Heterozygous truncating variants of the SUFU negative regulator of hedgehog signaling (SUFU) gene cause congenital oculomotor apraxia (COMA), a rare eye movement disorder. Patients with this condition are unable to voluntarily move their eyes horizontally to fixate on an object. To compensate for this, they develop jerking head movements to bring the eyes in a position where they can view the object. The genetic basis of COMA has so far been unknown and it has been debated whether it is a distinct clinical entity or rather part of a genetic syndrome, specifically Joubert syndrome.

Led by Prof Knut Brockmann, Head of Community Pediatric Services (SPZ) of the Pediatric Department, and including scientists at the Institute of Human Genetics of the University Medical Center Göttingen (UMG), a recent study investigated six unrelated families with 15 affected individuals. All patients showed distinct features of COMA but no other common diagnostic characteristics of Joubert syndrome. The researchers detected six autosomal dominant truncating variants of the gene encoding SUFU. This protein is an important negative regulator of the hedgehog signalling pathway and thus plays an important role in embryonic development. Functional studies performed on patient-derived fibroblasts showed an increased basal activity of hedgehog signalling, which, however, can be regulated by exogenous HH signaling activator or inhibitor treatment. Neuroimaging revealed that the patients presented hindbrain malformations but not the characteristic features seen in typical Joubert syndrome. Therefore, the authors consider COMA as a mild and genetically specific form of Joubert syndrome. Interestingly, autosomal recessive mutations in SUFU have been reported in children with Joubert syndrome.

The results of the study have been published in Genetics in Medicine.