# Perspectives from cystinosis: access to healthcare may be a confounding factor for variant classification

## TL;DR

The paper discusses how differences in healthcare access may affect the classification of genetic variants in cystinosis, a metabolic disease.

## Contribution

The study highlights how disparities in healthcare access can confound the classification of CTNS gene variants across populations.

## Key findings

- The c.124G>A variant in the CTNS gene is classified as pathogenic in white populations but may be benign in African ancestral groups.
- Inclusion or exclusion of this variant significantly changes estimated disease prevalence.
- The study suggests underdiagnosis of cystinosis in African populations due to healthcare inequities and variable expressivity.

## Abstract

Genetic variability persists across diverse populations, and it may impact the characterization of heritable diseases in different ancestral groups. Cystinosis is a metabolic disease caused by pathogenic variants in the CTNS gene causing the cellular accumulation of cystine. We attempted to assess the currently poorly characterized prevalence of cystinosis by employing a population genetics methodology. However, we encountered a significant challenge due to genetic variations across different populations, and the consideration of potential disparities in access to healthcare made our results inconclusive. Pathogenic CTNS variants were identified in a representative global population cohort using The Human Gene Mutation Database (HGMD) and the 1000 Genomes (1 KG) database. The c.124G>A (p.Val42Ile) variant was reported to be pathogenic based on an observation in the white population presenting with atypical phenotypes, but it would be reclassified as benign in the African ancestral group if applying the ACMG allele frequency guideline due to its high allele frequency specifically in this population. Inclusion or exclusion of this c.124G>A (p.Val42Ile) variant results in a significant change in estimated disease prevalence, which can impact the diagnosis and treatment of affected patients with a broad range of phenotypic presentations. This observation led us to postulate that pathogenic manifestations of the disease may be underdiagnosed due to variable expressivity and systemic inequities in access to care, specifically in the African subpopulation. We call for a more cautious and inclusive approach to achieve more equitable care across diverse populations.