The intent of this document is to provide guidance on the optimal coordination of X-Linked Intellectual Disability Syndrome (XLID) gene panels. There is a growing list of genes (>100) associated with XLID and a plethora of large panel options that differ in cost, gene content and methodology. The following variables should be considered prior to ordering an XLID gene panel, and when in doubt, consider reviewing the order with an internal expert/manager/leader.
What is Intellectual Disability?
A clinical diagnosis of severe intellectual disability (ID) is generally based on an IQ of less than 50 and substantial limitations in activities of daily living. In early childhood, the diagnosis is based on substantial developmental delays, including motor, cognitive, and speech delays. X-linked intellectual disability (XLID) describes a group of conditions caused by a pathogenic variant in one of the many X-linked genes or aberrations in the structure of the X chromosome. These include syndromic and non-syndromic forms of intellectual disability.
A majority of individuals with XLID are considered non-syndromic with no other features to guide the diagnostic evaluation. In boys, XLID is believed to account for 10% of ID. One of the first genes identified as involved in XLID was FMR1. An unstable expansion mutation in FMR1 is responsible for fragile X syndrome, accounting for about 2%–3% of all ID cases; this mutation is the most common genetic cause of XLID. Although the availability and accessibility of gene panels will increase in the near future, the impact on clinical management is changing more slowly and still rests largely on patient findings from examinations, history, and other investigations.
When is XLID testing considered for a patient?
Genetic testing for individuals with XLID is typically pursued for the following reasons:
- To guide medical interventions (e.g., medications, other treatment or surveillance)
- To inform prognosis (anticipatory guidance)
- To preclude further unnecessary invasive testing (e.g. repeated blood tests, MRIs)
- To provide information regarding recurrence risk (guide reproductive planning)
- To end the diagnostic odyssey
- To facilitate access to appropriate medical and supportive services
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What genetic tests are available for patients suspected to have XLID?
There are several genetic tests that can help determine the underlying molecular etiology of XLID in an individual. Decisions about which test(s) to perform can be complex due to the high frequency of non-specific features shared among numerous potential syndromes, genetic heterogeneity of XLID and the rapid pace of genetic discovery. Selecting the optimal test depends on careful review of personal and family medical histories (e.g. gender, pattern of inheritance, possible skewed x-inactivation in females), physical exam (e.g. screen for associated comorbidities such as dysmorphic features, epilepsy, Autism Spectrum Disorder, psychiatric and behavioral issues), and imaging (e.g. MRI to look for brain malformations). Results of this evaluation might suggest a syndrome associated with variants in a specific gene or set of genes; targeted testing of an individual gene or small set of genes (including both sequencing and testing for deletions and duplications within the gene) is likely to be the most appropriate option for such patients.
Chromosomal microarray (CMA) and Fragile X testing are recommended first tier tests for XLID. If the clinical features do not point to a particular syndrome or molecular etiology and the first-tier tests return as normal, use of a panel that includes sequencing and deletion or duplication testing for XLID genes may be considered. It is important to recognize that even though several of the large XLID sequencing panels include the FMR1 gene, the testing methodology does not include expansion analysis that would detect the molecular variant underlying the majority of cases of fragile X syndrome.
What important factors should be considered before ordering an XLID gene panel?
The following questions provide a helpful framework when considering XLID gene panels and its appropriateness for the individual:
When is it not appropriate to order an XLID gene panel?
- When fragile X analysis and chromosomal microarray analysis (CMA) have not yet been performed
- When an X-linked pattern of inheritance can be confidently ruled out
- When standard biochemical work-up has not been completed (i.e., screening fasting plasma amino acids and urine organic acids)
- When there has been no pre-test counseling for the individual (or legal guardian) regarding risks, benefits, and potential out of pocket costs of the genetic testing.
When the order is requested by a provider who may not have the appropriate training/expertise to select the optimal test and/or interpret the results.
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General utilization management interventions & considerations
There are a variety of utilization management (UM) tools that can support appropriate ordering of XLID genetic testing. In addition, each case is unique and will require a balanced consideration of factors unique to XLID genetic testing.
