Genetic Testing Program Lowered Age of Molecular Diagnosis in Children

Genetic Testing Program Lowered Age of Molecular Diagnosis in Children
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By implementing a free-of-charge epilepsy genetic testing program, it is possible to lower the average age of molecular diagnosis of children with epileptic disorders caused by mutations in the SCN1A gene, such as Dravet syndrome, from more than 6 to less than 2 years of age.

The study with that finding, “Reducing the Time to Diagnosis and Increasing the Detection of Individuals With SCN1A-Related Disease Through a No Cost, Sponsored Epilepsy Genetic Testing Program,” was presented during the American Epilepsy Society (AES) 2020 Virtual Annual Meeting.

Genetic mutations in the SCN1A gene have been associated with a wide spectrum of epileptic disorders, including Dravet syndrome, generalized epilepsy with febrile seizures plus (GEFS+), and early infantile epileptic encephalopathy (EIEE).

According to a previous study, from 2011 to 2015, the average age of molecular diagnosis of patients with forms of epilepsy associated with SCN1A mutations was 6.2 years.

“As precision medicine therapies emerge, it is becoming increasingly important to diagnose SCN1A-related disorders before disease progression,” the researchers wrote.

In an effort to lower the age at which patients with these forms of genetic epilepsy were found to carry SCN1A mutations, Stoke Therapeutics, Invitae, and Encoded Therapeutics joined forces to launch a no-cost genetic testing program specifically intended for children who were thought to have one of these disorders.

This genetic test uses next-generation sequencing to analyze the DNA sequence of up to 186 genes potentially associated with epilepsy, including SCN1A.

Here, investigators reported the results of 6,874 infants and children who were tested in the program. At the time of testing, children ranged from newborns up to age 8 (96 months) and had experienced a single spontaneous seizure.

Physicians requesting the test also provided brief clinical data on the children, which included their family history, severity of speech and motor impairments, and type of seizure they had experienced.

From the 6,874 children given the test, 152 (2.2%) tested positive for the presence of SCN1A mutations. In this subset of children who had a positive test result, the average age of molecular diagnosis was 23 months (just under 2 years), and the average age at which they had their first seizure was 9.8 months.

“Our results demonstrate a substantial decrease in the average age at molecular diagnosis from over 6 years of age in 2015 to under 2 years of age as of June 2020,” the researchers wrote.

More than half of these children had generalized seizures (76.3%) and febrile seizures (65.8%), while about a third (30%) had focal seizures.

Generalized seizures are those caused by abnormal electrical activity affecting the whole brain, while focal seizures are those resulting from abnormal  activity in a specific region of the brain. Febrile seizures refer to convulsions triggered by a spike in body temperature.

Motor impairments were observed in about 30% or the children who had a positive test result, and language delays were seen in about 15% of the children. Only nine of the 152 children (around 6%) who tested positive for SCN1A mutations had a family history of epilepsy.

“Based on the reported clinical findings of the tested participants, we expect most individuals to have a clinical diagnosis of GEFS+ or Dravet syndrome. As precision medicine therapies emerge, rapid and early molecular diagnosis is vital to enable early intervention, before disease has progressed, to ensure transformative outcomes in patients with SCN1A-related disorders,” the researchers wrote.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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