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