Biallelic TXNDC15 variants associated with Joubert syndrome-related molar tooth sign and forebrain malformation

TXNDC15 encodes thioredoxin domain-containing protein 15, a protein disulfide isomerase that plays a role in ciliogenesis. Biallelic TXNDC15 variants have been reported in six individuals of Meckel syndrome (MKS) with perinatal lethal phenotypes, but have not been reported in patients with Joubert syndrome (JS). Here, we describe a 1-year-old female patient with compound heterozygous TXNDC15 variants demonstrating cerebellar vermis hypoplasia with the molar tooth sign, mild holoprosencephaly, and cortical abnormalities. She had severe developmental delay and epilepsy. Her clinical features were similar to those of JS, but distinctive forebrain abnormalities were also noted including mild holoprosencephaly and cortical abnormalities, which have been reported in a severe form of ciliopathy. Biallelic TXNDC15 variants manifest as overlapping phenotypes of JS and MKS, including the molar tooth sign, cortical dysgenesis, and mild holoprosencephaly. This report supports the hypothesis that JS and MKS are spectrum ciliopathy disorders with overlapping causative genes and hypomorphic TXNDC15 variants might contribute to JS.