@article {Falbjmedgenet-2021-108064, author = {Ruth J Falb and Amelie J M{\"u}ller and Wolfram Klein and Mona Grimmel and Ute Grasshoff and Stephanie Spranger and Petra St{\"o}be and Darja Gauck and Alma Kuechler and Nicola Dikow and Eva M C Schwaibold and Christoph Schmidt and Luisa Averdunk and Rebecca Buchert and Tilman Heinrich and Natalia Prodan and Joohyun Park and Martin Kehrer and Marc Sturm and Olga Kelemen and Silke Hartmann and Denise Horn and Dirk Emmerich and Nina Hirt and Armin Neumann and Glen Kristiansen and Ulrich Gembruch and Susanne Haen and Reiner Siebert and Sabine Hentze and Markus Hoopmann and Stephan Ossowski and Stephan Waldm{\"u}ller and Stefanie Beck-W{\"o}dl and Dieter Gl{\"a}ser and Ismail Tekesin and Felix Distelmaier and Olaf Riess and Karl-Oliver Kagan and Andreas Dufke and Tobias B Haack}, title = {Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex}, elocation-id = {jmedgenet-2021-108064}, year = {2021}, doi = {10.1136/jmedgenet-2021-108064}, publisher = {BMJ Publishing Group Ltd}, abstract = {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{\textendash}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 T{\"u}bingen, including VCV{\textellipsis} through VCV{\textellipsis}.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/early/2022/07/04/jmedgenet-2021-108064}, eprint = {https://jmg.bmj.com/content/early/2022/07/04/jmedgenet-2021-108064.full.pdf}, journal = {Journal of Medical Genetics} }