Reclassification of a variant of uncertain clinical significance in a case of non-classic MPS type IV-A

Abstract

Introduction: Mucopolysaccharidosis type IV - A (MPS IV-A, Morquio Syndrome type A) is an autosomal recessive hereditary disorder and one of the common lysosomal diseases, caused by a deficiency in the activity of lysosomal hydrolase, N-acetylglucosamine- 6-sulfatase (GALNS) which leads to an accumulation of glycosaminoglycans (GAGs) such as keratan sulfate (KS) and chondroitin-6-sulfate (C6S) in multiple tissues. As in the other MPS, there are different phenotypes, ranging from severe forms also called classic MPS IV-A to mild forms called attenuated or non-classic MPS IV-A. Material and methods: Clinical case report. The analyzes carried out on leukocyte isolates were carried out by sedimentation using Dextran-Heparin, releasing the enzyme by sonication, and adjusting the protein concentration, the enzymatic assessment was carried out by means of a fluorometric assay, the sequence analysis of the genes of interest was carried out by sequencing of new generation (NGS) and in silico analysis was performed with bioinformatics tools to predict the biological effect of the variant. Results: A 12-year-old male patient with a clinical, paraclinical, and enzymatic diagnosis and molecular study with two heterozygous variants, one with a pathogenic clinical significance classification and the other with uncertain clinical significance of MPS IV-A, with subsequent reclassification of significance according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, and their phenotype, endotype, and genotype correlation. Conclusions: MPS IV-A in an attenuated manner represents a diagnostic challenge for health professionals, which is why it is of great importance to identify mild clinical manifestations of the disease early. With bioinformatics tools, it was possible to establish the pathogenic significance of the nonsense variant c.1088T>C (p. Ile363Thr) and thus report it as a new variant associated with MPS IV-A.