Victorian Clinical Genetics Services, Parkville, VIC 3052, Australia.
Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Genes (Basel). 2024 Jul 23;15(8):967. doi: 10.3390/genes15080967.
The Human Genome Project, completed in 2003, heralded a new era in precision medicine. Somewhat tempering the excitement of the elucidation of the human genome is the emerging recognition that there are fewer single gene disorders than first anticipated, with most diseases predicted to be polygenic or at least gene-environment modified. Hereditary haemochromatosis (HH) is an inherited iron overload disorder, for which the vast majority of affected individuals (>90%) have homozygosity for a single pathogenic variant in the gene, resulting in p.Cys282Tyr. Further, there is significant benefit to an individual in identifying the genetic risk of HH, since the condition evolves over decades, and the opportunity to intervene and prevent disease is both simple and highly effective through regular venesection. Add to that the immediate benefit to society of an increased pool of ready blood donors (blood obtained from HH venesections can generally be used for donation), and the case for population screening to identify those genetically at risk for HH becomes more cogent. Concerns about genetic discrimination, creating a cohort of "worried well", antipathy to acting on medical advice to undertake preventive venesection or simply not understanding the genetic risk of the condition adequately have all been allayed by a number of investigations. So why then has HH population genetic screening not been routinely implemented anywhere in the world? The answer is complex, but in this article we explore the pros and cons of screening for HH and the different views regarding whether it should be phenotypic (screening for iron overload by serum ferritin and/or transferrin saturation) or genotypic (testing for HFE p.Cys282Tyr). We argue that now is the time to give this poster child for population genetic screening the due consideration required to benefit the millions of individuals at risk of -related iron overload.
人类基因组计划于 2003 年完成，标志着精准医学的新时代的到来。尽管人类基因组的阐明令人兴奋，但人们逐渐认识到，单基因疾病的数量比最初预期的要少，大多数疾病预计是多基因的，或者至少是基因-环境共同作用的。遗传性血色素沉着症（HH）是一种遗传性铁过载疾病，绝大多数受影响的个体（>90%）在基因中携带单个致病变异的纯合子，导致 p.Cys282Tyr。此外，个体识别 HH 的遗传风险具有重要意义，因为这种情况会在几十年内发展，通过定期静脉放血，干预和预防疾病既简单又非常有效。此外，由于 HH 静脉切开术获得的血液通常可用于捐赠，因此增加了现成献血者的储备，这对社会也有直接的好处，因此，对人群进行筛查以确定那些具有 HH 遗传风险的人群变得更加合理。人们对遗传歧视、制造一群“担心健康”的人群、对按照医疗建议进行预防性静脉切开术的反感，或者只是对该疾病的遗传风险没有足够的了解等问题，都已经通过多项调查得到了解决。那么，为什么 HH 人群遗传筛查在世界任何地方都没有常规实施呢？答案很复杂，但在本文中，我们探讨了筛查 HH 的利弊，以及关于应该进行表型（通过血清铁蛋白和/或转铁蛋白饱和度筛查铁过载）还是基因型（检测 HFE p.Cys282Tyr）筛查的不同观点。我们认为，现在是时候对这种人群遗传筛查的典范进行适当的考虑，以使数百万处于 HH 相关铁过载风险的个体受益。
