Neuronal intranuclear inclusion disease is genetically heterogeneous

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Neuronal intranuclear inclusion disease (NIID) is a heterogeneous neurodegenerative disorder.
• Pathological hallmarks include intranuclear eosinophilic inclusions.
• A CGG repeat expansion in NOTCH2NLC is linked to NIID in Japanese populations.

Purpose of the Study:

• To investigate the genetic basis of European NIID cases.
• To determine if the NOTCH2NLC CGG repeat expansion is present in European NIID patients.
• To compare European NIID with East Asian NIID based on genetic findings.

Main Methods:

• Screening of pathologically confirmed European NIID cases.
• Analysis of neurodegenerative disease cases with intranuclear inclusions.
• In silico screening using whole-genome sequencing data from the 100,000 Genomes Project (20,536 participants).

Main Results:

• A single European case with the pathogenic NOTCH2NLC CGG repeat expansion was identified.
• This European case exhibited a distinct haplotype structure compared to previously reported cases.
• The findings suggest genetic heterogeneity within NIID.

Conclusions:

• European NIID may represent a distinct disease entity from East Asian NIID.
• New diagnostic criteria for European NIID are proposed based on genetic findings.
• Further research is needed to fully characterize the genetic landscape of NIID globally.