Genomics Assay Provides Companion Diagnostic for Some Intellectual Disabilities

A new study is one of the first to show the benefits of whole exome sequencing (WESeq) based diagnostics for children with certain kinds of intellectual disability, enabling physicians to prescribe more appropriate, personalized treatment.

The researchers diagnosed 68% of the 41 families in the study with the precise underlying genetic condition and, based on this, were able to offer targeted treatments for over 40% of cases. They also discovered 11 new disease genes and described new physical traits and symptoms associated with a number of known diseases.

“This research is very encouraging because for a subset of patients we can identify the genetic underpinning of their intellectual disability and then determine the right intervention,” said team leader Dr. Clara van Karnebeek of BC Children’s Hospital, and principal investigator in the Centre for Molecular Medicine and Therapeutics at the University of British Columbia (Canada), “There’s a bright future ahead for personalized medicine informed by genetic diagnosis.”

Some people’s intellectual disability is due to rare genetic conditions that interfere with the processes the body uses to break down food, resulting in an energy deficit and build-up of toxins in the brain and body leading to symptoms such as developmental and cognitive delays, epilepsy, and organ dysfunction. Dr. van Karnebeek’s work is changing the paradigm for diagnosing and treating these conditions. In previous research, her team developed a mobile app that helps clinicians review patient symptoms and arrive at diagnosis as early as possible.

The goal of the current study was to diagnose patients with genetic conditions and discover and describe new diseases with potential for treatment. The study included patients with neurodevelopmental conditions that doctors suspected were genetic or metabolic in origin but had not been diagnosed using conventional methods. Patient selection, characterization and interpretation of the WESeq data involved an international team of clinicians and scientists. The study was conducted as part of the Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC).

Children and their parents were tested using a combination of metabolomic (large scale chemical) analysis and WESeq. They discovered a new genetic disease called carbonic anhydrase VA deficiency that presents during early childhood with life-threatening sleepiness and coma due to hyperammonemia. Researchers found that a drug called carglumic acid can prevent brain damage in children with this condition.

They also discovered a new metabolic disease called glutamic oxalo-acetic transaminase 2 deficiency that affects the brain and is characterized by small head size, seizures, and developmental delays. Treatment with the amino-acid serine and vitamin B6 improved the symptoms.

The study provided insights into brain development and functioning. For example, the importance of sialic acid production for normal brain and bone development was demonstrated by the discovery of NANS deficiency in one of the TIDEX study patients. Detailed description of this disorder in 9 individuals from B.C. and Europe with bone abnormalities and intellectual disability, along with a potential treatment target, was recently published in Nature Genetics, by Dr. Superti-Furga (Lausanne, Switzerland) and an international group including Dr. van Karnebeek.

“Our findings open the door to life-changing treatments for a small yet meaningful percentage of patients,” said Dr. van Karnebeek, “We’re learning more about brain function and the mechanisms underlying intellectual disability. These results are meaningful to individuals around the world who suffer these rare conditions.”

The study, by Maja Tarailo-Graovac M et al, was published May 25, 2016 in the New England Journal of Medicine.

Related Links:
Centre for Molecular Medicine and Therapeutics at the University of British Columbia
Treatable Intellectual Disability Endeavour in British Columbia