Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease

Nat Genet. 2019 Aug;51(8):1215-1221. doi: 10.1038/s41588-019-0459-y. Epub 2019 Jul 22.

Abstract

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1-8, but skin biopsy enables its ante-mortem diagnosis9-12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Brain / metabolism
  • Brain / pathology*
  • Case-Control Studies
  • Female
  • Genetic Markers / genetics
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Intranuclear Inclusion Bodies / genetics
  • Intranuclear Inclusion Bodies / pathology
  • Linkage Disequilibrium*
  • Male
  • Middle Aged
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / pathology*
  • Pedigree
  • Receptors, Notch / genetics*
  • Receptors, Notch / metabolism
  • Trinucleotide Repeat Expansion / genetics*
  • Young Adult

Substances

  • Genetic Markers
  • Receptors, Notch

Supplementary concepts

  • Neuronal intranuclear inclusion disease