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.
- skin disease
- neurological disease
- de novo mutation
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AK-K and MR contributed equally.
Contributors Conceptualisation: RP, MR and AK-K. Methodology: RP, WN, RJ, KK-K and JG. Software: WN and RJ. Validation: AP, PG and AW. Formal analysis: RP, TJS, WN, RJ, TS and AM. Investigation: RP, MR, AP, PG, AW, JK, TJS, WN, RJ, AC, KK, JG, TS, AM, DŚ, AK-K, EJ-S, EJ,CK, TK and EO. Resources: WN, RJ, DS and EJ. Writing: original draft preparation: RP, MR, TJS, AK-K and EJ. Writing: review and editing: RP, MR, TJS, WN, RJ, TS, AM, AK-K and EJ. Visualisation: RP, MR, WN, RJ and EJ. Supervision: RP and AD. Project administration: RP. Funding acquisition: RP and AD.
Funding The study was supported by the National Science Centre (NCN) Poland grant 2013/11/B/NZ7/04944 to RP. The work in the AD laboratory was supported by Foundation for Polish Science grant TEAM/2016-1/3. Some of the experiments were carried out with the use of CePT infrastructure (Innovative economy 2007–13, Agreement POIG.02.02.00-14-024/08-00). Calculations were possible due to ICNT UMK infrastructure. Support by Polish Ministry for Science and Higher Education Grant 0003/ID3/2016/64 (Ideas Plus II) is acknowledged (RJ).
Competing interests None declared.
Patient consent Guardian consent obtained.
Ethics approval The study protocol was approved by the Ethical Committee at Warsaw Medical University.
Provenance and peer review Not commissioned; externally peer reviewed.