TY - JOUR T1 - Bi-allelic loss-of-function variants in <em>KIF21A</em> cause severe fetal akinesia with arthrogryposis multiplex JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2021-108064 SP - jmedgenet-2021-108064 AU - Ruth J Falb AU - Amelie J Müller AU - Wolfram Klein AU - Mona Grimmel AU - Ute Grasshoff AU - Stephanie Spranger AU - Petra Stöbe AU - Darja Gauck AU - Alma Kuechler AU - Nicola Dikow AU - Eva M C Schwaibold AU - Christoph Schmidt AU - Luisa Averdunk AU - Rebecca Buchert AU - Tilman Heinrich AU - Natalia Prodan AU - Joohyun Park AU - Martin Kehrer AU - Marc Sturm AU - Olga Kelemen AU - Silke Hartmann AU - Denise Horn AU - Dirk Emmerich AU - Nina Hirt AU - Armin Neumann AU - Glen Kristiansen AU - Ulrich Gembruch AU - Susanne Haen AU - Reiner Siebert AU - Sabine Hentze AU - Markus Hoopmann AU - Stephan Ossowski AU - Stephan Waldmüller AU - Stefanie Beck-Wödl AU - Dieter Gläser AU - Ismail Tekesin AU - Felix Distelmaier AU - Olaf Riess AU - Karl-Oliver Kagan AU - Andreas Dufke AU - Tobias B Haack Y1 - 2021/11/05 UR - http://jmg.bmj.com/content/early/2022/05/02/jmedgenet-2021-108064.abstract N2 - Background Fetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We aimed to further define the set of genes involved.Methods We performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature.Results We identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in the kinesin family member 21A gene (KIF21A) was found.Conclusion Our study underlines the broad locus heterogeneity of FA with well-established and atypical genotype–phenotype associations. We describe KIF21A as a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets.Data are available upon reasonable request. All variants have been deposited into ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) under Institute of Medical Genetics and Applied Genomics, University of Tübingen, including VCV… through VCV…. ER -