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Order Guide: XLIDBackground
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.
General Information
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.
Genetic testing for individuals with XLID is typically pursued for the following reasons:
Order Considerations
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.
The following questions provide a helpful framework when considering XLID gene panels and its appropriateness for the individual:
Is there suspicion for a novel condition/gene?
If the testing is being pursued to discover the first case of something, enrolling the individual in a research study may be more appropriate.
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.
XLID genetic testing is well-suited for strong UM interventions, including formularies, requirement for high-level approval and privileging.
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.
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.
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:
References
Baird G. The laboratory test utilization management toolbox. Biomedia Chemica 2014;24(2):223-234.
Manning, M, Hudgins, L. ACMG Practice Guidelines. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. 2010 Genet Med 12:11:742-745
Moeschler, JB, Shevell, M. American Academy of Pediatrics. Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays. Sept 2014. 134:3
Piton, A, Redin C, Mandel J., American Journal of Human Genetics. XLID-Causing Mutations and Associated Genes Challenged in Light of Data From Large-Scale Human Exome Sequencing. Aug 8; 93(2): 368–383.
Sherman, S, Pletcher, BA & Driscoll, DA. ACMG Practice Guidelines. Fragile X syndrome: Diagnostic and carrier testing. 2005 Genet Med 7:8:584-587