1. The genomic and clinical landscape of fetal akinesia
- Author
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Eva Maria Christina Schwaibold, Katharina Schoner, Harald von Pein, Haluk Topaloglu, Harald Ehrhardt, Goknur Haliloglu, Raoul Heller, Haicui Wang, Mona Kreutzer, Mireille Cossée, Andreas Hahn, Slavica Ostojic, Anne Schänzer, Cho-Ming Chao, Mert Karakaya, Özgür Duman, Janine Altmüller, Nursel Elcioglu, Susanne Motameny, Hülya-Sevcan Daimagüler, Holger Thiele, Anne Koy, Özkan Özdemir, Sebahattin Cirak, Marion Imbert-Bouteille, Kerstin Becker, Amit Kawalia, Jens Reimann, Peter Nürnberg, Matthias Pergande, Jens H. Westhoff, Center for Molecular Medicine [Cologne] (CMMC), University of Cologne, Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine, University of Cologne, Cologne Center for Genomics [Cologne] (CCG), University Hospital of Cologne [Cologne], Institute of Human Genetics [Cologne], Universitätsklinikum Köln (Uniklinik Köln)-University of Cologne, Justus-Liebig-Universität Gießen (JLU), Marmara University [Kadıköy - İstanbul], Eastern Mediterranean University (EMU), Mother and Child Health Care Institute of Serbia [Belgrade, Serbia] (MCHCI), Akdeniz University, Rheinische Friedrich-Wilhelms-Universität Bonn, Philipps University of Marburg, Department of Neurology, Justus-Liebig-University, University Children's Hospital of Heidelberg [Heidelberg, Germany], Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, University Medical Center of the Johannes Gutenberg-University Mainz, Hacettepe University Children's Hospital, Genetic Health Service New Zealand, Faculty of Medicine [Cologne], University Hospital of Cologne [Cologne]-University of Cologne, Pergande, Matthias, Motameny, Susanne, Oezdemir, Oezkan, Kreutzer, Mona, Wang, Haicui, Daimagueler, Huelya-Sevcan, Becker, Kerstin, Karakaya, Mert, Ehrhardt, Harald, Elcioglu, Nursel, Ostojic, Slavica, Chao, Cho-Ming, Kawalia, Amit, Duman, Ozgur, Koy, Anne, Hahn, Andreas, Reimann, Jens, Schoner, Katharina, Schaenzer, Anne, Westhoff, Jens H., Schwaibold, Eva Maria Christina, Cossee, Mireille, Imbert-Bouteille, Marion, von Pein, Harald, Haliloglu, Goknur, Topaloglu, Haluk, Altmueller, Janine, Nuernberg, Peter, Thiele, Holger, Heller, Raoul, and Cirak, Sebahattin
- Subjects
Male ,Candidate gene ,Myopathy ,VARIANTS ,Fetal akinesia ,MESH: Ryanodine Receptor Calcium Release Channel ,0302 clinical medicine ,MESH: Child ,Guanine Nucleotide Exchange Factors ,MESH: Guanine Nucleotide Exchange Factors ,Exome ,Copy-number variation ,Child ,MESH: High-Throughput Nucleotide Sequencing ,Genetics (clinical) ,Genetics ,Arthrogryposis ,0303 health sciences ,MESH: Infant, Newborn ,MESH: Genetic Predisposition to Disease ,High-Throughput Nucleotide Sequencing ,RNA-Binding Proteins ,MESH: Infant ,3. Good health ,Fetal Diseases ,MESH: Fetal Diseases ,MESH: Young Adult ,Child, Preschool ,ASAH1 ,Female ,MESH: DNA Copy Number Variations ,medicine.symptom ,Adult ,GENETICS ,Adolescent ,DNA Copy Number Variations ,MESH: Trans-Activators ,MESH: Arthrogryposis ,Biology ,ASPM ,Young Adult ,03 medical and health sciences ,Muscular Diseases ,medicine ,Humans ,Genetic Predisposition to Disease ,Gene ,030304 developmental biology ,MESH: Adolescent ,[SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics ,MESH: Humans ,MUTATIONS ,MESH: Child, Preschool ,Infant, Newborn ,MESH: Muscular Diseases ,Infant ,NEMALINE MYOPATHY ,Ryanodine Receptor Calcium Release Channel ,MESH: Adult ,medicine.disease ,Congenital myopathy ,MESH: Male ,MESH: RNA-Binding Proteins ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,DISTAL ARTHROGRYPOSIS ,Trans-Activators ,MESH: Female ,030217 neurology & neurosurgery - Abstract
International audience; 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.
- Published
- 2020