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Genomic Mosaicism in Human Development and Diseases
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Genomic Mosaicism in Human Development and Diseases

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 November 2024) | Viewed by 12054

Special Issue Editor

Dr. Xiaoxu Yang

E-Mail Website
Guest Editor
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
Interests: genomic mosaicism; diseases; cancer

Special Issue Information

Dear Colleagues,

Genomic mosaicism defines the phenomenon that different tissues and organs from the same individual present different genomic sequences. Mosaicism is a result of postzygotic mutations occurring during embryonic development, tissue self-renewal, environmental toxicity, aging, and disease. The failure to repair these mutations will leave them in the genome throughout one’s lifespan, and the mutations will be inherited by all the carrier’s daughter cells.

On the one hand, neutral or near-neutral genomic mosaic mutations can serve as recorders of human embryonic development. They are naturally barcoding the developmental cell clones, helping researchers to reconstruct lineage distribution patterns of early embryonic development.

On the other hand, emerging evidence has demonstrated that mosaic mutations are important genetic origins of disease. Cancer driver mutations have already shown to be detectable on adjacent tissues that are apparently normal. Apart from skin and skeletal disorders where mosaic mutations are already a known cause, developmental disorders and autoimmune disorders have also been demonstrated to be caused by mosaic mutations.

In this Special Issue, submissions on the following, but not limited to, topics are welcome:

    ● Mosaicism in human development;

    ● Somatic mosaicism that directly causes human disorders;

    ● Pre-disease mosaic mutation burdens for different disorders;

    ● Methodologies for mosaic studies.

Dr. Xiaoxu Yang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mosaicism
  • mutations
  • development
  • disorder
  • cancer

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Published Papers (6 papers)

