28 July 2020, Singapore – A team of clinicians and researchers from KK Women's and Children's Hospital (KKH) and the Agency for Science, Technology and Research’s (A*STAR) Institute of Medical Biology (IMB), have identified the world’s first known case of a previously undiagnosed genetic syndrome. Their work was published in Nature Communications this January 2020.

The newly-identified ‘Jamuar Syndrome’ is named after Dr Saumya Jamuar, Senior Consultant, Genetics Service, KKH, who first encountered the disease in a pair of young siblings who presented to the hospital in 2015.

“The siblings presented to KKH with a unique clinical profile, including epileptic seizures and developmental delay, and were enrolled in the BRIDGES (Bringing Research Innovations for the Diagnosis of Genetic diseases in Singapore) programme which looks into undiagnosed diseases of young children,” says Dr Jamuar, who is also Head, SingHealth Duke-NUS Genomic Medicine Centre.

UGDH gene plays key role in human brain developments

Whole exome sequencing performed by Dr Bruno Reversade, Research Director at IMB, A*STAR, discovered a unique DNA change in the siblings – a new mutation Ala82Thr in the gene, UGDH, which had never been associated with any genetic disease in humans. A search for international patients with undiagnosed genetic diseases further identified patients from 24 other families worldwide with similar clinical presentation. All 36 children, including affected siblings, were found to carry mutations in the same UGDH gene. Another UGDH mutation, Arg317Gln, was found to be widespread in the Saudi population accounting for 11 children with epileptic encephalopathy.

Dr Reversade's team then brought this genetic finding to the lab, and using patients' cells, characterised the effect of this variation of UGDH on brain development. They first demonstrated that the mutations affect either the stability, structure or function of the enzyme encoded by the UGDH gene. Using the siblings’ skin cells, they then developed mini brain models in the lab and compared these to those of healthy controls. They noted that patients' mini brains were smaller and showed reduced number of brain progenitor cells, demonstrating that UGDH plays an indispensable role during human brain development.

Based on the currently known variants, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy, which is characterised by epileptic seizures and speech and developmental delays of varying severity.

“Our discovery of the disease-causing mutations in the UGDH gene could pave the way to finding new therapeutic targets for epilepsies. On a more personal note, having a novel genetic disease named after the discoverer, is a formidable accolade. Dr Jamuar was instrumental in this discovery and this is a well-deserved international recognition for his clinical acumen,” says Dr Reversade.

As collaborative genomic research continues to identify and characterise diseases that have never been reported in humans before, Dr Jamuar explains the benefits, “Understanding the biology of previously undiagnosed diseases such as Jamuar Syndrome empowers physicians to act and make an impact on patients and their families’ lives in a tangible way. This information also enables us to develop and improve treatments that may be best suited for the patients' needs.”