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

Transmembrane protein 63B gene (TMEM63B) encodes a mechanosensitive ion channel expressed in alveolar type II epithelial cells, where it mediates stretch-induced surfactant secretion. While heterozygous gain-of-function variants in TMEM63B have been associated with developmental and epileptic encephalopathy, no human disorder has previously been linked to bi-allelic loss-of-function variants. Here, we report five individuals from four unrelated families with childhood interstitial lung disease and bi-allelic predicted loss-of-function variants in TMEM63B. Affected individuals presented with early-onset respiratory distress, chronic hypoxemia, and diffuse parenchymal lung abnormalities on chest imaging. One individual died in infancy, two underwent bilateral lung transplantation, and two require oxygen supplementation. Lung histopathology showed alveolar simplification and type II pneumocyte hyperplasia with electron-dense cores in lamellar bodies and interstitial fibrotic changes, findings consistent with impaired surfactant homeostasis. Developmental delay was observed in all individuals, with speech and language development more severely affected. One presented with white matter changes, and another had mild global atrophy on brain imaging. None of the individuals had epilepsy. Identified variants included two splice donor variants, two nonsense variants, and one frameshift variant, all of which were absent or extremely rare in population databases and segregated with disease. Functional evaluation of the splice donor and nonsense variants from three families supported a loss-of-function mechanism. The pulmonary phenotype of these individuals closely parallels that of Tmem63b-knockout mice, which exhibit neonatal respiratory failure due to impaired surfactant secretion. Collectively, these findings define an autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder and expand the phenotypic spectrum of TMEM63B-associated disease beyond the central nervous system.