The genomic and clinical landscape of fetal akinesia

Item Type:	Article
Title:	The genomic and clinical landscape of fetal akinesia
Creators Name:	Pergande, M. and Motameny, S. and Özdemir, Ö. and Kreutzer, M. and Wang, H. and Daimagüler, H.S. and Becker, K. and Karakaya, M. and Ehrhardt, H. and Elcioglu, N. and Ostojic, S. and Chao, C.M. and Kawalia, A. and Duman, Ö. and Koy, A. and Hahn, A. and Reimann, J. and Schoner, K. and Schänzer, A. and Westhoff, J.H. and Schwaibold, E.M.C. and Cossee, M. and Imbert-Bouteille, M. and von Pein, H. and Haliloglu, G. and Topaloglu, H. and Altmüller, J. and Nürnberg, P. and Thiele, H. and Heller, R. and Cirak, S.
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.
Keywords:	Fetal Akinesia, Arthrogryposis, Myopathy, Exome, Copy-Number Variation
Source:	Genetics in Medicine
ISSN:	1098-3600
Publisher:	Nature Publishing Group
Volume:	22
Number:	3
Page Range:	511-523
Date:	March 2020
Additional Information:	Erratum in: Genet Med 22(8): 1426-1428.
Official Publication:	https://doi.org/10.1038/s41436-019-0680-1
PubMed:	View item in PubMed

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