Matthias Pergande1,2, Susanne Motameny3, Özkan Özdemir1,2, Mona Kreutzer1,2, Haicui Wang1,2, Hülya-Sevcan Daimagüler1,2, Kerstin Becker1,2, Mert Karakaya1,4, Harald Ehrhardt5, Nursel Elcioglu6,7, Slavica Ostojic8, Cho-Ming Chao5, Amit Kawalia3, Özgür Duman9, Anne Koy2, Andreas Hahn10, Jens Reimann11, Katharina Schoner12, Anne Schänzer13, Jens H Westhoff14, Eva Maria Christina Schwaibold15, Mireille Cossee16, Marion Imbert-Bouteille17, Harald von Pein18, Göknur Haliloglu19, Haluk Topaloglu19, Janine Altmüller1,3, Peter Nürnberg1,3, Holger Thiele3, Raoul Heller4,20,21, Sebahattin Cirak22,23,24. 1. University of Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany. 2. University of Cologne, University Hospital Cologne and Faculty of Medicine, Department of Pediatrics, Cologne, Germany. 3. University of Cologne, Cologne Center for Genomics CCG, Cologne, Germany. 4. University of Cologne, University Hospital Cologne, Institute of Human Genetics, Cologne, Germany. 5. Department of General Pediatrics and Neonatology, Justus-Liebig-University, Gießen, Germany. 6. Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey. 7. Eastern Mediterranean University Medical School, Mersin, Turkey. 8. Department of Neurology, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", Belgrade, Serbia. 9. Department of Pediatric Neurology, Akdeniz University Hospital, Antalya, Turkey. 10. Department of Pediatric Neurology, Social Pediatrics and Epileptology, Justus-Liebig-University, Gießen, Germany. 11. Department of Neurology, Rheinische Friedrich-Wilhelms-University, Bonn, Germany. 12. Institute of Pathology, Philipps University of Marburg, Marburg, Germany. 13. Institute of Neuropathology, Justus-Liebig-University, Gießen, Germany. 14. Heidelberg University, University Children's Hospital Heidelberg, Department of Pediatrics, Heidelberg, Germany. 15. Institute of Human Genetics, Heidelberg University, Institute of Human Genetics, Heidelberg, Germany. 16. University of Montpellier, University Hospital of Montpellier, Molecular Diagnostic Laboratory, Montpellier, France. 17. University of Montpellier, University Hospital of Montpellier, Medical Genetics Department, Montpellier, France. 18. Johannes-Gutenberg University Mainz, University Medical Center Mainz, Institute of Neuropathology, Mainz, Germany. 19. Hacettepe University, Children's Hospital, Department of Pediatric Neurology, Ankara, Turkey. 20. Genetic Health Service NZ-Northern Hub, Auckland City Hospital, Auckland, New Zealand. 21. University of Cologne, Center for Rare Diseases Cologne (ZSEK), Cologne, Germany. 22. University of Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany. sebahattin.cirak@uk-koeln.de. 23. University of Cologne, University Hospital Cologne and Faculty of Medicine, Department of Pediatrics, Cologne, Germany. sebahattin.cirak@uk-koeln.de. 24. University of Cologne, Center for Rare Diseases Cologne (ZSEK), Cologne, Germany. sebahattin.cirak@uk-koeln.de.
Abstract
PURPOSE: Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood. METHODS: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA). RESULTS: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant in TNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis. CONCLUSION: Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.
PURPOSE: Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood. METHODS: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA). RESULTS: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant in TNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis. CONCLUSION: Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.
Authors: Miriam Potrony; Antoni Borrell; Narcís Masoller; Alfons Nadal; Leonardo Rodriguez-Carunchio; Karmele Saez de Gordoa Elizalde; Juan Francisco Quesada-Espinosa; Jose Luis Villanueva-Cañas; Montse Pauta; Meritxell Jodar; Irene Madrigal; Celia Badenas; Maria Isabel Alvarez-Mora; Laia Rodriguez-Revenga Journal: J Clin Med Date: 2022-06-21 Impact factor: 4.964
Authors: Tanya Lehky; Reversa Joseph; Camilo Toro; Tianxia Wu; Carol Van Ryzin; Andrea Gropman; Flavia M Facio; Bryn D Webb; Ethylin W Jabs; Brenda S Barry; Elizabeth C Engle; Francis S Collins; Irini Manoli Journal: Muscle Nerve Date: 2021-01-19 Impact factor: 3.217
Authors: Xenia Latypova; Stefan Giovanni Creadore; Noémi Dahan-Oliel; Anxhela Gjyshi Gustafson; Steven Wei-Hung Hwang; Tanya Bedard; Kamran Shazand; Harold J P van Bosse; Philip F Giampietro; Klaus Dieterich Journal: Genes (Basel) Date: 2021-07-08 Impact factor: 4.096