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

J Med Genet. 2017 Dec;54(12):830-835. doi: 10.1136/jmedgenet-2017-104748. Epub 2017 Oct 26.


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.

Keywords: Bohring-Opitz like syndrome; klhl7; whole exome sequencing.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantigens / genetics*
  • Brain / abnormalities
  • Brain / diagnostic imaging
  • Child, Preschool
  • Craniosynostoses / diagnosis*
  • Craniosynostoses / genetics*
  • Facies
  • Female
  • Genes, Recessive*
  • Genetic Association Studies
  • Humans
  • Infant
  • Intellectual Disability / diagnosis*
  • Intellectual Disability / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Mutation*
  • Phenotype*
  • Young Adult


  • Autoantigens
  • KLHL7 protein, human

Supplementary concepts

  • Bohring syndrome