Utilization Management Techniques
XLID genetic testing is well-suited for strong UM interventions, including formularies, requirement for high-level approval and privileging.
- Establish a formulary for XLID genetic testing to limit ordering to a defined reference laboratory (or set of laboratories) to ensure quality of the test and improve ease of test coordination/logistics. This may also help with negotiating the best price.
- Privilege ordering to the experts. Given the genetic heterogeneity, complex inheritance pattern, and nuances of distinguishing between syndromic and non-syndromic intellectual disability (e.g., dysmorphology exam), some institutions may consider privileging XLID gene panel orders to genetics providers only.
- Require that requests for XLID gene panels be reviewed by an expert (pathologist or laboratory genetic counselor) prior to approval.
- Develop practice parameters with input from experts (e.g. neurologists, geneticists, neurodevelopmental pediatricians), including guidelines for evaluation and screening, as well as testing algorithms.
Provider and Patient Expectations
Set clear expectations for providers regarding the use of this test and process for requesting and obtaining approval. Providers may feel that the patient came to them for evaluation, and genetic tests are their primary “tool”, so if a test isn’t ordered, they haven’t done their job. Similarly, it is critical for providers to set clear expectations for the patient or family, particularly if there are limits placed on when and how XLID gene panels can be ordered.
- Reflex testing options: Many reference laboratories have the option of running the whole exome, but masking the majority of genes and only reporting out on genes of interest (for instance, a defined subset of XLID genes or a customized panel). This may be defined by the reference laboratory, or with input from the ordering provider. If this analysis is negative, there may be an option to reflex to the whole exome.
- Gene coverage by test platform: When considering a targeted approach or whole exome sequencing, it is necessary to evaluate whether the gene(s) of most interest have good coverage on the platform and modify your testing approach accordingly.
- Size of the panel: A balance must be achieved, likely on a case-by-case basis between a broad approach (test lots of genes regardless of clinical presentation, increased risk of variants) and a targeted panel based on phenotype (risk of not finding an answer with the first test).
- Family member testing options: It is advantageous to be able to test family members to clarify the significance of uncertain variants. Some reference labs perform this targeted familial variant testing at no charge and can perform the testing using saliva or buccal specimens. Other reference labs charge a per variant fee, which can be costly if many variants are identified and warrant further investigation. When selecting the optimal reference lab/test for XLID gene panels, it’s critical to consider the charges and logistics of familial variant testing.
- Panel updates & variant re-interpretation: Some reference labs have policies regarding re-analysis of variants (e.g. ad-hoc, systematic at time intervals, etc). Given the rapid evolution of knowledge, there will be a need for reinterpretation and for laboratories to be nimble in expanding panels to include new genes. When considering a reference lab, inquire about how genes are included on panels and how panels are kept up to date.
In addition to the above considerations, there can be subtle aspects of a request that are worth mentioning. For example, has the patient already had all imaging studies they would need if they were diagnosed with the suspected condition? (e.g. would it change the management of the patient now?) Does the provider already have a sense for prognosis? (e.g., intellect/prognosis in a 7 year old may be more clear than a 6 month old). Conversations regarding optimal XLID gene panel selection and medical necessity of testing for insurance coverage can be strengthened by examples of how XLID-related genetic variants could impact clinical management for the specific individual.
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Recommendations for responsible coordination of XLID testing
Once XLID genetic testing has been established as the most appropriate test, the following recommendations are suggested as a responsible approach to test coordination:
- Pre-test counseling to provide clear information regarding the benefits, limitations and results of XLID gene panel. The counseling approach should be tailored to the individual; the focus of counseling might differ depending on whether it involves a teenager with XLID, the parents of a young child with XLID, or an at-risk family member.
- Clear documentation of medical rationale and necessity, combined with insurance pre-authorization for the testing to protect the patient/institution from avoidable financial liability.
Results communication plan established at time of test coordination, to include post-test counseling discussion. The possibility of identifying a variant of uncertain clinical significance is high and the family should be prepared for the potential need to test other family members to help better understand the patient’s results.
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Moeschler, JB, Shevell, M. American Academy of Pediatrics. Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays. Sept 2014. 134:3
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