker-graded recommendations, resting on lower-level evidence.

  Genetic counseling should be provided before testing, to empower persons with ALS to weigh the potential benefits, risks and limitations of testing, and anticipate the possible impact of testing on themselves and their family members.

  Recommendation 9

• Why might I consider genetic testing, and what could it tell me?

  ✓Supports this

  “A genetic test result usually does not tell you how ALS/MND will progress for you.”

  The consensus guideline says a result does not allow prediction of disease course in most cases, with some notable exceptions. It describes links between gene and disease course as trends in grouped data with low predictive value for an individual.

  When a pathogenic or likely pathogenic variant is identified, persons with ALS should understand that the genetic result does not allow prediction of disease course in most cases.

  Recommendation 21

• Why might I consider genetic testing, and what could it tell me?

  ✓Supports this

  “For some genetic changes, knowing your result can open access to particular clinical trials or gene-targeted treatments.”

  The consensus guideline recommends that anyone found to have a disease-causing variant is told about approved or investigational treatments aimed at their particular gene, and about relevant trials and observational studies. It expects such opportunities to grow.

  Persons with ALS identified to have a pathogenic or likely pathogenic variant should be informed of FDA-approved or investigational therapies which are targeted to their particular gene; opportunities for gene-targeted interventions are likely to increase in coming years.

  Recommendation 23

• Why might I consider genetic testing, and what could it tell me?

  ✓Supports this

  “Testing can return an uncertain result, where a change of unclear significance is found.”

  The consensus guideline treats an uncertain result as a common outcome rather than a rare one. It recommends preparing people for it before testing, and telling them afterwards that such a change may or may not be contributing to their ALS.

  A significant proportion of patients who undergo ALS genetic testing will receive an uncertain result.

  Recommendation 25