Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York, USA.
Am J Med Genet A. 2021 Nov;185(11):3287-3293. doi: 10.1002/ajmg.a.62463. Epub 2021 Aug 21.
In medical genetics, the vast majority of patients with a currently known genetic basis harbor a rare deleterious allele explaining its Mendelian inheritance. Increasingly, for these phenotypes, we recognize exceptions to Mendelian expectations from non-penetrance of clinical disease to significant inter-individual variation in clinical manifestations, likely reflecting the actions of additional modifier genes. Despite recent progress, we still remain ignorant about the molecular basis for many rare disorders presumed to be Mendelian. The molecular evidence increasingly suggests a role for multiple genes in some of these cases, but for how many? In this article, I discuss why equating a phenotype as Mendelian or complex may be short-sighted or even erroneous. As we learn more about the functions of the human genome with its genes in networks, we should view the phenotype of an individual patient as arising from his or her total genomic deleterious burden in a set of functionally inter-related genes affecting that phenotype. This can sometimes arise from deleterious allele(s) at a single gene (Mendelian inheritance) creating a specific biochemical deficiency (or excess) but could just as frequently arise from the cumulative effects of multiple disease alleles (complex inheritance) leading to the same biochemical deficiency (or excess).
在医学遗传学中，绝大多数具有当前已知遗传基础的患者都携带有一个罕见的有害等位基因，该基因解释了其孟德尔遗传方式。对于这些表型，我们越来越多地认识到孟德尔预期的例外情况，从临床疾病的非外显到临床表现的显著个体间差异，这可能反映了其他修饰基因的作用。尽管最近取得了进展，但我们仍然不知道许多被认为是孟德尔的罕见疾病的分子基础。分子证据越来越表明，在某些情况下，多个基因起作用，但有多少呢？在本文中，我讨论了将表型等同于孟德尔或复杂可能是短视的，甚至是错误的原因。随着我们对人类基因组及其基因在网络中的功能有了更多的了解，我们应该将个体患者的表型视为其在一组功能上相互关联的基因中总基因组有害负担的结果，这些基因会影响该表型。这有时可能是由于单个基因的有害等位基因（孟德尔遗传）导致特定的生化缺陷（或过剩），但也可能经常是由于多个疾病等位基因（复杂遗传）的累积效应导致相同的生化缺陷（或过剩）。
