Metachromatic Leukodystrophy in Morocco: Identification of Causative Variants by Next-Generation Sequencing (NGS)

• Published in: Genes 2024-11, Vol.15 (12), p.1515
• Main Authors: Hammoud, Miloud, Domínguez-Ruiz, María, Assiri, Imane, Rodrigues, Daniel, Aboussair, Nisrine, Lanza, Val F, Villarrubia, Jesús, Colón, Cristóbal, Fdil, Naima, Del Castillo, Francisco J
• Format: Article
• Language: English
• Subjects: Acids; Adult; Cerebroside-sulfatase; Cerebroside-Sulfatase - genetics; Child; Child, Preschool; Chromatography; Diagnosis; Enzymes; Female; Genes; High performance liquid chromatography; High-Throughput Nucleotide Sequencing - methods; Homozygotes; Hospitals; Humans; Leukodystrophy; Leukodystrophy, Metachromatic - diagnosis; Leukodystrophy, Metachromatic - genetics; Male; Mass spectrometry; Mass spectroscopy; Metabolism; Morocco; Mucolipidosis; Mutation; Next-generation sequencing; Pedigree; Phenotyping; Primary care; Rare diseases; Solvents; Sphingolipidoses; Thin-layer chromatography; Transferases (Other Substituted Phosphate Groups) - genetics
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes15121515

(1) Background: Most rare disease patients endure long delays in obtaining a correct diagnosis, the so-called "diagnostic odyssey", due to a combination of the rarity of their disorder and the lack of awareness of rare diseases among both primary care professionals and specialists. Next-generation sequencing (NGS) techniques that target genes underlying diverse phenotypic traits or groups of diseases are helping reduce these delays; (2) Methods: We used a combination of biochemical (thin-layer chromatography and high-performance liquid chromatography-tandem mass spectrometry), NGS (resequencing gene panels) and splicing assays to achieve a complete diagnosis of three patients with suspected metachromatic leukodystrophy, a neurologic lysosomal disorder; (3) Results: Affected individuals in each family were homozygotes for harmful variants in the gene, one of them novel (c.854+1dup, in family 1) and the other already described (c.640G>A, p.(Ala214Thr), in family 2). In addition, both affected individuals in family 2 were carriers of a known pathogenic variant in an additionallysosomal disease gene, (for mucolipidosis III). This additional variant may modify the clinical presentation by increasing lysosomal dysfunction. (4) Conclusions: We demonstrated the deleterious effect of the novel variant c.854+1dup on the splicing of transcripts. We also confirmed the involvement of variant c.640G>A in metachromatic leukodystrophy. Our results show the power of diagnostic approaches that combine deep phenotyping, NGS, and biochemical and functional techniques.