Simone Schröder 1, Yun Li 2, Gökhan Yigit 2, Janine Altmüller 3, Ingrid Bader 4, Andrea Bevot 5, Saskia Biskup 6, Steffi Dreha-Kulaczewski 1, G Christoph Korenke 7, Raimund Kottke 8, Johannes A Mayr 9, Martin Preisel 9, Sandra P Toelle 10 Sarah Wente-Schulz 11, Saskia B Wortmann 9 12, Heidi Hahn 2, Eugen Boltshauser 10, Anja Uhmann 2, Bernd Wollnik 2 13, Knut Brockmann 14
Purpose: This study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable.
Methods: We compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts.
Results: In 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient-derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign.
Conclusion: Taken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome.
Keywords: COMA; Joubert syndrome; SUFU; congenital ocular motor apraxia; sonic hedgehog.
- Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Department of Pediatrics and Adolescent Medicine, University Medical Center, Göttingen, Germany.
- Institute of Human Genetics, University Medical Center, Göttingen, Germany.
- Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
- Department of Clinical Genetics, University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria.
- Department of Pediatric Neurology, University Hospital Tübingen, Tübingen, Germany.
- Praxis für Humangenetik Tübingen, Tübingen, Germany.
- Department of Pediatric Neurology, University Hospital Oldenburg, Oldenburg, Germany.
- Department of Diagnostic Imaging, University Children’s Hospital, Zurich, Switzerland.
- Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria.
- Department of Pediatric Neurology, University Children’s Hospital, Zurich, Switzerland.
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children’s Hospital, Hannover, Germany.
- Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children’s Hospital, Radboudumc, Nijmegen, The Netherlands.
- Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany.
- Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Department of Pediatrics and Adolescent Medicine, University Medical Center, Göttingen, Germany. firstname.lastname@example.org.