PT  - JOURNAL ARTICLE
AU  - Anna Kutkowska-Kaźmierczak
AU  - Małgorzata Rydzanicz
AU  - Aleksander Chlebowski
AU  - Kamila Kłosowska-Kosicka
AU  - Adriana Mika
AU  - Jakub Gruchota
AU  - Elżbieta Jurkiewicz
AU  - Cezary Kowalewski
AU  - Agnieszka Pollak
AU  - Teresa Joanna Stradomska
AU  - Tomasz Kmieć
AU  - Rafał Jakubowski
AU  - Piotr Gasperowicz
AU  - Anna Walczak
AU  - Dariusz Śladowski
AU  - Ewa Jankowska-Steifer
AU  - Lech Korniszewski
AU  - Joanna Kosińska
AU  - Ewa Obersztyn
AU  - Wieslaw Nowak
AU  - Tomasz Śledziński
AU  - Andrzej Dziembowski
AU  - Rafał Płoski
TI  - Dominant <em>ELOVL1</em> mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features
AID  - 10.1136/jmedgenet-2017-105172
DP  - 2018 Mar 01
TA  - Journal of Medical Genetics
PG  - jmedgenet-2017-105172
4099  - http://jmg.bmj.com/content/early/2018/03/01/jmedgenet-2017-105172.short
4100  - http://jmg.bmj.com/content/early/2018/03/01/jmedgenet-2017-105172.full
AB  - 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.