Childhood interstitial lung disease

Gene: TMEM63B

Green List (high evidence)

Comment on list classification: Rating amber but with a recommendation for green rating following GMS review. There are 4 families with biallelic loss of function variants in this gene and a relevant phenotype.

Created: 25 Jun 2026, 5:01 p.m. | Last Modified: 25 Jun 2026, 5:01 p.m.

Panel Version: 1.4

Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, doi:10.1016/j.bdcasr.2024.100043. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature

Created: 25 Jun 2026, 4:57 p.m. | Last Modified: 25 Jun 2026, 5:19 p.m.

Panel Version: 1.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder

Publications

• 42259295