Novel USP18 Gene Mutation Identified in Rare Pediatric Neurological Disorder

Overview

• A multidisciplinary research team including Redcliffe Labs has identified a previously unreported USP18 gene variant associated with a rare pediatric neurological disorder.
• The finding represents the first documented report of this USP18-related disorder in India.
• The research identified the variant c.358C>T (p.Pro120Ser) in the USP18 gene.
• The case involved an 11-year-old girl with recurrent fever-triggered neurological episodes, seizures, developmental delay, and progressive brain calcifications.
• Exome sequencing and mitochondrial genome sequencing helped identify the underlying genetic cause after years of unexplained neurological symptoms.
• The findings were published in Clinical Dysmorphology and add to the limited global understanding of USP18-related disorders.

About the Research

Some rare neurological disorders can resemble infections, metabolic conditions or other more commonly recognized diseases, making their underlying cause difficult to establish.

The research involved an 11-year-old girl who had experienced recurrent episodes of fever-associated unconsciousness, seizures, developmental delays and progressive neurological deterioration since infancy. Brain imaging also showed increasing calcifications.

Because the clinical presentation remained unexplained, advanced genetic testing was undertaken to investigate a possible inherited disorder.

The genetic analysis identified a previously unreported variant in the USP18 gene, providing a molecular explanation for the child's clinical presentation and supporting a diagnosis of Pseudo-TORCH syndrome type 2.

What Is USP18?

USP18 (Ubiquitin-Specific Peptidase 18) is a gene that regulates the body's type I interferon response.

Type I interferons are important components of the immune system. They help the body respond to infections, but their activity also needs tight regulation.

USP18 contributes to this regulation by limiting excessive interferon signaling.

When disease-causing variants affect USP18 function, immune activation can become abnormal. In severe forms of USP18-related disease, this dysregulated immune response can affect multiple organs, including the developing brain.

What Did the Research Identify?

The genetic analysis identified a previously unreported homozygous missense variant:

c.358C>T (p.Pro120Ser)

in the USP18 gene.

The variant had not previously been documented in the reported literature and was associated with the patient's clinical presentation.

Genetic analysis of the parents showed that both were asymptomatic carriers of the variant, while the affected child had inherited both copies. This pattern is consistent with autosomal recessive inheritance.

What Is Pseudo-TORCH Syndrome Type 2?

Pseudo-TORCH syndrome type 2 is an extremely rare inherited neurological disorder associated with abnormalities in the body's immune response.

The condition can resemble congenital infections such as those caused by TORCH pathogens, particularly because affected children may develop:

• Neurological abnormalities
• Seizures
• Developmental delay
• Brain calcifications
• Recurrent episodes of encephalopathy
• Progressive neurological deterioration

However, unlike true congenital infections, the underlying cause is genetic rather than infectious.

USP18-related disease is exceptionally rare, with only a small number of cases reported globally.

What Were the Clinical Features in This Case?

The child had experienced neurological symptoms from infancy, including:

• Recurrent fever-triggered unconsciousness
• Seizures
• Developmental delay
• Progressive neurological decline
• Reduced head growth
• Progressive intracranial calcifications

The combination of recurrent febrile neurological episodes and progressive brain abnormalities created a complex diagnostic picture.

The absence of a clear infectious cause prompted further investigation through advanced genetic testing.

How Did Genetic Testing Help?

Genetic testing played a central role in identifying the underlying cause.

The research team used:

Exome Sequencing

Exome sequencing analyses the protein-coding regions of genes and can help identify genetic variants associated with rare and unexplained disorders.

In this case, exome sequencing identified the USP18 variant that provided a potential molecular explanation for the child's symptoms.

Mitochondrial Genome Sequencing

The team also performed mitochondrial genome sequencing as part of the genetic investigation to evaluate possible mitochondrial causes of the neurological presentation.

Together, these investigations narrowed the diagnostic possibilities and identified the USP18-related disorder.

Why Was the Diagnosis Challenging?

Rare genetic neurological disorders can share clinical features with more common conditions.

In this case, recurrent fever, seizures, encephalopathy, and intracranial calcifications could suggest an infectious or inflammatory disorder.

