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Bi-allelic loss-of-function variants inKIF21Acause severe fetal akinesia with arthrogryposis multiplex

Authors :
Alma Kuechler
Wolfram Klein
Ruth Falb
Tilman Heinrich
Susanne Haen
Amelie J. Müller
Natalia Prodan
Eva M. C. Schwaibold
Andreas Dufke
Marc Sturm
Nina Hirt
Mona Grimmel
Markus Hoopmann
Ulrich Gembruch
Petra Stöbe
Dirk Emmerich
Silke Hartmann
Stephan Waldmüller
Ute Grasshoff
Glen Kristiansen
Olga Kelemen
Armin Neumann
Darja Gauck
Dieter Gläser
Karl Oliver Kagan
Tobias B. Haack
Rebecca Buchert
Stefanie Beck-Wödl
Nicola Dikow
Christoph Schmidt
Ismail Tekesin
Sabine Hentze
Denise Horn
Olaf Riess
Martin Kehrer
Joohyun Park
Stephan Ossowski
Felix Distelmaier
Stephanie Spranger
Reiner Siebert
Luisa Averdunk
Source :
Journal of Medical Genetics. 60:48-56
Publication Year :
2021
Publisher :
BMJ, 2021.

Abstract

BackgroundFetal 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.MethodsWe performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature.ResultsWe 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.ConclusionOur 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.<br />publishedVersion

Details

ISSN :
14686244 and 00222593
Volume :
60
Database :
OpenAIRE
Journal :
Journal of Medical Genetics
Accession number :
edsair.doi.dedup.....6fc67063fced297732b175a2a131ead1