Scholarlink

<p>Cystine stones are caused by pathogenic variants in <i>SLC3A1</i> or <i>SLC7A9</i>. Our prior study revealed a large gap between genetic and clinical prevalence. With increasing discovery of novel variants, we aim to assess how these impact genetic prevalence estimates. Due to the disease rarity, direct patient recruitment and observation is impractical. We applied a population genetics approach to estimate genetic burden and prevalence. Pathogenic variants were identified from the 2022 Human Gene Mutation Database and intersected with population variants from the 1000 Genomes Project Phase 3. Allele frequency, carrier rate, and affected rate were calculated. Results were compared to prior data, and simulations were performed across varying initial allele frequencies. We identified 116 and 76 novel pathogenic variants in <i>SLC3A1</i> and <i>SLC7A9</i>, respectively. Pathogenic allele frequencies increased by +0.12% (<i>SLC3A1</i>) and 0.16% (<i>SLC7A9</i>), leading to fold-changes in genetic prevalence of 1.51x and 2.78x. The combined updated prevalence is 1 in 17,612, a 1.74x increase. Simulations confirmed the fold-change magnitude. In rare diseases, even modest discovery of new variants can significantly increase genetic prevalence. As shown in cystine stone, this helps narrow—but not close—the gap with clinical prevalence. Further efforts are needed to bridge this gap and guide treatment development.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

How variant discovery redefines genetic prevalence: the case of cystine stone disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月9日

查看全文
  • Chen-Han Wilfred Wu,
  • Joshua Chang,
  • Katreya Lovrenert,
  • Donald Bodner,
  • Friedhelm Hildebrandt,
  • Fredrick R. Schumacher

摘要

Cystine stones are caused by pathogenic variants in SLC3A1 or SLC7A9. Our prior study revealed a large gap between genetic and clinical prevalence. With increasing discovery of novel variants, we aim to assess how these impact genetic prevalence estimates. Due to the disease rarity, direct patient recruitment and observation is impractical. We applied a population genetics approach to estimate genetic burden and prevalence. Pathogenic variants were identified from the 2022 Human Gene Mutation Database and intersected with population variants from the 1000 Genomes Project Phase 3. Allele frequency, carrier rate, and affected rate were calculated. Results were compared to prior data, and simulations were performed across varying initial allele frequencies. We identified 116 and 76 novel pathogenic variants in SLC3A1 and SLC7A9, respectively. Pathogenic allele frequencies increased by +0.12% (SLC3A1) and 0.16% (SLC7A9), leading to fold-changes in genetic prevalence of 1.51x and 2.78x. The combined updated prevalence is 1 in 17,612, a 1.74x increase. Simulations confirmed the fold-change magnitude. In rare diseases, even modest discovery of new variants can significantly increase genetic prevalence. As shown in cystine stone, this helps narrow—but not close—the gap with clinical prevalence. Further efforts are needed to bridge this gap and guide treatment development.