An estimated 1 in 10 000 people are born without the ability to smell, a condition known as congenital anosmia, and about one third of those people have non-syndromic, or isolated congenital anosmia (ICA). Despite the significant impact of olfaction for our quality of life, the underlying causes of ICA remain largely unknown. Using whole exome sequencing (WES) in 10 families and 141 individuals with ICA, we identified a candidate list of 162 rare, segregating, deleterious variants in 158 genes. We confirmed the involvement of CNGA2, a previously implicated ICA gene that is an essential component of the olfactory transduction pathway. Furthermore, we found a loss-of-function variant in SREK1IP1 from the family gene candidate list, which was also observed in 5% of individuals in an additional non-family cohort with ICA. Although SREK1IP1 has not been previously associated with olfaction, its role in zinc ion binding suggests a potential influence on olfactory signaling. This study provides a more comprehensive understanding of the spectrum of genetic alterations and their etiology in ICA patients, which may improve the diagnosis, prognosis, and treatment of this disorder and lead to better understanding of the mechanisms governing basic olfactory function.

中文翻译：

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识别孤立性先天性嗅觉缺失症的候选基因

据估计，万分之一的人出生时就没有嗅觉，这种情况被称为先天性嗅觉缺失症，其中约三分之一患有非综合征或孤立性先天性嗅觉缺失症 (ICA)。尽管嗅觉对我们的生活质量有重大影响，但 ICA 的根本原因仍然很大程度上未知。通过对 10 个 ICA 家族和 141 个个体进行全外显子组测序 (WES)，我们确定了 158 个基因中 162 个罕见、分离、有害变异的候选列表。我们确认了 CNGA2 的参与，CNGA2 是一个先前涉及的 ICA 基因，是嗅觉转导途径的重要组成部分。此外，我们在家族基因候选列表中发现了 SREK1IP1 的功能丧失变异，在另外一个 ICA 非家族队列中，5% 的个体也观察到了这种情况。尽管 SREK1IP1 之前并未与嗅觉相关，但其在锌离子结合中的作用表明对嗅觉信号传导具有潜在影响。这项研究提供了对 ICA 患者遗传改变谱及其病因学的更全面的了解，这可能会改善这种疾病的诊断、预后和治疗，并导致更好地了解控制基本嗅觉功能的机制。