Inborn errors of metabolism have traditionally been viewed as the quintessential single gene disorders; defects in one gene leads to loss of activity of one enzyme causing a metabolic imbalance and clinical disease. However, reality has never been quite that simple, and the classic "one gene-one enzyme" paradigm has been upended in many ways. Multiple gene defects can lead to the same biochemical phenotype, often with different clinical symptoms. Additionally, different mutations in the same gene can cause variable phenotypes, often most dramatic when a disease can be identified by pre-symptomatic screening. Moreover, response to therapy is not homogeneous across diseases and specific mutations. Perhaps the biggest deviation from traditional monogenic inheritance is in the setting of synergistic heterozygosity, a multigenic inheritance pattern in which mutations in multiple genes in a metabolic pathway lead to sufficient disruption of flux through the pathway, mimicking a monogenic disorder caused by homozygous defects in one gene in that pathway. In addition, widespread adoption of whole exome and whole genome sequencing in medical genetics has led to the realization that individual patients with apparently hybrid phenotypes can have mutations in more than one gene, leading to a mixed genetic disorder. Each of these situations point to a need for as much precision as possible in diagnosing metabolic disease, and it is likely to become increasingly critical to drive therapy. This article examines examples in traditional monogenic disorders that illustrates these points and define inborn errors of metabolism as complex genetic traits on the leading edge of precision medicine.

中文翻译：

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先天性代谢错误中复杂的遗传模式，包括协同杂合性：对精准医学驱动的诊断和治疗的影响。


传统上，先天性代谢缺陷被视为典型的单基因疾病。一种基因的缺陷会导致一种酶的活性丧失，从而导致代谢失衡和临床疾病。然而，现实从来没有那么简单，经典的“一个基因一个酶”范式在很多方面都被颠覆了。多种基因缺陷可导致相同的生化表型，但往往具有不同的临床症状。此外，同一基因的不同突变可能会导致不同的表型，当可以通过症状前筛查识别疾病时，通常最为引人注目。此外，不同疾病和特定突变对治疗的反应并不相同。也许与传统单基因遗传的最大偏差在于协同杂合性，这是一种多基因遗传模式，其中代谢途径中多个基因的突变导致该途径的通量被充分破坏，模仿由一个基因中的纯合子缺陷引起的单基因疾病。该途径中的基因。此外，医学遗传学中全外显子组和全基因组测序的广泛采用使人们认识到，具有明显混合表型的个体患者可能在多个基因中发生突变，从而导致混合遗传性疾病。这些情况都表明在诊断代谢疾病时需要尽可能精确，并且驱动治疗可能变得越来越重要。本文研究了传统单基因疾病的例子，这些例子说明了这些观点，并将先天性代谢缺陷定义为精密医学前沿的复杂遗传特征。