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

Bi-allelic loss-of-function TMEM63B variants (mechanosensitive channel in type II pneumocytes) impairing surfactant homeostasis — mirroring the gain-of-function variants causing epileptic encephalopathy

TMEM63B encodes a mechanosensitive ion channel expressed in type II pneumocytes, where it mediates stretch-induced surfactant secretion. Heterozygous gain-of-function variants were linked to developmental and epileptic encephalopathy, but no disorder had been tied to bi-allelic loss of function. The authors report five individuals from four families with childhood interstitial lung disease and bi-allelic loss-of-function TMEM63B variants: early-onset respiratory distress, chronic hypoxemia, and histology consistent with impaired surfactant homeostasis. Developmental delay is present in all, without epilepsy.

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

A neat example of mechanism-phenotype correlation: bi-allelic loss of function of TMEM63B causes syndromic surfactant dysfunction, opposite to the gain-of-function variants causing epileptic encephalopathy. Worth knowing in the differential diagnosis of childhood interstitial lung disease with neurodevelopmental involvement.

Analysis by Dr Thibaut Benquey