Hereditary neuropathy or pain disorder

Gene: RCC1

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - number of cases with the same phenotype and functional support.

At least 12 unrelated families reported (PMID: 40683276) with biallelic variants in this gene associated with severe, acute-onset axonal neuropathy following infection. Eight different missense variants were identified. In vitro studies indicate that variants reduced the thermal stability of the RCC1 protein and some variants decreased GDP-to-GTP exchange activity. Patient fibroblasts under stress, revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model demonstrated that altered Rcc1 function leads to fatal intolerance to oxidative stress.

Created: 1 Aug 2025, 2:56 p.m. | Last Modified: 1 Aug 2025, 2:56 p.m.

Panel Version: 7.3

Green List (high evidence)

Paper referenced by previous reviewer has now been published

Created: 23 Jul 2025, 4:01 p.m. | Last Modified: 23 Jul 2025, 4:01 p.m.

Panel Version: 7.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 40683276

I don't know

Present in medrxiv, https://www.medrxiv.org/content/10.1101/2024.10.04.24314535v1. As not formally published left as amber rating.
24 individuals from 12 families with acute onset axonal neuropathy. Very severe disease in acutely unwell children. Neurological presentation was secondary to infection.
Sources: NHS GMS

Created: 23 Apr 2025, 8:37 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal