CNPY3 variants associated with a recessive developmental and epileptic encephalopathy affect inflammasome and TLR function.

CNPY3

Biallelic CNPY3 variants affecting an endoplasmic reticulum chaperone: allele-dependent defects in TLR2 maturation, downstream signalling and NLRP3 inflammasome activation

This international series brings together 50 individuals from 38 unrelated families with biallelic CNPY3 variants and developmental and epileptic encephalopathy (DEE); CNPY3 encodes an endoplasmic reticulum chaperone required for toll-like receptor (TLR) folding and inflammasome activation. Onset is very early (median 68 days), with global developmental delay (100%), intractable epilepsy (86%), spasticity (77%), microcephaly (70%) and early mortality (38%); epileptic spasms and tonic seizures predominate, with suppression-burst (37%) or hypsarrhythmia (28%) on EEG. Variants, homozygous in 95% of cases, remain classified as of uncertain significance in 71% under ACMG/AMP criteria, and patients with truncating variants are more severely affected (median score 18 vs 14.5). In cells, some missense variants allow TLR2 surface expression but impair downstream signalling and inflammasome activation, uncoupling trafficking from signal transduction.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The size of the series makes it the clinical reference for CNPY3-related DEE: a severe picture, onset within the first months and high early mortality. The most telling point for exome/genome interpretation is the share of variants still classified as of uncertain significance (71%) despite a homogeneous phenotype; the functional data reported here could help reclassify them, but the abstract does not say which ones were. The link between the innate immunity defect and the neurological disease remains to be established.

Analysis by Dr Thibaut Benquey