Skin may hold key to neurodevelopmental disorder diagnosis

Currently, conditions caused by a significant disruption during brain development, like Rett Syndrome, epilepsy and Down Syndrome, affect one in 50 Australian children.

But there are around 6000 rare disorders, many of which don't have names as they are defined more by symptoms or the genetic variations which cause them.

A team at the Robinson Research Institute led by Dr Lachlan Jolly, Head of the University of Adelaide's School of Biomedicine's Neurobiology Research Group, and Professor Jozef Gecz, Head of the School of Medicine's Neurogenetics program, have developed a way to transcribe genetic variations into RNA to help determine if they are disease causing and therefore improve genetic diagnosis.

These findings, as part of the PERSYST Study, have been published in the American Journal of Human Genetics.

"A genetic diagnosis is a prerequisite to appropriate care, therapies, clinical trials, family planning and importantly, a community of belonging and support," said Dr Jolly.

"What we've been able to do is activate the expression of brain disease genes in cells derived from a patient skin biopsy grown in the laboratory to obtain the genes RNA transcript; previously this would have only been possible through a sample of patient brain tissue, which is rarely available or advisable.

"Activating the disease genes in skin cells enables a functional RNA based study to resolve the pathology of the genetic variant. Such individuals would otherwise often never receive a genetic diagnosis because the genes RNA is unobtainable without highly invasive procedures.

"Variants in these genes account for 22.2 per cent of all variants of uncertain pathology, which currently equates to hundreds of thousands of people world-wide living without a diagnosis, and that number continues to rise."

This breakthrough approach underpins the PERSYST study, a national collaboration between scientists, clinicians, diagnostic laboratories and rare disease community groups across Australia. The PERSYST study, which currently runs until 2027, utilises this new skin-based diagnostic technology and has a national recruitment program for a subset of individuals living with a genetically undiagnosed rare disease.

"PERSYST is providing the critical evidence to support the genetic diagnosis of Australian individuals and their families, ending the burden of their diagnostic odysseys and providing opportunities for better care, support, and access to precision treatments," said Dr Jolly.