Submission Details

The gene SCN11A encodes the voltage-gated sodium channel Nav1.9 that was first discovered to be expressed in sensory neurons in 1998 (PMID: 9671787). Together with other voltage-gated sodium channel genes (SCN9A, SCN10A), likewise associated with hereditary neuropathic pain syndromes, it is responsible for the generation of action potentials in nociceptive nerve fibers (PMID: 27556810). In 2013, Leipold et al. (PMID: 24036948) described two families with the same de-novo SCN11A missense variant in association with congenital insensitivity to pain. Both affected individuals showed severe self-mutilation and autonomic disturbances. This phenotype was reproduced in patients with the same (PMIDs: 30395542, 25118027) and two different (PMIDs: 28289907, 26746779) SCN11A missense variants, all located in the terminal segment of one of the transmembrane domains (S6) constituting the pore-forming part of the sodium channel (PMIDs: 32601768, 28289907). By patch-clamp analysis, variants were shown to results in a prominent gain-of-function phenotype mediated by a leftward shift in channel activation and deactivation kinetics as well as by a slow- down in channel inactivation. A reduced density of spontaneous synaptic events in mouse dorsal horn neurons from a respective mouse model was observed (PMID: 24036948). In a heterozygous knock-in mouse model, the patient phenotype was reproduced showing non-healing wounds, increased amounts of scratch-bouts, and reduced grip-strength (PMIDs: 24036948, 32817686).

In parallel, SCN11A has also been reported in association with an autosomal dominant neuropathic pain disorder described as recurrent episodes of severe distal limb and facial pain responding to NSAIDs and being aggravated by cold. Heterozygous missense mutations were found to segregate in large families (PMIDs: 24207120, 28298626, 30046661). On functional level, the variants increased current densities, but did not change the channel’s activation or deactivation thresholds (PMIDs: 24207120). In a heterozygous knock-in mouse model, the phenotype reproduced the phenomenon of cold-aggravated allodynia (PMID: 32970203).

We therefore conclude that heterozygous missense mutations in SCN11A can cause both loss and gain of pain, depending on the respective consequences on cellular level. In other neuropathic pain disorder such as small fiber neuropathies, screening studies revealed the presence of SCN11A variants in several unrelated cases (PMID: 24776970). Despite causing a gain of channel function in voltage-clamp analyses, these variants show a variable allele frequency in control populations. It is therefore unclear to date, to what extent they constitute risk factors or contribute to the phenotype. In summary, the panel concludes that the gene disease relationship for SCN11A and autosomal dominant hereditary sensory and autonomic neuropathy is definitive. Of note, yet no clear pathological or electrophysiological signs of neuropathy have been reported in these pain perception disorders. Considering the expression in nociceptive sensory neurons and their expected dysfunction, however, the panel decided to call this disease “neuropathy”.