SHANK3 Genetic Testing Program

Genetic sequencing studies indicate SHANK3 pathogenic variants may be present in approximately 0.5%-0.69% of individuals with ASD.^1,7 The prevalence of SHANK3-related autism in the U.S. is estimated to be more than 45,000 patients.^1,7,8,9

GeneDx partners with biopharma companies to accelerate the development of novel therapies by sharing de-identified genetic data from patients tested through specific programs.

The process is similar to a standard GeneDx exome test order, with a few differences:

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Eligibility: Patients must meet the program’s criteria.
Ordering: Use the designated program code (ESAS3) when ordering through the portal or the specific TRF for paper orders.
Data Sharing: Providers must confirm patient consent for mandatory data sharing practices.
Billing: If insurance denies coverage or the patient is uninsured, costs are covered by Jaguar.

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Individuals with SHANK3-related autism present with lifelong and severe neurobehavioral, motor, social, communicative, and cognitive impairments characterized by delayed or absent developmental milestones.^2,3,5,10

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- Almost all activities of daily living, including being able to communicate their needs, ability to self-care, including dressing, bathing and toileting, and socialization with family or peers are absent or severely impaired, requiring 24-hour care and/or supervision.¹¹
- Additional features of SHANK3-related autism may include neonatal hypotonia (low muscle tone), seizures, impaired sleep, and gastrointestinal problems.^2,3

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A diagnosis of PMS is established when genetic testing confirms a pathogenic variant in SHANK3 or chromosome 22q13.3 deletion encompassing the SHANK3 gene.^2,3,4,5

Consensus guidelines on managing patients with PMS highlight multidisciplinary care across genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, and other specialties.⁴
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Click HERE to reference the current consensus guidelines on the management of PMS.

If an eligible patient’s insurance provider denies coverage for the genetic test, or if the patient is uninsured, Jaguar will cover the cost of testing. This ensures that eligible patients can access genetic testing. Note: costs of exome testing will be covered by Jaguar when patients have Medicare / Medicare Advantage.

SHANK3 haploinsufficiency is a leading monogenic cause of ASD that is clinically diagnosed as Phelan McDermid syndrome.¹

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- SHANK3 haploinsufficiency is caused by a pathogenic variant in SHANK3 or by a chromosome 22q13.3 deletion encompassing the SHANK3 gene.^2,3,4,5  
- SHANK3 is essential for building and maintaining connections between neurons, which is required for learning and development.²

SHANK3-related autism is a genetic form of autism caused by pathogenic variants or deletions of the SHANK3 gene that result in SHANK3 haploinsufficiency. SHANK3-related autism is common among individuals with PMS, but not all people with PMS have autism.^3,6

The Phelan-McDermid Syndrome Foundation and CureSHANK are patient advocacy groups dedicated to supporting people affected by PMS.

Patients must meet all program-specific eligibility criteria. For example, the SHANK3 Genetic Testing Program requires:

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- No prior genetic testing confirming Phelan-McDermid syndrome or genetically confirmed SHANK3 haploinsufficiency.
- Clinical presentation of moderate-to-severe developmental delay, intellectual disability, autism spectrum disorder, or autistic-like behavior with clinical suspicion of PMS.
- Patient must reside in the United States.

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Additional clinical features must be present, refer to the full list of eligibility criteria.

PMS is underdiagnosed due to challenges in current genetic testing practices and gaps in clinical guidelines. Although professional society clinical guidelines recommend genetic testing for children who present with key features of PMS such as developmental delay, intellectual disability, and autism spectrum disorder, many guidelines do not prioritize the most sensitive technologies, such as exome and genome sequencing.^12,13 These guidelines are important because they are referenced by clinicians when deciding on genetic testing plans and by insurance companies when determining coverage for testing. As a result, clinicians may rely on older methods like chromosomal microarray (CMA), which can miss smaller deletions or sequence variants in SHANK3, leading to missed or false-negative diagnoses.¹⁴ Additionally, some laboratories do not include SHANK3 in their genetic testing panels.¹⁵ Insurance reimbursement policies that follow older guidelines may further limit access to advanced genetic testing, including exome and genome sequencing, compounding the risk of underdiagnosis.