RT Journal Article
SR Electronic
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
FD BMJ Publishing Group Ltd
SP jmedgenet-2021-108064
DO 10.1136/jmedgenet-2021-108064
A1 Falb, Ruth J
A1 Müller, Amelie J
A1 Klein, Wolfram
A1 Grimmel, Mona
A1 Grasshoff, Ute
A1 Spranger, Stephanie
A1 Stöbe, Petra
A1 Gauck, Darja
A1 Kuechler, Alma
A1 Dikow, Nicola
A1 Schwaibold, Eva M C
A1 Schmidt, Christoph
A1 Averdunk, Luisa
A1 Buchert, Rebecca
A1 Heinrich, Tilman
A1 Prodan, Natalia
A1 Park, Joohyun
A1 Kehrer, Martin
A1 Sturm, Marc
A1 Kelemen, Olga
A1 Hartmann, Silke
A1 Horn, Denise
A1 Emmerich, Dirk
A1 Hirt, Nina
A1 Neumann, Armin
A1 Kristiansen, Glen
A1 Gembruch, Ulrich
A1 Haen, Susanne
A1 Siebert, Reiner
A1 Hentze, Sabine
A1 Hoopmann, Markus
A1 Ossowski, Stephan
A1 Waldmüller, Stephan
A1 Beck-Wödl, Stefanie
A1 Gläser, Dieter
A1 Tekesin, Ismail
A1 Distelmaier, Felix
A1 Riess, Olaf
A1 Kagan, Karl-Oliver
A1 Dufke, Andreas
A1 Haack, Tobias B
YR 2021
UL http://jmg.bmj.com/content/early/2021/12/05/jmedgenet-2021-108064.abstract
AB 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.