Biallelic Variants in TMEM17 Cause Meckel-Gruber Syndrome Within the Ciliopathy Spectrum

TMEM17 encodes a transition zone protein essential for ciliary function. Three cases with homozygous variants in TMEM17 in primary ciliopathies (Joubert and Oral-Facial-Digital syndrome) have been reported. We investigated whether biallelic TMEM17 variants contribute to primary ciliopathies. We queried our Biodatabank and evaluated the gene-disease relationship (GDR) according to the ClinGen recommendations. Four unrelated patients (four families) were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) and novel homozygous variants: NM_198276.3:c.4del p.(Glu2Serfs*58); NM_198276.3:c.366dup p.(Pro123Thrfs*9); and NM_198276.3:c.368C>G p.(Pro123Arg). A fifth family lost three foetuses with MGS phenotype, both parents are heterozygote carriers (NM_198276.3:c.4del p.(Glu2Serfs*58)) but biological material from the foetuses was not available. The cases in this study had a severe prenatal phenotype, including encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality. This study strengthens the gene-disease association of TMEM17, upgrading it from “limited” to “moderate.” We expand the phenotypic spectrum, ranging from MGS—with prenatal onset and early lethality—to Oral-Facial-Digital and Joubert syndromes. Our findings indicate that loss-of-function variants may underlie the most severe TMEM17 ciliopathy manifestations, suggesting a potential genotype–phenotype correlation.