CMT-NOTCH2NLC

Genetic Context

HGNC-Approved Gene Symbol

NOTCH2NLC

Gene Full Name

notch 2 N-terminal like C

Chromosome

1q21.2

Zygosity of Responsible Variant

Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Repeat expansion

Confidence:
High

Prediction:
The literature supports a repeat-expansion gain-of-function mechanism for CMT-NOTCH2NLC: a heterozygous GGC expansion in the 5'UTR drives repeat-associated non-AUG translation of a polyglycine protein, and both the expanded transcript and that product are toxic. The signature here is pathological rather than biochemical, the ubiquitin-positive eosinophilic intranuclear inclusion shared with neuronal intranuclear inclusion disease, seen in patients whose presentation is CMT. Toxicity comes from what the expansion makes, not from reduced NOTCH2NLC activity.

Rationale:
One expanded allele fills nuclei with inclusions, and those inclusions contain the polyglycine translation product, so the pathology is assembled from a molecule the repeat creates and the genome does not otherwise encode. Phenotype across the NOTCH2NLC spectrum follows the expanded repeat, not any shortfall of normal protein.

ClinVar Pathogenic Variants

View NOTCH2NLC ClinVar Variants

NOTCH2NLC OMIM Entry

NOTCH2NLC OMIM