Very long‐chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt‐like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single‐nucleotide variants.
We performed clinical exome sequencing on probands from four unrelated families with neuro‐ichthyosis.
We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three.
ELOVL4‐related ichthyosis, spastic quadriplegia and mental retardation (ISQMR) is a rare autosomal recessive disorders characterized by ichthyosis with neurological features. Only five families with ISQMR with biallelic single‐nucleotide variants have been described date and no families with copy number variants (CNVs) have been described. We include four new families with ISQMR, including two that carry a biallelic CNV and originate from the same tribe suggesting a tribal founder variant.