Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa

Am J Hum Genet. 2016 Jul 7;99(1):236-45. doi: 10.1016/j.ajhg.2016.05.026.


Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) is a very rare autosomal-recessive disorder characterized by a complex phenotype with high neonatal lethality, associated with the following main clinical features: hyperthermia and feeding difficulties in the neonatal period, scoliosis, and paradoxical sweating induced by cold since early childhood. CS/CISS1 can be caused by mutations in cytokine receptor-like factor 1 (CRLF1). However, the physiopathological role of CRLF1 is still poorly understood. A subset of CS/CISS1 cases remain yet genetically unexplained after CRLF1 sequencing. In five of them, exome sequencing and targeted Sanger sequencing identified four homozygous disease-causing mutations in kelch-like family member 7 (KLHL7), affecting the Kelch domains of the protein. KLHL7 encodes a BTB-Kelch-related protein involved in the ubiquitination of target proteins for proteasome-mediated degradation. Mono-allelic substitutions in other domains of KLHL7 have been reported in three families affected by a late-onset form of autosomal-dominant retinitis pigmentosa. Retinitis pigmentosa was also present in two surviving children reported here carrying bi-allelic KLHL7 mutations. KLHL7 mutations are thus associated with a more severe phenotype in recessive than in dominant cases. Although these data further support the pathogenic role of KLHL7 mutations in a CS/CISS1-like phenotype, they do not explain all their clinical manifestations and highlight the high phenotypic heterogeneity associated with mutations in KLHL7.

Publication types

  • Case Reports

MeSH terms

  • Alleles*
  • Amino Acid Sequence
  • Autoantigens / chemistry
  • Autoantigens / genetics*
  • Child
  • Child, Preschool
  • Death, Sudden
  • Facies
  • Female
  • Hand Deformities, Congenital / complications*
  • Hand Deformities, Congenital / genetics*
  • Humans
  • Hyperhidrosis / complications*
  • Hyperhidrosis / genetics*
  • Infant
  • Male
  • Models, Molecular
  • Mutation*
  • Pedigree
  • Phenotype
  • Retinitis Pigmentosa / complications*
  • Retinitis Pigmentosa / genetics*
  • Syndrome
  • Trismus / complications
  • Trismus / congenital*
  • Trismus / genetics


  • Autoantigens
  • KLHL7 protein, human

Supplementary concepts

  • Crisponi syndrome