PMID- 33024317 OWN - NLM STAT- MEDLINE DCOM- 20210603 LR - 20220531 IS - 1530-0366 (Electronic) IS - 1098-3600 (Print) IS - 1098-3600 (Linking) VI - 23 IP - 2 DP - 2021 Feb TI - Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia. PG - 341-351 LID - 10.1038/s41436-020-00979-w [doi] AB - 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. FAU - Schroder, Simone AU - Schroder S AD - Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Department of Pediatrics and Adolescent Medicine, University Medical Center, Gottingen, Germany. FAU - Li, Yun AU - Li Y AD - Institute of Human Genetics, University Medical Center, Gottingen, Germany. FAU - Yigit, Gokhan AU - Yigit G AD - Institute of Human Genetics, University Medical Center, Gottingen, Germany. FAU - Altmuller, Janine AU - Altmuller J AD - Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. FAU - Bader, Ingrid AU - Bader I AD - Department of Clinical Genetics, University Children's Hospital, Paracelsus Medical University, Salzburg, Austria. FAU - Bevot, Andrea AU - Bevot A AD - Department of Pediatric Neurology, University Hospital Tubingen, Tubingen, Germany. FAU - Biskup, Saskia AU - Biskup S AD - Praxis fur Humangenetik Tubingen, Tubingen, Germany. FAU - Dreha-Kulaczewski, Steffi AU - Dreha-Kulaczewski S AD - Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Department of Pediatrics and Adolescent Medicine, University Medical Center, Gottingen, Germany. FAU - Christoph Korenke, G AU - Christoph Korenke G AD - Department of Pediatric Neurology, University Hospital Oldenburg, Oldenburg, Germany. FAU - Kottke, Raimund AU - Kottke R AD - Department of Diagnostic Imaging, University Children's Hospital, Zurich, Switzerland. FAU - Mayr, Johannes A AU - Mayr JA AD - Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria. FAU - Preisel, Martin AU - Preisel M AD - Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria. FAU - Toelle, Sandra P AU - Toelle SP AD - Department of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland. FAU - Wente-Schulz, Sarah AU - Wente-Schulz S AD - Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany. FAU - Wortmann, Saskia B AU - Wortmann SB AD - Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria. AD - Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands. FAU - Hahn, Heidi AU - Hahn H AD - Institute of Human Genetics, University Medical Center, Gottingen, Germany. FAU - Boltshauser, Eugen AU - Boltshauser E AD - Department of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland. FAU - Uhmann, Anja AU - Uhmann A AD - Institute of Human Genetics, University Medical Center, Gottingen, Germany. FAU - Wollnik, Bernd AU - Wollnik B AD - Institute of Human Genetics, University Medical Center, Gottingen, Germany. AD - Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Gottingen, Gottingen, Germany. FAU - Brockmann, Knut AU - Brockmann K AUID- ORCID: 0000-0001-6823-9091 AD - Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Department of Pediatrics and Adolescent Medicine, University Medical Center, Gottingen, Germany. kbrock@med.uni-goettingen.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201007 PL - United States TA - Genet Med JT - Genetics in medicine : official journal of the American College of Medical Genetics JID - 9815831 RN - 0 (Hedgehog Proteins) RN - 0 (Kruppel-Like Transcription Factors) RN - 0 (Repressor Proteins) RN - 0 (SUFU protein, human) RN - Apraxia, oculomotor, Cogan type SB - IM MH - Apraxias/congenital MH - *Cogan Syndrome MH - *Hedgehog Proteins/genetics MH - Humans MH - Kruppel-Like Transcription Factors MH - Repressor Proteins PMC - PMC7862056 OTO - NOTNLM OT - COMA OT - Joubert syndrome OT - SUFU OT - congenital ocular motor apraxia OT - sonic hedgehog COIS- The authors declare no conflicts of interest. EDAT- 2020/10/08 06:00 MHDA- 2021/06/04 06:00 PMCR- 2020/10/07 CRDT- 2020/10/07 05:48 PHST- 2020/06/24 00:00 [received] PHST- 2020/09/17 00:00 [accepted] PHST- 2020/09/11 00:00 [revised] PHST- 2020/10/08 06:00 [pubmed] PHST- 2021/06/04 06:00 [medline] PHST- 2020/10/07 05:48 [entrez] PHST- 2020/10/07 00:00 [pmc-release] AID - S1098-3600(21)02539-9 [pii] AID - 979 [pii] AID - 10.1038/s41436-020-00979-w [doi] PST - ppublish SO - Genet Med. 2021 Feb;23(2):341-351. doi: 10.1038/s41436-020-00979-w. Epub 2020 Oct 7.