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Research

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15 pages, 2253 KiB  
Article
Identification of Novel Mosaic Variants in Focal Epilepsy-Associated Patients’ Brain Lesions
by Camila Araújo Bernardino Garcia, Muhammad Zubair, Marcelo Volpon Santos, Sang Hyun Lee, Ian Alfred Graham, Valentina Stanley, Renee D. George, Joseph G. Gleeson, Hélio Rubens Machado and Xiaoxu Yang
Genes 2025, 16(4), 421; https://doi.org/10.3390/genes16040421 - 31 Mar 2025
Viewed by 408
Abstract
Focal cortical dysplasia type III (FCDIII) is a rare and complex condition associated with drug-resistant epilepsy and often characterized by cortical lamination abnormalities, along with a variety of neoplasms and vascular abnormalities. Objectives: This study aimed to elucidate the genetic architecture underlying FCDIII [...] Read more.
Focal cortical dysplasia type III (FCDIII) is a rare and complex condition associated with drug-resistant epilepsy and often characterized by cortical lamination abnormalities, along with a variety of neoplasms and vascular abnormalities. Objectives: This study aimed to elucidate the genetic architecture underlying FCDIII through the use of whole-exome sequencing (WES) of brain and peripheral blood samples from 19 patients who had been diagnosed with FCDIII. Methods: Variants were identified through a series of machine-learning-based detection and functional prediction methods and were not previously associated with FCDIII. Mosaic fraction scores of these variants validated the variants’ pathogenicity, and in silico and gene ontology enrichment analyses demonstrated that these variants had severe destabilizing effects on protein structure. Results: We reported ten novel pathogenic somatic missense and loss of function variants across eight genes, including CNTNAP2, ACY1, SERAC1, and BRAF. Genetic alterations were linked to clinical manifestations, such as encephalopathies and intellectual disabilities, thereby emphasizing their role as molecular drivers of FCDIII. Conclusions: We demonstrated that next-generation sequencing-based mosaic variant-calling pipelines are useful for the genetic diagnosis of FCDIII, opening up avenues for targeted therapies, yet further research is required to validate these findings and examine their therapeutic implications. Full article
(This article belongs to the Special Issue Genomic Mosaicism in Human Development and Diseases)
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10 pages, 232 KiB  
Article
Mosaicism for Autosomal Trisomies: A Comprehensive Analysis of 1266 Published Cases Focusing on Maternal Age and Reproductive History
by Natalia V. Kovaleva and Philip D. Cotter
Genes 2024, 15(6), 778; https://doi.org/10.3390/genes15060778 - 13 Jun 2024
Viewed by 1201
Abstract
Mosaicism for autosomal trisomy is uncommon in clinical practice. However, despite its rarity among both prenatally and postnatally diagnoses, there are a large number of characterized and published cases. Surprisingly, in contrast to regular trisomies, no attempts at systematic analyses of mosaic carriers’ [...] Read more.
Mosaicism for autosomal trisomy is uncommon in clinical practice. However, despite its rarity among both prenatally and postnatally diagnoses, there are a large number of characterized and published cases. Surprisingly, in contrast to regular trisomies, no attempts at systematic analyses of mosaic carriers’ demographics were undertaken. This is the first study aimed to address this gap. For that, we have screened more than eight hundred publications on mosaic trisomies, reviewing data including gender and clinical status of mosaic carriers, maternal age and reproductive history. In total, 596 publications were eligible for analysis, containing data on 948 prenatal diagnoses, including true fetal mosaicism (TFM) and confined placental mosaicism (CPM), and on 318 cases of postnatally detected mosaicism (PNM). No difference was found in maternal age between normal pregnancy outcomes with appropriate birth weight and those with intrauterine growth restriction. Unexpectedly, a higher proportion of advanced maternal ages (AMA) was found in normal outcomes compared to abnormal ones (abnormal fetus or newborn) and fetal losses, 73% vs. 56% and 50%, p = 0.0015 and p = 0.0011, correspondingly. Another intriguing finding was a higher AMA proportion in mosaic carriers with concomitant uniparental disomy (UPD) for chromosomes 7, 14, 15, and 16 compared to carriers with biparental disomy (BPD) (72% vs. 58%, 92% vs. 55%, 87% vs. 78%, and 65% vs. 24%, correspondingly); overall figures were 78% vs. 48%, p = 0.0026. Analysis of reproductive histories showed a very poor reporting but almost two-fold higher rate of mothers reporting a previous fetal loss from PNM cohort (in which almost all patients were clinically abnormal) compared to mothers from the TFM and CPM cohorts (with a large proportion of normal outcomes), 30% vs. 16%, p = 0.0072. The occurrence of a previous pregnancy with a chromosome abnormality was 1 in 13 in the prenatal cohort and 1 in 16 in the postnatal cohort, which are five-fold higher compared to published studies on non-mosaic trisomies. We consider the data obtained in this study to be preliminary despite the magnitude of the literature reviewed since reporting of detailed data was mostly poor, and therefore, the studied cohorts do not represent “big data”. Nevertheless, the information obtained is useful both for clinical genetic counseling and for modeling further studies. Full article
