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 Ruth J Falb
A1 Amelie J Müller
A1 Wolfram Klein
A1 Mona Grimmel
A1 Ute Grasshoff
A1 Stephanie Spranger
A1 Petra Stöbe
A1 Darja Gauck
A1 Alma Kuechler
A1 Nicola Dikow
A1 Eva M C Schwaibold
A1 Christoph Schmidt
A1 Luisa Averdunk
A1 Rebecca Buchert
A1 Tilman Heinrich
A1 Natalia Prodan
A1 Joohyun Park
A1 Martin Kehrer
A1 Marc Sturm
A1 Olga Kelemen
A1 Silke Hartmann
A1 Denise Horn
A1 Dirk Emmerich
A1 Nina Hirt
A1 Armin Neumann
A1 Glen Kristiansen
A1 Ulrich Gembruch
A1 Susanne Haen
A1 Reiner Siebert
A1 Sabine Hentze
A1 Markus Hoopmann
A1 Stephan Ossowski
A1 Stephan Waldmüller
A1 Stefanie Beck-Wödl
A1 Dieter Gläser
A1 Ismail Tekesin
A1 Felix Distelmaier
A1 Olaf Riess
A1 Karl-Oliver Kagan
A1 Andreas Dufke
A1 Tobias B Haack
YR 2021
UL http://jmg.bmj.com/content/early/2022/07/04/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. 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….