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Original research
Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex
  1. Ruth J Falb1,
  2. Amelie J Müller1,
  3. Wolfram Klein2,
  4. Mona Grimmel1,
  5. Ute Grasshoff1,
  6. Stephanie Spranger3,
  7. Petra Stöbe1,
  8. Darja Gauck1,
  9. Alma Kuechler4,
  10. Nicola Dikow5,
  11. Eva M C Schwaibold5,
  12. Christoph Schmidt6,
  13. Luisa Averdunk7,
  14. Rebecca Buchert1,
  15. Tilman Heinrich1,
  16. Natalia Prodan8,
  17. Joohyun Park1,
  18. Martin Kehrer1,
  19. Marc Sturm1,
  20. Olga Kelemen1,
  21. Silke Hartmann6,
  22. Denise Horn9,
  23. Dirk Emmerich10,
  24. Nina Hirt11,
  25. Armin Neumann12,
  26. Glen Kristiansen13,
  27. Ulrich Gembruch14,
  28. Susanne Haen15,
  29. Reiner Siebert16,
  30. Sabine Hentze17,
  31. Markus Hoopmann8,
  32. Stephan Ossowski1,
  33. Stephan Waldmüller1,
  34. Stefanie Beck-Wödl1,
  35. Dieter Gläser6,
  36. Ismail Tekesin18,
  37. Felix Distelmaier7,
  38. Olaf Riess1,19,
  39. Karl-Oliver Kagan8,
  40. Andreas Dufke1,19,
  41. Tobias B Haack1,19
  1. 1Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
  2. 2genetikum Stuttgart, Stuttgart, Germany
  3. 3Practice of Human Genetics, Bremen, Germany
  4. 4Institute of Human Genetics, University Hospital Essen, Essen, Germany
  5. 5Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
  6. 6genetikum Neu-Ulm, Neu-Ulm, Germany
  7. 7Department of General Pediatrics, Neonatology and Pediatric Cardiology, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany
  8. 8Department of Women's Health, University Women's Hospital, Tuebingen, Germany
  9. 9Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany
  10. 10Practice for Ultrasound and Prenatal Medicine, Freiburg, Germany
  11. 11Institute of Human Genetics, University Medical Center Freiburg, Freiburg, Germany
  12. 12Practice for Prenatal Medicine, Bremen, Germany
  13. 13Institute of Pathology, Center for Integrated Oncology, University of Bonn, Bonn, Germany
  14. 14Department of Obstetrics and Prenatal Medicine, University Hospital Bonn, Bonn, Germany
  15. 15Institute of Pathology and Neuropathology, University of Tuebingen, Tuebingen, Germany
  16. 16Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany
  17. 17Practice for Human Genetics, Heidelberg, Germany
  18. 18Prenatal Medicine Stuttgart, Stuttgart, Germany
  19. 19Centre for Rare Diseases, University of Tuebingen, Tuebingen, Germany
  1. Correspondence to Dr Amelie J Müller; Amelie.Mueller{at}med.uni-tuebingen.de

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–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.

  • nervous system diseases
  • neuromuscular diseases

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • RJF and AJM contributed equally.

  • Contributors Conceptualisation—RF, AM and TBH. Data curation—RF, AM, MG and MS. Investigation—RF, AM, WK, MG, SS, PS, DG, AK, ND, EMCS, LA, UGr, RB, TH, NP, JP, MK, SH, DH, DE, NH, AN, GK, UGe, SHa, RS, SHe, MH, SO, SW, SB-W, DG, IT, OR, FD, KK, AD and TBH. Methodology—CS and OK. Software—MS and SO. Supervision—TBH. Visualisation—RF and MG. Writing (original draft)—RF, AM and TBH. Writing (review and editing)—RF, AM, MG and TBH. TBH is responsible for the overall content as guarantor.

  • Funding TBH was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation: 418081722, 433158657).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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