| Verf.angabe: | Matthias Pergande MSc, Susanne Motameny, PhD, Özkan Özdemir, PhD, Mona Kreutzer, Haicui Wang, PhD, Hülya-Sevcan Daimagüler, MSc, Kerstin Becker, PhD, Mert Karakaya, MD, Harald Ehrhardt, MD, Nursel Elcioglu, MD, Prof, Slavica Ostojic, MD, Cho-Ming Chao, MD, PhD, Amit Kawalia, PhD, Özgür Duman, MD, Prof, Anne Koy, MD, Andreas Hahn, MD, Prof, Jens Reimann, MD, Katharina Schoner, MD, Anne Schänzer, MD, Jens H. Westhoff, MD, Eva Maria Christina Schwaibold, MD, Mireille Cossee, MD, Marion Imbert-Bouteille, MSc, Harald von Pein, MD, Göknur Haliloglu, MD, Prof, Haluk Topaloglu, MD, Prof, Janine Altmüller, MD, Peter Nürnberg, PhD, Prof, Holger Thiele, MD, Raoul Heller, MD, PhD and Sebahattin Cirak MD |
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| Abstract: | Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood. 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). 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. 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. |
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