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The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue
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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454578/ https://www.ncbi.nlm.nih.gov/pubmed/37628614 http://dx.doi.org/10.3390/genes14081562 |
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author | Kalyta, Kateryna Stelmaszczyk, Weronika Szczęśniak, Dominika Kotuła, Lidia Dobosz, Paula Mroczek, Magdalena |
author_facet | Kalyta, Kateryna Stelmaszczyk, Weronika Szczęśniak, Dominika Kotuła, Lidia Dobosz, Paula Mroczek, Magdalena |
author_sort | Kalyta, Kateryna |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10454578 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104545782023-08-26 The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue Kalyta, Kateryna Stelmaszczyk, Weronika Szczęśniak, Dominika Kotuła, Lidia Dobosz, Paula Mroczek, Magdalena Genes (Basel) Review 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. MDPI 2023-07-31 /pmc/articles/PMC10454578/ /pubmed/37628614 http://dx.doi.org/10.3390/genes14081562 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Kalyta, Kateryna Stelmaszczyk, Weronika Szczęśniak, Dominika Kotuła, Lidia Dobosz, Paula Mroczek, Magdalena The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue |
title | The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue |
title_full | The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue |
title_fullStr | The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue |
title_full_unstemmed | The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue |
title_short | The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue |
title_sort | spectrum of the heterozygous effect in biallelic mendelian diseases—the symptomatic heterozygote issue |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454578/ https://www.ncbi.nlm.nih.gov/pubmed/37628614 http://dx.doi.org/10.3390/genes14081562 |
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