Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features

J Med Genet. 2018 Jun;55(6):408-414. doi: 10.1136/jmedgenet-2017-105172. Epub 2018 Mar 1.


Background: Ichthyosis and neurological involvement occur in relatively few known Mendelian disorders caused by mutations in genes relevant both for epidermis and neural function.

Objectives: To identify the cause of a similar phenotype of ichthyotic keratoderma, spasticity, mild hypomyelination (on MRI) and dysmorphic features (IKSHD) observed in two unrelated paediatric probands without family history of disease.

Methods: Whole exome sequencing was performed in both patients. The functional effect of prioritised variant in ELOVL1 (very-long-chain fatty acids (VLCFAs) elongase) was analysed by VLCFA profiling by gas chromatography-mass spectrometry in stably transfected HEK2932 cells and in cultured patient's fibroblasts.

Results: Probands shared novel heterozygous ELOVL1 p.Ser165Phe mutation (de novo in one family, while in the other family, father could not be tested). In transfected cells p.Ser165Phe: (1) reduced levels of FAs C24:0-C28:0 and C26:1 with the most pronounced effect for C26:0 (P=7.8×10-6 vs HEK293 cells with wild type (wt) construct, no difference vs naïve HEK293) and (2) increased levels of C20:0 and C22:0 (P=6.3×10-7, P=1.2×10-5, for C20:0 and C22:0, respectively, comparison vs HEK293 cells with wt construct; P=2.2×10-7, P=1.9×10-4, respectively, comparison vs naïve HEK293). In skin fibroblasts, there was decrease of C26:1 (P=0.014), C28:0 (P=0.001) and increase of C20:0 (P=0.033) in the patient versus controls. There was a strong correlation (r=0.92, P=0.008) between the FAs profile of patient's fibroblasts and that of p.Ser165Phe transfected HEK293 cells. Serum levels of C20:0-C26:0 FAs were normal, but the C24:0/C22:0 ratio was decreased.

Conclusion: The ELOVL1 p.Ser165Phe mutation is a likely cause of IKSHD.

Keywords: ELOVL1; VLCFA; de novo mutation; neurological disease; skin disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / genetics*
  • Adolescent
  • Body Dysmorphic Disorders / complications
  • Body Dysmorphic Disorders / diagnostic imaging
  • Body Dysmorphic Disorders / genetics*
  • Body Dysmorphic Disorders / physiopathology
  • Child
  • Child, Preschool
  • Exome Sequencing
  • Fatty Acid Elongases
  • HEK293 Cells
  • Humans
  • Ichthyosis / complications
  • Ichthyosis / diagnostic imaging
  • Ichthyosis / genetics*
  • Ichthyosis / physiopathology
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Mutation
  • Nervous System Diseases / complications
  • Nervous System Diseases / diagnostic imaging
  • Nervous System Diseases / genetics*
  • Nervous System Diseases / physiopathology


  • ELOVL1 protein, human
  • Acetyltransferases
  • Fatty Acid Elongases