A new stand-alone test can more precisely diagnose people with a common genetic cause of autism than the current testing regime.

The international study, led by the Murdoch Children's Research Institute in collaboration with Lineagen, Inc., an innovative diagnostic genetic testing and clinical information services company based in Utah, published in Scientific Reports, describes a trial of a more cost-effective, accurate and timely way to identify those with Fragile X syndrome, one of the most common genetic causes of intellectual disability and autism spectrum disorder.

Fragile X associated costs to raise one affected child have been estimated at more than $2.5 million to the health system.*

Fragile X affects about 1 in 4,000 children with about 90,000 Australians and over one million Americans impacted in some way. A large proportion of these are women who themselves are not affected with Fragile X, but carry a DNA 'premutation' in their FMR1 gene. This premutation predisposes these women to have children with Fragile X.  

A major issue with Fragile X is that at a young age, the syndrome is not clinically distinct, with an average age of diagnosis in Australia of about five years, and, according to the Centers for Disease Control and Prevention, over three 3 years in the US.

As a result of delayed diagnosis, affected children do not receive the medical care they need in a timely manner, and families may end up having multiple affected children before they receive a diagnosis for their first child.

Lead study researcher MCRI's Associate Professor David Godler said families that have carriers of 'premutation' could have an option of having unaffected children if provided timely advice regarding alternative reproductive options. 

"The impact of delayed diagnosis is significant and potentially preventable not only to the families but also for our health system," he said.

"This is why we developed our new test, called Methylation Specific Quantitative Melt Analysis (MS-QMA). This is a one-step process, to assist in more accurate and timely diagnosis of Fragile X in affected children referred for genetic testing."

The one-step test looks at the number of chemical modifications or "marks", called methylation, added to a patient's FMR1 gene in Fragile X, which are not present in typically developing children without Fragile X syndrome. Increasing these marks reduces the production of a protein called FMRP required for healthy brain development and function. This study for the first time shows that the number of these marks can be increased, even in people without the usual genetic changes seen in Fragile X syndrome (called CGG repeats). Until now, this was not known, in part because current standard testing does not involve looking at these marks as part of the initial CGG screen.

The current standard testing only examines these marks using a second separate test, and only on the limited number of patients suspected of having the typical genetic change (CGG repeats) associated with Fragile X, called full mutation, and 'large' permutation alleles. One reason for this is that this second methylation test is too expensive to be used to test all patients initially suspected of having Fragile X and therefore, some patients affected with Fragile X go undetected.

In this study, Lineagen and MCRI compared DNA test results on more than 300 patients from pediatric clinics in the United States and Australia. These patients were known to either contain Fragile X mutations as detected by standard testing or no mutations detected by standard testing.  While the second group of patients had no Fragile X mutations detected by standard CGG repeat testing, they were likewise diagnosed by physicians as having a form of intellectual disability with/or without autism.

All genetic testing was carried out in Associate Professor Godler's laboratory at MCRI using MS-QMA on male and female samples blinded by Lineagen. Once the blind was lifted, all male and female patients with known Fragile X diagnosis received the correct diagnosis using MS-QMA.

The study also identified one additional female patient with a Fragile X full mutation in a small proportion of cells, which wasn't detected by the standard two-step testing process.

"We also identified, for the first time, smaller more common FMR1 alleles that are not usually tested for methylation (a tell-tale sign of Fragile X), that had abnormal methylation signatures in a significant number of affected patients," Associate Professor Godler said. 

"These abnormal signatures were confirmed to be present by the current standard confirmatory methylation test performed by Lineagen. These signatures may compromise the function of the FMR1 gene, and potentially lead to Fragile X-like clinical features, and is an active area of research for my group."

Lineagen CEO Dr Michael Paul said even after a series of the best possible clinical genetic tests, almost half of the children with autism spectrum disorders don't receive a genetic diagnosis, so anything we can do to improve genetic diagnostic precision is important for families and their children.

Dr Paul also said, "we are pleased to have collaborated with Associate Professor Golder and his team to identify up to 15 per cent of patients with Fragile X syndrome than is currently revealed through the current testing paradigm which includes FMR1 CGG repeat analysis as the front-line Fragile X test currently performed for children who are suspected of having the condition."

"Lineagen's mission is to help provide more accurate and precise genetic diagnoses of pediatric neurodevelopmental disorders sooner, so this is a community we must help and a challenge we cannot ignore."

Researchers from Lineagen Inc in Utah, the University of Melbourne, Victorian Clinical Genetics Services, Genetics of Learning Disability in Newcastle, and The Royal Children's Hospital also contributed to the findings.

Publication: Charles H. Hensel, Rena J. Vanzo, Megan M. Martin, Ling Ling, Solange M. Aliaga, Minh Bui, David I. Francis, Hope Twede, Mike H. Field, Jonathon W. Morison, David J. Amor and David E. Godler. 'Abnormally Methylated FMR1 in Absence of a Detectable Full Mutation in a U.S.A Patient Cohort Referred for Fragile X Testing,' Scientific Reports. DOI: 10.1038/s41598-019-51618-7

Available for interview:

  • Associate Professor David Godler 
  • Michael S. Paul, PhD, CEO and President, Lineagen

Media contact for Murdoch Children's

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About MCRI

The Murdoch Children's Research Institute (MCRI) is the largest child health research institute in Australia committed to making discoveries and developing treatments to improve child and adolescent health in Australia and around the world. They are pioneering new treatments, trialling better vaccines and improving ways of diagnosing and helping sick babies, children and adolescents. It is one of the only research institutes in Australia to offer genetic testing to find answers for families of children with previously undiagnosed conditions. 

About Lineagen
Lineagen assists families and their healthcare providers with access to high-quality genetic tests with the goal of helping personalize medical management for those with autism spectrum disorder (ASD) and other neurodevelopmental disabilities. Lineagen's services are designed specifically for these families, which include DNA collection through a cheek swab, comprehensive reimbursement support, and access to licensed/certified genetic counsellors for all services provided. Physician-prescribed genetic testing options include assessment for deletions/duplications, fragile X syndrome testing, whole exome and whole genome sequencing, and pharmacogenomic testing. Lineagen also seeks to speed up the diagnostic process, so we offer m-chat.org to help screen children at risk for ASD, and a telehealth platform through MyDevelopingChild that allows families access to genetic testing from the convenience of home. Lineagen has been providing genetic testing services to families and their healthcare providers for over nine years and performed over 60,000 tests for those with neurodevelopmental concerns. Details: www.lineagen.com.

Media Contact:

Calvin Chan, Lineagen Director of Marketing

[email protected]


  • The study was funded by The Victorian Government's Operational Infrastructure Support Program, Murdoch Children's Research Institute, The Royal Children's Hospital Foundation, Martin & E.H. Flack Trust, Pierce Armstrong Trust, Financial Markets Foundation for Children (Australia) (FMFC; grant number: 2017-361), the National Health and Medical Research Council (NHMRC; project grant numbers: 104299 and 1103389 to D.E.G.), and Lineagen. D.E.G. salary was also supported by the Next Generation Clinical Researchers Program - Career Development Fellowship Funded by the Medical Research Future Fund (grant number 1141334). Megan Martin, Rena Vanzo, Hope Twede, and Charles Hensel were employees of Lineagen Inc. (commercial company) and received funding and stock options from Lineagen Inc.

*Hollingsworth B, Harris A. Economic evaluation of prenatal population screening for Fragile X syndrome. Community Genet. 2005;8(2):68-72