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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MDPI AG
2023-07-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/8/1562 |
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| author | Kateryna Kalyta Weronika Stelmaszczyk Dominika Szczęśniak Lidia Kotuła Paula Dobosz Magdalena Mroczek |
| author_facet | Kateryna Kalyta Weronika Stelmaszczyk Dominika Szczęśniak Lidia Kotuła Paula Dobosz Magdalena Mroczek |
| author_sort | Kateryna Kalyta |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T23:55:37Z |
| format | Article |
| id | doaj.art-bcb26460d1544bda96c8202a18a8f442 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T23:55:37Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-bcb26460d1544bda96c8202a18a8f4422023-11-19T01:15:03ZengMDPI AGGenes2073-44252023-07-01148156210.3390/genes14081562The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote IssueKateryna Kalyta0Weronika Stelmaszczyk1Dominika Szczęśniak2Lidia Kotuła3Paula Dobosz4Magdalena Mroczek5School of Life Sciences, FHNW—University of Applied Sciences, 4132 Muttenz, SwitzerlandSchool of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UKInstitute of Psychiatry and Neurology in Warsaw, Genetics Department, 02-957 Warsaw, PolandDepartment of Genetics, Medical University, 20-080 Lublin, PolandInstitute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5A, 02-106 Warsaw, PolandUniversity Hospital Basel, University of Basel, 4031 Basel, SwitzerlandHeterozygous 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.https://www.mdpi.com/2073-4425/14/8/1562symptomatic carrierheterozygous effectsymptomatic heterozygotes |
| spellingShingle | Kateryna Kalyta Weronika Stelmaszczyk Dominika Szczęśniak Lidia Kotuła Paula Dobosz Magdalena Mroczek The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue Genes symptomatic carrier heterozygous effect symptomatic heterozygotes |
| 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 | symptomatic carrier heterozygous effect symptomatic heterozygotes |
| url | https://www.mdpi.com/2073-4425/14/8/1562 |
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