Next-generation sequencing uncovers another genetic mystery in skeletal dysplasia

1 Mar 2012

Following on from the success of last year’s UQDI and UQCCG collaborative approach of gene-mapping a new form of dwarfism (anauxetic dysplasia), yet another achievement in the genetics of skeletal dysplasias has come to light.

Over the last 12 months, the team has identified the responsible gene for multicentric carpotarsal osteolysis (MCTO), by using exome sequencing in just five individuals. The research team then examined another six affected individuals, and two families afflicted by the disease, discovering they also all carried mutations in the same gene. All the patients and their families were recruited through the Bone Dysplasia Registry, established at UQCCR by Associate Professor Andreas Zankl. Their findings have been published in the American Journal of Human Genetics.

Researchers at the UQDI and UQCCR now feel they can confidently move forward with an identified therapeutic target to treat the disease.

“We’ve discovered a pathway with a potential solution already available,” Associate Professor Emma Duncan from UQDI says. “We are now hoping to translate our findings from the lab to the clinic once we’ve established that the available treatment – which is currently used to prevent bone loss in osteoporosis patients – can be safely and effectively used in this patient group also.”

Skeletal dysplasias are a group of genetic diseases that cause abnormalities in the skeleton’s growth and function. This can lead to problems such as short stature, joint pain or bone fragility and complications that significantly affect the quality of life of affected individuals. Families affected by skeletal dysplasias are usually very small in number, which can make it difficult to find the disease-causing gene for that family.

Associate Professor Andreas Zankl, a clinical geneticist from The University of Queensland Centre for Clinical Research, developed a Bone Dysplasia registry to follow patients and their families long term - the first of its kind in Australia.

The team used next-generation sequencing to compare the affected individuals’ exomes - the coding section of the genes – to each other and against the reference sequence from the international Human Genome Project.  They were able to discover which gene within each person caused the abnormality.

Impressively, the mapping process took only a few weeks. The UQDI researchers then successfully determined how the genetic abnormality caused the skeletal disease.

In the past, researchers could only sequence and compare a few genes at a time, which was expensive and time consuming.  For example, UQDI researchers had spent a decade finding the responsible gene for another type of skeletal dysplasia, fibrodysplasia ossificans progressiva. In contrast, next-generation sequencing technology can provide more rapid results for mapping genes in these particular types of diseases. However, despite this breakthrough in progress, Associate Professor Emma Duncan reiterates it’s still an intensive process.

The paper has been published online on the American Journal of Human Genetics.

The success of this discovery was due to funding by the Australian Cancer Research Foundation,  NAB and NHMRC, The Rebecca L Cooper Foundation, the Royal Children’s Hospital Research Foundation and an ANZ Medical Research Grant.

Finally, the team of dedicated UQDI researchers: Professor Matthew Brown, Associate Professor Emma Duncan, Associate Professor Andreas Zankl,  Dr Evgeny Glazov, Dr Graeme Clark, Dr Paul Leo and Dr Aideen McInerney.

The UQDI would also like to thank the patients and their families who generously participated in the project.