Expanding the allelic spectrum of ELOVL4‐related autosomal recessive neuro‐ichthyosis

• Published in: Molecular genetics & genomic medicine Vol. 11; no. 12; pp. e2256 - n/a
• Main Authors: Alabdulrazzaq, Fatima, Alanzi, Talal, Al‐Balool, Haya H., Gardham, Alice, Wakeling, Emma, Leitch, Harry G., AlSayed, Moeenaldeen, Abdulrahim, Maha, Aladwani, Abdulaziz, Romito, Antonio, Kampe, Kapil, Ferdinandusse, Sacha, Aboelanine, Ashraf H., Abdullah, Amira, Alwadani, Amal, Bastaki, Laila, Vaz, Frédéric M., Bertoli‐Avella, Aida M., Marafi, Dana
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-12-2023; John Wiley and Sons Inc; Wiley
• Subjects: Ataxia; Atrophy; autosomal recessive; Biosynthesis; Brain; Carbon; Cell membranes; Congenital diseases; copy number variant; Corpus callosum; Cyanosis; Dystrophy; ELOVL4; Epilepsy; Families & family life; Fatty acids; Gastroesophageal reflux; Gene deletion; Genes; Genetic testing; Genomes; Hereditary diseases; Hypoplasia; Hypotonia; Ichthyosis; Intellectual development; Machado-Joseph disease; Mitochondrial DNA; Myelination; Neuroimaging; neuro‐ichthyosis; Nucleotides; Original; Skin diseases; Ultrasonic imaging; copy number variant; neuro-ichthyosis; ELOVL4; autosomal recessive
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.2256

Background
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.
Methods
We performed clinical exome sequencing on probands from four unrelated families with neuro‐ichthyosis.
Results
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.
Conclusion
Our study expands the allelic spectrum of ELOVL4‐related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation.
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.