School of Life Sciences, FHNW-University of Applied Sciences, 4132 Muttenz, Switzerland.
School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
Genes (Basel). 2023 Jul 31;14(8):1562. doi: 10.3390/genes14081562.
Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number of case reports have suggested that mild and unspecific symptoms can occur in some heterozygotes, as symptomatic heterozygotes have been identified across different disease types, including neurological, neuromuscular, hematological, and pulmonary diseases. The symptoms are usually milder in heterozygotes than in biallelic variants and occur "later in life". The status of symptomatic heterozygotes as separate entities is often disputed, and alternative diagnoses are considered. Indeed, often only a thin line exists between dual, dominant, and recessive modes of inheritance and symptomatic heterozygosity. Interestingly, recent population studies have found global disease effects in heterozygous carriers of some genetic variants. What makes the few heterozygotes symptomatic, while the majority show no symptoms? The molecular basis of this phenomenon is still unknown. Possible explanations include undiscovered deep-splicing variants, genetic and environmental modifiers, digenic/oligogenic inheritance, skewed methylation patterns, and mutational burden. Symptomatic heterozygotes are rarely reported in the literature, mainly because most did not undergo the complete diagnostic procedure, so alternative diagnoses could not be conclusively excluded. However, despite the increasing accessibility to high-throughput technologies, there still seems to be a small group of patients with mild symptoms and just one variant of autosomes in biallelic diseases. Here, we present some examples, the current state of knowledge, and possible explanations for this phenomenon, and thus argue against the existing dominant/recessive classification.
常染色体隐性疾病的杂合致病性/可能致病性变异携带者似乎无症状。然而，近年来，越来越多的病例报告表明，一些杂合子中可能会出现轻微和非特异性症状，因为已在不同疾病类型（包括神经、神经肌肉、血液和肺部疾病）中发现了有症状的杂合子。杂合子的症状通常比双等位基因变异者更轻，且“出现在生命后期”。有症状的杂合子作为独立实体的状态经常存在争议，并考虑其他诊断。事实上，双等位基因、显性和隐性遗传以及有症状的杂合性之间通常只有一线之隔。有趣的是，最近的人群研究发现，一些遗传变异的杂合子携带者存在全球疾病效应。是什么使少数杂合子出现症状，而大多数没有症状？这种现象的分子基础尚不清楚。可能的解释包括未发现的深剪接变异、遗传和环境修饰物、双基因/寡基因遗传、偏置甲基化模式和突变负担。有症状的杂合子在文献中很少报道，主要是因为大多数患者没有接受完整的诊断程序，因此无法排除其他诊断。然而，尽管高通量技术的可及性不断提高，但在双等位基因疾病中仍有一小部分患者有轻微症状且只有一条常染色体变异。在这里，我们介绍了一些例子、目前的知识状况以及对这种现象的可能解释，并因此反对现有的显性/隐性分类。
