#IARC2017 – New Genetic Variants May Explain Childhood-onset Ataxias, Finnish Study Suggests

A next-generation sequencing technique known as whole exome sequencing (WES) led to new genetic variants for childhood-onset ataxias being identified — including some in genes not previously linked to ataxia, and some that are disease-causing when only one mutation is inherited — Finnish researchers reported at IARC 2017.

The presentation, at Wednesday morning’s Molecular Basis of Disease session, was given by Erika Ignatius of the University of Helsinki and titled “Elucidating the genetic background of childhood-onset ataxias.” IARC 2017, the International Ataxia Research Conference, is underway in Pisa, Italy, through Sept. 30.

A large proportion of ataxia cases are still genetically uncharacterized, meaning that the probable genetic cause of an established ataxia in a person is unidentified.

Ataxias characterized by heterogeneous clinical phenotypes, such as those with a childhood onset, are usually also heterogeneous genetically, meaning that multiple disease-causing variations exist in several genes. This diversity in genetic background represents a challenge to more traditional molecular diagnostic approaches.

The advent of next-generation sequencing techniques, such as WES, promises to revolutionize the diagnosis of neurodevelopmental and neurodegenerative disorders with a genetic cause, since it can extract much more information from the genome than can traditional techniques.

Whole exome sequencing, in particular, analyzes the protein-coding region of the human genome, or the information in a person’s genes that will be converted into proteins.

In their study, the researchers used WES to characterize the genetic background of children diagnosed with ataxia at Helsinki University Central Hospital between 1999 and 2016.  In total, 74 children (42 families) without a genetic diagnosis were analyzed by whole exome sequencing.

WES found the likely disease-causing mutation for 16 families (38%). And, using sequencing analysis, researchers were also able to identify known and new genetic variants in previously identified ataxia genes, including HIBCH, STUB1, ADCK3, B9D1, CLN5, PTRH2, and TPP1, as well as in the most recently identified gene, SQSTM1.

A third of the genetic variants underlying ataxia in the families analyzed were dominant, meaning that only one copy of the variant could induce disease. These dominant variants were identified in four genes — EBF3, ITPR1, NKX2-1, and ATP1A3.

Most importantly, whole exome sequencing analysis found new variants in genes not previously linked to ataxia.

Ignatius suggested that next-generation sequencing techniques may help to further uncover new genetic causes to childhood ataxias.

The researcher spotted the SQSTM1 gene, in particular, as one of the possible drivers of childhood-onset ataxias. “SQSTM1 serves as a key gene in several processes but we suspect its role in autophagy causes the patients’ phenotype,” she said.

Autophagy is a natural cellular process that destroys old or faulty proteins to prevent them from accumulating and damaging a cell — including the faulty proteins associated with ataxias. Autophagy is required for cellular equilibrium, or homeostasis. Problems in this process are associated with neurodegenerative disorders.

“This is why autophagy is one potential therapeutic target for ataxia and we expect that more autophagy genes will be identified in the coming years,” Ignatius said in her presentation.

Currently, researchers believe that autophagy plays a critical role in preventing neurological diseases and maintaining neuronal health. In fact, according to Ignatius, “neurons are among the cells most dependent on autophagy” for homeostasis.