Wu Chen-Han Wilfred, Tomaszewski Alicja, Stark Louisa, Scaglia Fernando, Elenberg Ewa, Schumaker Fredrick R
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, United States.
Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, United States.
Front Genet. 2024 Jul 24;15:1402667. doi: 10.3389/fgene.2024.1402667. eCollection 2024.
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 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 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.
遗传变异性在不同人群中持续存在，并且可能影响不同祖先群体中遗传性疾病的特征描述。胱氨酸贮积症是一种由基因突变导致细胞内胱氨酸蓄积引起的代谢性疾病。我们试图采用群体遗传学方法评估目前特征描述不足的胱氨酸贮积症患病率。然而，由于不同人群之间的基因变异，我们遇到了重大挑战，并且考虑到获得医疗保健的潜在差异，我们的结果尚无定论。使用人类基因突变数据库（HGMD）和千人基因组（1KG）数据库在一个具有代表性的全球人群队列中鉴定出致病变异。c.124G>A（p.Val42Ile）变异基于在表现出非典型表型的白人群体中的观察结果被报告为致病，但如果应用美国医学遗传学与基因组学学会（ACMG）等位基因频率指南，由于其在非洲祖先群体中的高等位基因频率，它在该群体中将被重新分类为良性。包含或排除此c.124G>A（p.Val42Ile）变异会导致估计疾病患病率的显著变化，这可能影响具有广泛表型表现的受影响患者的诊断和治疗。这一观察结果使我们推测，由于可变表达性和获得医疗服务的系统性不平等，特别是在非洲亚群体中，该疾病的致病表现可能未得到充分诊断。我们呼吁采取更谨慎和包容的方法，以在不同人群中实现更公平的医疗服务。
