Expanding the Phenotypic Spectrum of TXNDC15-Related Ciliopathies to Include Joubert Syndrome.

Biallelic loss-of-function variants in TXNDC15 are a known cause of the perinatally lethal ciliopathy Meckel syndrome (MKS). TXNDC15 encodes an endoplasmic reticulum (ER)-resident thioredoxin-domain protein required for ciliary transition zone integrity. Many ciliopathy genes show a spectrum of severity, producing a clinical continuum from lethal MKS to the less severe Joubert syndrome (JS). Using genome and exome sequencing analysis, we identified four unrelated children with JS who harbor rare biallelic variants in TXNDC15. In contrast to the biallelic truncating variants typical of MKS, all individuals with JS carried a missense variant in trans with a truncating variant. Three of four missense variants cluster within the functionally critical thioredoxin domain. In silico structural modeling using AlphaFold and variant effect prediction (AlphaMissense, DynaMut2) support a deleterious effect on protein stability and function for the majority of these missense variants. This work expands the phenotypic spectrum of TXNDC15-related ciliopathies to include JS. All four individuals carried a missense allele in trans with a truncating allele. Our findings underscore the importance of including TXNDC15 in the genetic diagnosis of JS.