Case Report: Reinterpretation and Reclassification of ARSB:p.Arg159Cys Variant Identified in an Emirati Patient With Hearing Loss Caused by a Pathogenic Variant in the CDH23 Gene.

Nahid Al Dhahouri,Fatma Al-Jasmi,Jozef Hertecant,Amanat Ali

doi:10.3389/fped.2021.803732

Nahid Al Dhahouri, Fatma Al-Jasmi + Show 2 more

Open Access

https://doi.org/10.3389/fped.2021.803732

Copy DOI

Abstract

Arylsulfatase B is an enzyme present in the lysosomes that involves in the breakdown of large sugar molecules known as glycosaminoglycans (GAGs). Arylsulfatase B chemically modifies two GAGs, namely, dermatan sulfate and chondroitin sulfate, by removing the sulfate group. Mutations in the gene encoding the arylsulfataseB enzyme causes lysosomal storage disorder, mucopolysaccharidosis type VI (MPS VI), or Maroteaux–Lamy syndrome. In this study, we report a case of congenital hearing loss with mild pigmentary changes in the retina, indicative of Usher syndrome, and a missense variant reported as likely pathogenic for MPS VI. Sequencing results identified a pathogenic missense variant p.Arg1746Gln in the CDH23 gene. However, another missense variant ARSB:p.Arg159Cys was reported as likely pathogenic to the treating physician. Mutations in ARSB gene have been associated with MPS VI. Subsequently, ARSB enzyme activity was found low twice in dried blood spot (DBS), suggestive of MPS VI. The patient did not have the clinical features of MPS VI, but considering the wide clinical spectrum, progressive nature of MPS VI, and the fact that a treatment for MPS VI is available to prevent disease progression, further biochemical, enzymatic, and in silico studies were performed to confirm the pathogenicity of this variant. In silico tools predicted this variant to be pathogenic. However, the results of urine and serum GAGs and ARSB enzyme levels measured from patient's fibroblast were found normal. Based on clinical and biochemical findings, ARSB:p.Arg159Cys is likely benign and did not support the diagnosis of MPS VI. However, CDH23:p.Arg1746Gln, a pathogenic variant, supports the underlying cause of hearing loss. This study highlights the importance of a robust correlation between genetic results and clinical presentation, and biochemical and enzymatic studies, to achieve a differential diagnosis.

Highlights

Mucopolysaccharidoses (MPSs) are lysosomal storage disorders (LSDs) caused by inherited deficiencies of lysosomal hydrolases responsible for the catabolism of mucopolysaccharide molecules known as glycosaminoglycans (GAGs) [1]
An incidental finding of likely pathogenic mutation ARSB:p.Arg159Cys based on Centogene American College of Medical Genetics (ACMG) criteria, suggestive of mucopolysaccharidosis type VI (MPS VI) diagnosis, was reported to the treating physician
ARSB:p.Arg159Cys variant was reported as likely pathogenic. This variant was not reported in any public database. This variant has recently been classified as variant of unknown significance (VUS) in ClinVar

Summary

Introduction

Mucopolysaccharidoses (MPSs) are lysosomal storage disorders (LSDs) caused by inherited deficiencies of lysosomal hydrolases responsible for the catabolism of mucopolysaccharide molecules known as glycosaminoglycans (GAGs) [1]. 13 enzyme deficiencies have been identified that lead to an accumulation of different species of GAGs including dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS), chondroitin sulfate (CS), and hyaluronic acid in blood, tissues, and urine [2]. Hearing loss is one of the most common clinical presentation in MPSs [4]. Patients with MPSs usually do not present with congenital hearing loss. ERT in MPS VI has been shown to reduce GAG accumulation in clinical trials [9]. The effects of ERT on the hearing loss is inconclusive [10]. Differential diagnosis based solely on clinical observations are rarely conclusive, and additional biochemical and genetic confirmatory tests are often required. Linker regions that connect different EC repeats are highly conserved and are important for the binding of Ca2+ ions [12]

Methods

Results

Conclusion