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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...

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Autores principales: Kalyta, Kateryna, Stelmaszczyk, Weronika, Szczęśniak, Dominika, Kotuła, Lidia, Dobosz, Paula, Mroczek, Magdalena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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