Curation NIID NOTCH2NLC

Gene NOTCH2NLC

Disease NIID

Inheritance AD

Score

12 + 2 = 14 / 18

Genetic + experimental = total

Classification

Definitive

Refuted

Moderate

Definitive

Last Updated 08/14/2025

Pubs Reviewed 8

Publication Span 5.08 years

Publication Interval 5.08 years

Curator(s) Macayla Weiner, Laurel Hiatt

Description

Autosomal dominant NIID is caused by heterozygous GGC/CGG repeat expansions in the 5′ UTR of NOTCH2NLC (also reported as NBPF19/NOTCH2NLC). The association is supported by independent long-read sequencing and repeat-primed/GC-rich PCR studies in familial and sporadic NIID, segregation in affected families, expansion enrichment in disease cohorts compared with controls, and replicated clinical/pathologic findings including multisystem neurodegeneration, characteristic DWI corticomedullary-junction hyperintensity/white matter disease, and eosinophilic p62/ubiquitin-positive intranuclear inclusions. Reported functional observations include altered methylation/regulatory findings and patient tissue pathology.

All criTRia Curations Locus Page

Genetic evidence

Total: 12

Per page

Category	Type	Citation	Score	Details
Singular Evidence	Probands	PMID:37090934	6	A multicenter Chinese NIID cohort described 223 patients/probands with NOTCH2NLC 5′ UTR GGC repeat expansions (>60 repeats), skin-biopsy p62-positive intranuclear inclusions, and characteristic neurologic/MRI features; for familial NIID, only probands were included in the final analysis.
Collective Evidence	Segregation	PMID:31178126	1.5	In a five-generation Chinese Han NIID family, linkage mapped the disease locus to 1p13.3–q23.1 (maximum LOD 3.184), WES did not identify a causal coding variant, and long-read sequencing identified a NOTCH2NLC 5′ GGC expansion. RP-PCR/GC-PCR showed expanded alleles in affected family members, whereas unaffected relatives carried normal-range repeats; additional familial/sporadic NIID cases also carried expansions.
Statistics	Case-control data	PMID:36570826 PMID:36086903 PMID:35857137 PMID:34675106	6	Available genetic case-control support includes NOTCH2NLC GGC expansions in 7/127 genetically undiagnosed Taiwanese CMT patients, including 7/66 CMT2 cases (10.6%), and 0/200 controls (pmid:34675106), plus pathogenic expansions in 27/597 ET pedigrees and 3/412 sporadic ET cases with intermediate alleles enriched versus 1085 controls (pmid:36086903). PMID:35857137 and pmid:36570826 are case-control studies of methylation/perfusion phenotypes rather than primary genetic enrichment studies.

Experimental evidence

Total: 2

Per page

Category	Type	Citation	Score	Details
Function	Regulatory impact	PMID:31332380	1	SMRT/IPD analysis suggested the expanded CGG repeat in the 5′ UTR of NBPF19/NOTCH2NLC tended to be hypermethylated, but RNA-seq from NIID brains (n=3) versus controls (n=8) did not show a significant difference in NBPF19 expression.
Functional Alteration	Patient cells	PMID:39055960	1	In a Korean NOTCH2NLC-expanded NIID cohort/family study, skin biopsies from two patients confirmed intranuclear inclusions using H&E with ubiquitin and p62 immunostaining; patient/family DNA methylation profiling showed lower promoter methylation in affected offspring than an asymptomatic expanded-repeat father.

Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.