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.

This work examines the impact of energy over-minimization on an ensemble of biological molecules subjected to the potential energy minimization procedure in vacuum. In the studied structures, long potential energy minimization stage leads to an increase of the main- and side-chain entropies in proteins. We show that such over-minimization may diverge the protein structures from the near-native attraction basin which possesses a minimum of free energy. We propose a measure based on the Pareto front of total entropy for quality assessment of minimized protein conformation. This measure may help in selection of adequate number of energy minimization steps in protein modelling and, thus, in preservation of the near-native protein conformation.