Bi-allelic loss-of-function variants in TMEM63B cause syndromic surfactant dysfunction disorder

Mechanosensitive ion channel TMEM63B, deficient surfactant secretion via biallelic loss of function

Biallelic loss-of-function variants in TMEM63B, a mechanosensitive ion channel expressed in alveolar type II cells, are identified in 5 individuals from 4 unrelated families with pediatric interstitial lung disease. TMEM63B was previously linked only to developmental and epileptic encephalopathy via heterozygous gain-of-function variants — this study describes the first human disorder caused by biallelic loss of function. The clinical phenotype includes neonatal respiratory failure, progressive interstitial lung disease, and variable neurological involvement. Functional studies confirm loss of stretch-induced surfactant secretion.

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

This princeps publication of TMEM63B-LOF completes the allelic spectrum with a recessive disease distinct from the dominant GOF form — a rare example of allelic plasticity. The impact on diagnostic panels is immediate: TMEM63B should now appear in pediatric rare lung disease panels in addition to epilepsy-encephalopathy panels.

Clinical impact: 3/3 · Evidence strength: 3/3 · Novelty: 2/2 · Sample size: 1/1 · Publication status: 1/1 → Total: 10/10