Pseudo-TORCH syndrome can closely resemble congenital infection despite the absence of an infectious cause.

This overlap can make diagnosis difficult without molecular testing.

Identifying the USP18 variant provided a genetic explanation that connected the child's clinical history, neurological findings, and underlying immune dysregulation.

Why Does Identifying the USP18 Variant Matter?

Identifying the genetic cause of a rare disorder can have implications beyond establishing a diagnosis.

A confirmed molecular diagnosis can help:

• Clarify the cause of unexplained neurological symptoms
• Distinguish genetic disease from infectious conditions
• Guide clinical monitoring and management
• Avoid unnecessary or prolonged treatments when an infectious cause has been ruled out
• Enable appropriate genetic counseling
• Inform risk assessment for future pregnancies
• Support recognition of similar cases in other children

The researchers highlighted the importance of genetic diagnosis in complex pediatric neurological presentations where conventional investigations do not explain the findings.

What Does This Research Add to Medical Knowledge?

The research expands the known genetic spectrum of USP18-related disease by documenting a previously unreported USP18 variant.

It also represents the first reported case of this USP18-related disorder in India, adding clinical and molecular information from an Indian patient to the limited global literature.

The case highlights the value of considering rare genetic disorders when children present with unexplained, recurrent neurological deterioration and progressive brain abnormalities.

The Role of Genomics in Rare Disease Diagnosis

Rare diseases often present with symptoms that overlap with more common conditions.

For children with unexplained neurological symptoms, genomic testing can help move the diagnostic process beyond symptom-based assessment toward identifying the underlying molecular cause.

Depending on the clinical presentation, testing approaches such as exome sequencing, genome sequencing, and targeted genetic analysis may help identify disease-associated variants.

In this case, advanced genomic testing provided the information needed to identify the USP18 variant and establish a molecular diagnosis.

What Does This Mean for Families?

A rare disease diagnosis can provide families with an explanation for symptoms that may have remained unexplained for years.

A molecular diagnosis can also support genetic counseling, helping families understand the inheritance pattern and potential implications for future pregnancies.

Because USP18-related disease follows an autosomal recessive pattern, identifying carrier status in parents can be relevant when assessing reproductive risk and discussing appropriate prenatal or preimplantation genetic testing options with qualified specialists.

Key Findings at a Glance

Research Parameter	Finding
Disorder	Pseudo-TORCH syndrome type 2
Gene identified	USP18
Variant	c.358C>T (p.Pro120Ser)
Patient	11-year-old girl
Key clinical features	Recurrent febrile encephalopathy, seizures, developmental delay, brain calcifications
Genetic investigations	Exome sequencing and mitochondrial genome sequencing
Inheritance	Autosomal recessive
Significance	Previously unreported USP18 variant
Geographic significance	First documented report in India
Publication	Clinical Dysmorphology

What Does the Research Mean for Rare Neurological Disorders?

This research highlights how advanced genomics can help solve complex diagnostic questions in children with unexplained neurological disease.

When recurrent symptoms, neurological deterioration, and imaging abnormalities do not fit a clear infectious or metabolic diagnosis, genomic testing can provide an additional route to identifying the underlying cause.

Identifying a rare USP18 variant in this case reinforces the role of precision diagnostics in rare disease evaluation and adds new information to the global understanding of USP18-related disorders.

Research Team

Dr. Himani Pandey
Lab Head – Genomics, Redcliffe Labs

Dr. Vykuntaraju K. Gowda
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bengaluru

The research was conducted in collaboration with experts from the Indira Gandhi Institute of Child Health, Bengaluru; Ramjas College, University of Delhi; and Redcliffe Labs.

Publication Details

Research Topic: USP18 gene mutation and Pseudo-TORCH syndrome type 2

Gene: USP18

Variant: c.358C>T (p.Pro120Ser)

Journal: Clinical Dysmorphology

Research Area: Clinical Genomics | Rare Diseases | Pediatric Neurology | Genetic Disorders

Read the Research

The research documents a novel USP18 variant associated with Pseudo-TORCH syndrome type 2 and expands the understanding of rare genetic causes of recurrent neurological decline in children.

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