AI Article Synopsis

  • Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative condition linked to GGC repeat expansions in the NOTCH2NLC gene, with potential impacts on various organs, including the kidneys.
  • A study on a family with NIID found that four out of five members experienced proteinuria and had a renal pathology diagnosis of focal segmental glomerulosclerosis (FSGS), alongside other neurological symptoms.
  • Advanced genetic analyses, including exome and whole-genome sequencing, identified STR expansions in NOTCH2NLC, indicating a possible connection between this genetic alteration and renal diseases.

Article Abstract

Background: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease caused by the expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of NOTCH2NLC. Although increasing evidence suggests that NIID affects various organs, its association with renal involvement remains unclear. We studied the genetic background of a family with NIID, in which four of five members presented with proteinuria as the initial manifestation. The renal pathology of three patients was diagnosed as focal segmental glomerulosclerosis (FSGS) at a previous hospital. These patients also presented with tremors, retinal degeneration, and episodic neurological events. Finally, one patient exhibited reversible bilateral thalamic high-intensity signal changes on diffusion-weighted imaging during episodic neurological events.

Methods: Exome sequencing (ES) and nanopore long-read whole-genome sequencing (LR-WGS) were performed on the index case, followed by nanopore target sequencing using Cas9-mediated PCR-free enrichment and methylation analysis.

Results: ES revealed no candidate variants; however, nanopore LR-WGS in the index case revealed expansion of short tandem repeats (STR) in NOTCH2NLC. Subsequent nanopore target sequencing using Cas9-mediated PCR-free enrichment showed STR expansion of NOTCH2NLC in an affected sibling and asymptomatic father. Methylation analysis using nanopore data revealed hypermethylation of the expanded allele in the asymptomatic father and partial hypermethylation in a mildly symptomatic sibling, whereas the expanded allele was hypomethylated in the index case.

Conclusions: This investigation expands the clinical spectrum of NIID, suggesting that STR expansion of NOTCH2NLC is a cause of renal diseases, including FSGS.

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Source
http://dx.doi.org/10.1007/s00415-024-12593-wDOI Listing

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