Hereditary neuropathy or pain disorder

Gene: JAG1

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Sullivan et al., 2020 (PMID:32065591) report two unrelated families with segregation, presenting vocal fold paresis. Knock in mouse model showed slight but nonsignificant reduction in compound muscle action potential and morphological assessments of the recurrent laryngeal nerve were normal. Mice did however display an increased frequency of axons with focally folded myelin. Notably, variants in JAG1 are associated with several phenotypes that have not included neuropathy and there was no history of cardiac, kidney, or liver disease in affected individuals in either of the two families discussed here (possibly different mechanisms of pathogenesis but further investigation may be warranted).

At this point there is not enough evidence to add this gene as diagnostic-grade; however, additional cases would corroborate this gene-disease association - rating Amber with 'watchlist' tag.

Created: 6 Sep 2021, 11:13 a.m. | Last Modified: 6 Sep 2021, 11:13 a.m.

Panel Version: 1.55

Green List (high evidence)

Two unrelated families reported with CMT type 2. Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Pre-existing rat model.
Sources: Literature

Created: 23 Apr 2020, 10:21 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Peripheral neuropathy

Publications

• 32065591
• 25707699

Mode of pathogenicity
Other