Missense Variants in the Second Transmembrane Domain of TMEM17 Disrupt Its Stability and Function and Lead to a Wide Phenotypic Spectrum of Ciliopathies.

Ciliopathies are rare genetic disorders characterized by significant genetic and phenotypic variability. Over 140 proteins localized to primary cilia, which are sensory organelles essential for vertebrate development, are implicated. TMEM17 encodes a transmembrane protein at the ciliary transition zone and was previously proposed as a potential ciliopathy gene, based on reports of individuals from two families with orofaciodigital syndrome type 6 (OFD6) and Joubert syndrome (JS). Here, we report two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts, in whom exome sequencing identified a founder homozygous missense variant (Arg94Trp) in TMEM17, affecting a highly conserved residue. This expands the TMEM17-associated phenotypic spectrum to include Meckel syndrome (MKS). Comprehensive functional analyses of all known TMEM17 variants, using patient tissues/cells and a C. elegans model system, demonstrate a loss-of-function mechanism. Our study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling. These experiments confirm the pathogenicity of all TMEM17 variants and underscore its essential role at the ciliary transition zone. Collectively, our findings establish TMEM17 as a bona fide ciliopathy gene, associated with a wide phenotypic spectrum ranging from viable syndromes (OFD6 and JS) to a fetal-lethal condition (MKS).