Autism spectrum disorders (ASDs) are neurodevelopmental disorders (NDDs) seen in 1-2% of children; symptoms and severity differ widely^1,2,3, so they can be difficult to diagnose. ASDs can be inherited and involve numerous genes, which creates a challenge for single gene testing.

How can genetic testing help children and families, if the child is already known or suspected to have an ASD? Genetic test results can pinpoint an underlying cause for the ASD, ending a family’s “diagnostic odyssey” and allowing specialized medical management for their child.¹ Genetic testing can also help a family understand how the condition could change over time and how it runs in the family.¹

Current medical guidelines recommend that chromosomal microarray (CMA) and testing for fragile X syndrome are offered as a first-tier test for those with ASDs, with consideration of single gene testing targeting syndromes that include ASDs.^3,4,5 These tests have varying diagnostic yields (9.3-24% for CMA and 0.4-8% for fragile X) and traditional chromosome analysis offers a diagnostic yield of 2.2-2.5%.^5-8

Diagnostic exome sequencing (DES), which Ambry introduced commercially in 2011, offers efficient, cost-effective analysis^9-10 of all exons in the genome, including newly characterized genes. DES offers an underlying diagnosis for many with previously undiagnosed genetic disorders¹¹, including those with NDDs.^10,12-13

To date, multiple studies have reported DES results in different, large groups of patients with autism^14-16; however, few have addressed the diagnostic yield of DES in patients with ASDs.^6,17 Estimates have varied between 3.1-28.6%, depending on symptoms.

Read the full publication here.

Key Results

In a study published in Pediatric Neurology, Ambry researchers looked at the first 1,200 samples sent to Ambry for DES. 163 (13.6%) patients had a diagnosis or characteristics of an ASD (as indicated in their clinical materials), and their DES results were analyzed in detail.

• 73% of study patients were male, 27% were female
• Overall, 25.8% of study patients received a positive/likely positive result in a characterized gene
  • 61.9% of positive/likely positive findings were brand-new (de novo) in a family
  • An additional 3.3% had positive results in candidate genes
• Many study patients had other neurologic symptoms, with intellectual disability/developmental delays (92.6%) being most common
• Those who also had a psychiatric condition, ataxia and/or paraplegia were significantly more likely to have a positive DES result
• 13.5% of study patients also had multiple congenital anomalies, and had a higher rate of positive DES results
• 96% of study patients already had a traditional “first-tier” test (e.g. CMA and fragile X testing)

What This Means for Clinical Practice

• DES was relevant and helpful for patients with diagnosed or suspected ASDs
  • Patients with multiple neurologic characteristics (e.g. ASD + psychiatric symptoms or ataxia) may particularly benefit from DES
  • Consistent with previous research, DES can be considered as a first-tier test for children with an ASD/autistic characteristics and congenital anomalies⁶
• DES identified findings that would be missed by other forms of genetic testing
  • 92.5% of positive findings found by DES were in recently identified genes and “non-classical” ASD genes
• Lacking a family history of an ASD does not remove the need for genetic testing
  • Many DES findings were de novo and brand new in a family
• Clinical guidelines for patients with autism need reassessment; currently, they may offer lower diagnostic yields than DES – and often at a higher cost

“Our study offers detailed insights into diagnostic exome sequencing results in the largest cohort of patients with autism spectrum disorders described to date,” said lead author Mari Rossi, MS, PhL, Clinical Genomics Scientist at Ambry. “These insights can guide clinicians who need to choose the most time- and cost-effective testing option that will also most likely provide an answer for their patient.”

April is Autism Awareness Month – Ambry remains committed to sharing data and collaborative research to further the understanding of autism spectrum disorders. The AmbryShare data sharing program is now open to clinicians caring for patients with ASDs. To read more about this project, click here.

To enroll your patients, click here.

To learn more about autism spectrum disorders on Ambry’s neurology website for patients and families, click here.

To learn more about Ambry’s comprehensive testing options for patients with ASDs (ExomeNext, AutismNext, fragile X testing and CMA), click here.

References

1. Rossi M, et al. Outcomes of diagnostic exome sequencing in patients with diagnosed or suspected autism spectrum disorders. Pediatr Neurol. 2017 Feb 8. [Epub ahead of print].
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5. 2013. Arlington: American Psychiatric Publishing.
3. Ronald A and Hoekstra RA. Autism spectrum disorders and autistic traits: a decade of new twin studies. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:255-274.
4. Miller DT, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010 May 14;86(5):749-64.