PT  - JOURNAL ARTICLE
AU  - Falb, Ruth J
AU  - Müller, Amelie J
AU  - Klein, Wolfram
AU  - Grimmel, Mona
AU  - Grasshoff, Ute
AU  - Spranger, Stephanie
AU  - Stöbe, Petra
AU  - Gauck, Darja
AU  - Kuechler, Alma
AU  - Dikow, Nicola
AU  - Schwaibold, Eva M C
AU  - Schmidt, Christoph
AU  - Averdunk, Luisa
AU  - Buchert, Rebecca
AU  - Heinrich, Tilman
AU  - Prodan, Natalia
AU  - Park, Joohyun
AU  - Kehrer, Martin
AU  - Sturm, Marc
AU  - Kelemen, Olga
AU  - Hartmann, Silke
AU  - Horn, Denise
AU  - Emmerich, Dirk
AU  - Hirt, Nina
AU  - Neumann, Armin
AU  - Kristiansen, Glen
AU  - Gembruch, Ulrich
AU  - Haen, Susanne
AU  - Siebert, Reiner
AU  - Hentze, Sabine
AU  - Hoopmann, Markus
AU  - Ossowski, Stephan
AU  - Waldmüller, Stephan
AU  - Beck-Wödl, Stefanie
AU  - Gläser, Dieter
AU  - Tekesin, Ismail
AU  - Distelmaier, Felix
AU  - Riess, Olaf
AU  - Kagan, Karl-Oliver
AU  - Dufke, Andreas
AU  - Haack, Tobias B
TI  - Bi-allelic loss-of-function variants in <em>KIF21A</em> cause severe fetal akinesia with arthrogryposis multiplex
AID  - 10.1136/jmedgenet-2021-108064
DP  - 2023 Jan 01
TA  - Journal of Medical Genetics
PG  - 48--56
VI  - 60
IP  - 1
4099  - http://jmg.bmj.com/content/60/1/48.short
4100  - http://jmg.bmj.com/content/60/1/48.full
SO  - J Med Genet2023 Jan 01; 60
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. 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….