SCN9A – Channelopathy-associated Congenital Insensitivity to Pain

Channelopathy-associated congenital insensitivity to pain is an extremely rare autosomal recessive disorder (MONDO:0009459), characterized by inability to perceive noxious stimuli and often anosmia. Loss-of-function variants in the voltage-gated sodium channel gene SCN9A, encoding Nav1.7, have been repeatedly identified in affected individuals since 2007. Initial mapping and sequencing in a Canadian family revealed a homozygous stop codon mutation c.984C>A (p.Tyr328Ter) abolishing Nav1.7 function and explaining the non-lethal human phenotype despite murine knockout lethality (PMID:17597096).

Genetic case series and consanguineous pedigrees now include >30 unrelated probands harboring homozygous or compound heterozygous SCN9A truncating or splice variants. Key reported alleles encompass nonsense and frameshift changes such as c.2723G>A (p.Trp908Ter) in exon 15 (PMID:25309764), splice site variants inducing exon skipping, and founder mutations in diverse populations. Segregation in multiple families confirms autosomal recessive inheritance with at least eight additional affected relatives demonstrating biallelic transmission.

Electrophysiological studies in heterologous systems and patient-derived cells consistently show complete loss of Nav1.7 sodium current for truncating variants. Patch-clamp analysis of the R1488* allele in HEK293 cells confirmed non-functional channels (PMID:30037327). Species-specific expression differences explain human viability despite Nav1.7 deficiency, and concordant animal knockout models recapitulate analgesia without lethality.

Clinically, SCN9A-related CIP presents with profound insensitivity to pain, anosmia (HP:0000458), hyposmia (HP:0004409), hypogeusia (HP:0000224), and sometimes bladder dysfunction or skeletal complications. Electrophysiological sensory testing is typically unremarkable, and skin biopsy shows loss of epidermal nociceptors.

No conflicting evidence disputes the causal role of SCN9A loss-of-function in congenital insensitivity to pain. Variants in other genes can present overlapping phenotypes but SCN9A LOF mutations remain the only monogenic cause of channelopathy-associated CIP.

Integration of genetic segregation, variant spectrum, and robust functional concordance establishes a Definitive gene–disease relationship for SCN9A and channelopathy-associated congenital insensitivity to pain. Early molecular diagnosis enables anticipatory care, prevents secondary injury, and guides potential Nav1.7-targeted therapies.

Key Take-home: Biallelic loss-of-function mutations in SCN9A cause autosomal recessive congenital insensitivity to pain with anosmia; functional assays uniformly confirm Nav1.7 inactivity, supporting definitive clinical validity and enabling genetic diagnosis.

References

• Human Molecular Genetics • 2007 • A stop codon mutation in SCN9A causes lack of pain sensation. PMID:17597096
• Case Reports in Neurological Medicine • 2014 • Congenital insensitivity to pain: a case report and review of the literature. PMID:25309764
• BMC Medical Genetics • 2018 • Functional confirmation that the R1488 variant in SCN9A results in complete loss-of-function of Nav1.7.* PMID:30037327

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