The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue

Abstract

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.

Rare Pathogenic Variants in Pooled Whole-Exome Sequencing Data Suggest Ciliary Defects and Hyperammoniemia as Possible Causes of Dementia Not Classified as Alzheimer’s Disease or Frontomteporal Dementia

“…The variant is most likely found in heterozygous state and we can presume that as such it can lead to structural alterations in neuronal cilia resulting in the development of dementia. This can be supported by many recent reports that have identified symptomatic heterozygotes with mild and unspecific symptoms, occurring later in life in many disorders, including neurological diseases [35].…”

Rare Pathogenic Variants in Pooled Whole-Exome Sequencing Data Suggest Hyperammonemia as a Possible Cause of Dementia Not Classified as Alzheimer’s Disease or Frontotemporal Dementia

“…Still, the detected ASS1 variants cause reduced argininosuccinate synthetase deficiency even in a heterozygous state, which then leads to increased ammonia levels exerting a toxic effect on the brain [46]. This can be supported by many recent reports that have identified symptomatic heterozygotes with mild and unspecific symptoms, occurring later in life in many disorders, including neurological diseases [47].…”