TTC21B: From Modifier to Causative Gene in Joubert Syndrome

Biallelic pathogenic variants in TTC21B, encoding the retrograde intraflagellar transport protein IFT139, are a known cause of renal and skeletal ciliopathies. Single heterozygous variants in this gene were found to be enriched in a cohort of patients with various ciliopathy phenotypes, including three individuals with Joubert syndrome (JS), a neurodevelopmental ciliopathy characterized by a peculiar cerebellar and brainstem malformation. It was then suggested that TTC21B could act as a modifier gene for ciliopathies. Here we report a patient homozygous for the hypomorphic founder variant p.Pro209Leu in TTC21B, who presented typical neurological and neuroradiological features of JS, along with mild renal dysplasia and retinal dystrophy. To our knowledge, this is the first case reported with molecularly confirmed JS caused by biallelic pathogenic variants in TTC21B, expanding the spectrum of TTC21B-associated ciliopathies, further highlighting the complex genetic basis of ciliopathies.