The genomic and clinical landscape of fetal akinesia

6533b85bfe1ef96bd12bb66f

RESEARCH PRODUCT

The genomic and clinical landscape of fetal akinesia

Eva Maria Christina Schwaibold Katharina Schoner Harald Von Pein Haluk Topaloglu Harald Ehrhardt Goknur Haliloglu Raoul Heller 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 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

subject

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 Exome MESH: High-Throughput Nucleotide Sequencing Genetics (clinical)Genetics Arthrogryposis 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 Copy-number variation 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

description

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.

year	journal	country	edition	language
2020-03-01

10.1038/s41436-019-0680-1 https://hal.umontpellier.fr/hal-03376439