Rare Gene Breakthrough: How Indian Researchers Unlocked a Child Neurological Mystery

The rare USP18 gene mutation offers crucial insights into a neurological disorder previously documented in only 11 cases worldwide and now reported for the first time in India, according to the team from Indira Gandhi Institute of Child Health, Bangalore, who conducted the research in collaboration with Ramjas College, University of Delhi, and Redcliffe Labs.

Pseudo-TORCH syndrome type 2 is a very rare inherited condition that affects how a child's brain grows and functions. Children with this disorder often show severe neurological symptoms that resemble congenital infections, but without any actual infection.

The USP18 gene usually helps regulate the body's immune response, preventing excessive inflammation. When this gene does not work correctly, the body's defence system becomes overactive and begins to harm the brain.

The research, published in the journal Clinical Dysmorphology, documented a previously unreported variant, c.358C-T (p.Pro120Ser), expanding clinical understanding of Pseudo-TORCH syndrome type 2.

"The discovery reinforces the power of clinical intuition backed by advanced genetic testing. For years, we treated symptoms without a definitive answer, but identifying this novel USP18 mutation has transformed not just the diagnosis, but the child’s future,” Dr. Vykuntaraju K. Gowda, Department of Pediatric Neurology, Indira Gandhi Institute of Child Health (IGICH, told IANS.

“The finding will help us avoid unnecessary treatments, provide precise therapy, and most importantly, guide families through informed genetic counselling. Our research shows how timely genetic insights can change the course of rare neurological disorders, offering hope where answers were once unknown," Gowda added.

The research was initiated with an 11-year-old girl who began experiencing symptoms from infancy, including repeated episodes of febrile encephalopathy, that is, fever-linked unconsciousness, seizures, delayed development, and a small head size.

Over the years, her scans also showed increasing calcium deposits in different parts of the brain.

To understand the underlying cause of these recurring neurological problems, advanced genetic testing was recommended. Through a focused DNA test called exome sequencing with mitochondrial genome sequencing, the team identified a previously unknown change in the USP18 gene, offering clarity after years of uncertainty.

The newly identified mutation alters the structure of the USP18 protein, weakening its ability to control inflammation. This overactive immune response can explain the child's repeated episodes of fever-triggered neurological decline.

Understanding this connection is essential because it helps doctors recognise early warning signs, avoid unnecessary treatments for infections, and focus instead on monitoring and managing conditions linked to immune overactivation.

"The case is also the first documented case of USP18-related disease presenting with recurrent febrile encephalopathy,” Dr Himani Pandey, one of the researchers.

The research highlights the importance of early genetic testing in children with unexplained neurological symptoms and opens the door for more targeted approaches to care in the future.

- IANS