Expanding the clinical spectrum of recessive truncating mutations of KLHL7 to a Bohring-Opitz-like phenotype

Ange-Line Bruel*, Stefania Bigoni, Joanna Kennedy, Margo Whiteford, Chris Buxton, Giulia Parmeggiani, Matt Wherlock, Geoff Woodward, Mark Greenslade, Maggie Williams, Judith St-Onge, Alessandra Ferlini, Giampaolo Garani, Elisa Ballardini, Bregje W. van Bon, Rocio Acuna-Hidalgo, Axel Bohring, Jean-Francois Deleuze, Anne Boland, Vincent MeyerRobert Olaso, Emmanuelle Ginglinger, Jean-Baptiste Riviere, Han G. Brunner, Alexander Hoischen, Ruth Newbury-Ecob, Laurence Faivre, Christel Thauvin-Robinet, Julien Thevenon*, DDD Study

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 of ASXL1. 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.

Original languageEnglish
Pages (from-to)830-835
Number of pages6
JournalJournal of Medical Genetics
Issue number12
Publication statusPublished - Dec 2017




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