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Expanding the clinical spectrum of recessive truncating mutations of KLHL7 to a Bohring-Opitz-like phenotype
  1. Ange-Line Bruel1,2,
  2. Stefania Bigoni3,4,
  3. Joanna Kennedy5,6,
  4. Margo Whiteford7,
  5. Chris Buxton8,
  6. Giulia Parmeggiani3,4,
  7. Matt Wherlock8,
  8. Geoff Woodward8,
  9. Mark Greenslade8,
  10. Maggie Williams8,
  11. Judith St-Onge9,
  12. Alessandra Ferlini3,4,
  13. Giampaolo Garani10,
  14. Elisa Ballardini10,
  15. Bregje W van Bon11,
  16. Rocio Acuna-Hidalgo11,
  17. Axel Bohring12,
  18. Jean-François Deleuze13,
  19. Anne Boland13,
  20. Vincent Meyer13,
  21. Robert Olaso13,
  22. Emmanuelle Ginglinger14,
  23. DDD Study15,
  24. Jean-Baptiste Rivière9,
  25. Han G Brunner11,
  26. Alexander Hoischen11,
  27. Ruth Newbury-Ecob5,6,
  28. Laurence Faivre1,2,
  29. Christel Thauvin-Robinet1,2,
  30. Julien Thevenon1,2,16
  1. 1 Inserm UMR 1231 GAD Team, Genetics of Developmental Anomalies, Université de Bourgogne-Franche Comté, Dijon, France
  2. 2 FHU-TRANSLAD, Université de Bourgogne/CHU, Dijon, France
  3. 3 Department of Reproduction and Growth, UOL of Medical Genetics, University Hospital St Anna, Ferrara, Italy
  4. 4 Department of Medical Science, UOL of Medical Genetics, University Hospital St Anna, Ferrara, Italy
  5. 5 Clinical Genetics Department, University Hospitals Bristol NHS Foundation Trust, St Michael’s Hospital, Bristol, UK
  6. 6 University of Bristol, Glasgow, UK
  7. 7 Department of Clinical Genetics, Queen Elizabeth University Hospital, Glasgow, UK
  8. 8 Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK
  9. 9 Department of Human Genetics, McGill University Health Centre, Montreal, Canada
  10. 10 Department of Reproduction and Growth, Neonatal Intensive Care Unit, University Hospital St Anna, Ferrara, Italy
  11. 11 Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
  12. 12 Institute of Human Genetics, Westfälische Wilhelms-Universität Münster, Münster, Germany
  13. 13 Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, Évry, France
  14. 14 Service de Génétique, Centre Hospitalier de Mulhouse, Mulhouse, Alsace, France
  15. 15 Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  16. 16 Centre de Génétique, Hôpital Couple Enfant, CHU de Grenoble Alpes, La Tronche, France
  1. Correspondence to Ange-Line Bruel, Genetics of Developmental Disorders, Bât B3, Université de Bourgogne-Franche Comté, Dijon 21070, France; ange-line.bruel{at} and Dr Julien Thevenon, Centre de génétique, Hôpital Couple-Enfant, CHU de Grenoble-Alpes, Avenue Maquis du Grésivaudan, La Tronche 38700, France; jthevenon{at}


Background Bohring-Opitz syndrome (BOS) is a rare genetic disorder characterised by a recognisable craniofacial appearance and a typical ‘BOS’ posture. BOS is caused by sporadic mutations ofASXL1. However, several typical patients with BOS have no molecular diagnosis, suggesting clinical and genetic heterogeneity.

Objectives To expand the phenotypical spectrum of autosomal recessive variants of KLHL7, reported as causing Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like syndrome.

Methods We performed whole-exome sequencing in two families with a suspected recessive mode of inheritance. We used the Matchmaker Exchange initiative to identify additional patients.

Results Here, we report six patients with microcephaly, facial dysmorphism, including exophthalmos, nevus flammeus of the glabella and joint contractures with a suspected BOS posture in five out of six patients. We identified autosomal recessive truncating mutations in the KLHL7 gene. KLHL7 encodes a BTB–kelch protein implicated in the cell cycle and in protein degradation by the ubiquitin–proteasome pathway. Recently, biallelic mutations in the KLHL7 gene were reported in four families and associated with CS/CISS1, characterised by clinical features overlapping with our patients.

Conclusion We have expanded the clinical spectrum of KLHL7 autosomal recessive variants by describing a syndrome with features overlapping CS/CISS1 and BOS.

  • Bohring-Opitz like syndrome
  • klhl7
  • whole exome sequencing

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  • A-LB, SB and JK contributed equally.

  • Contributors JK, SB, CB, JT, GP, AF, MWhi, MWhe, MG, MWi, GG, EB, BWvB, RA-H, CT-R, ABoh, HGB, AH, RN-E and LF ascertained the families. JT, J-BR, J-FD, ABol, VM and RO performed the bioinformatics analysis of the data. A-LB, JT, SB, CB, JS-O and JK carried out the molecular analysis and interpreted the results. All of the authors participated in writing and reviewing the manuscript.

  • Funding We thank the TRANSLAD and the Regional Council of Burgundy for their support (PARI2015).

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

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