(This article belongs to the Special Issue Genomic Mosaicism in Human Development and Diseases)
17 pages, 2637 KiB  
Article
Exploring the Micro-Mosaic Landscape of FGFR3 Mutations in the Ageing Male Germline and Their Potential Implications in Meiotic Differentiation
by Yasmin Striedner, Barbara Arbeithuber, Sofia Moura, Elisabeth Nowak, Ronja Reinhardt, Leila Muresan, Renato Salazar, Thomas Ebner and Irene Tiemann-Boege
Genes 2024, 15(2), 191; https://doi.org/10.3390/genes15020191 - 30 Jan 2024
Cited by 1 | Viewed by 2154
Abstract
Advanced paternal age increases the risk of transmitting de novo germline mutations, particularly missense mutations activating the receptor tyrosine kinase (RTK) signalling pathway, as exemplified by the FGFR3 mutation, which is linked to achondroplasia (ACH). This risk is attributed to the expansion of [...] Read more.
Advanced paternal age increases the risk of transmitting de novo germline mutations, particularly missense mutations activating the receptor tyrosine kinase (RTK) signalling pathway, as exemplified by the FGFR3 mutation, which is linked to achondroplasia (ACH). This risk is attributed to the expansion of spermatogonial stem cells carrying the mutation, forming sub-clonal clusters in the ageing testis, thereby increasing the frequency of mutant sperm and the number of affected offspring from older fathers. While prior studies proposed a correlation between sub-clonal cluster expansion in the testis and elevated mutant sperm production in older donors, limited data exist on the universality of this phenomenon. Our study addresses this gap by examining the testis-expansion patterns, as well as the increases in mutations in sperm for two FGFR3 variants—c.1138G>A (p.G380R) and c.1948A>G (p.K650E)—which are associated with ACH or thanatophoric dysplasia (TDII), respectively. Unlike the ACH mutation, which showed sub-clonal expansion events in an aged testis and a significant increase in mutant sperm with the donor’s age, as also reported in other studies, the TDII mutation showed focal mutation pockets in the testis but exhibited reduced transmission into sperm and no significant age-related increase. The mechanism behind this divergence remains unclear, suggesting potential pleiotropic effects of aberrant RTK signalling in the male germline, possibly hindering differentiation requiring meiosis. This study provides further insights into the transmission risks of micro-mosaics associated with advanced paternal age in the male germline. Full article
(This article belongs to the Special Issue Genomic Mosaicism in Human Development and Diseases)
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12 pages, 643 KiB  
Article
Choosing the Best Tissue and Technique to Detect Mosaicism in Fibrous Dysplasia/McCune–Albright Syndrome (FD/MAS)
by Yerai Vado, Africa Manero-Azua, Arrate Pereda and Guiomar Perez de Nanclares
Genes 2024, 15(1), 120; https://doi.org/10.3390/genes15010120 - 18 Jan 2024
Cited by 3 | Viewed by 2362
Abstract
GNAS-activating somatic mutations give rise to Fibrous Dysplasia/McCune–Albright syndrome (FD/MAS). The low specificity of extra-skeletal signs of MAS and the mosaic status of the mutations generate some difficulties for a proper diagnosis. We studied the clinical and molecular statuses of 40 patients [...] Read more.
GNAS-activating somatic mutations give rise to Fibrous Dysplasia/McCune–Albright syndrome (FD/MAS). The low specificity of extra-skeletal signs of MAS and the mosaic status of the mutations generate some difficulties for a proper diagnosis. We studied the clinical and molecular statuses of 40 patients referred with a clinical suspicion of FD/MAS to provide some clues. GNAS was sequenced using both Sanger and Next-Generation Sequencing (NGS). We were able to identify the pathogenic variants in 25% of the patients. Most of them were identified in the affected tissue, but not in blood. Additionally, NGS demonstrated the ability to detect more patients with mosaicism (8/34) than Sanger sequencing (4/39). Even if in some cases, the clinical information was not complete, we confirmed that, as in previous works, when the patients were young children with a single manifestation, such as hyperpigmented skin macules or precocious puberty, the molecular diagnosis was usually negative. In conclusion, as FD/MAS is caused by mosaic variants, it is essential to use sensitive techniques that allow for the detection of low percentages and to choose the right tissue to study. When not possible, and due to the low positive genetic rate, patients with FD/MAS should only be genetically tested when the clinical diagnosis is really uncertain. Full article
(This article belongs to the Special Issue Genomic Mosaicism in Human Development and Diseases)
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Review

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19 pages, 1738 KiB  
Review
Mosaicism in Short Tandem Repeat Disorders: A Clinical Perspective
by Rose M. Doss, Susana Lopez-Ignacio, Anna Dischler, Laurel Hiatt, Harriet Dashnow, Martin W. Breuss and Caroline M. Dias
Genes 2025, 16(2), 216; https://doi.org/10.3390/genes16020216 - 13 Feb 2025
Viewed by 980
Abstract
Fragile X, Huntington disease, and myotonic dystrophy type 1 are prototypical examples of human disorders caused by short tandem repeat variation, repetitive nucleotide stretches that are highly mutable both in the germline and somatic tissue. As short tandem repeats are unstable, they can [...] Read more.
Fragile X, Huntington disease, and myotonic dystrophy type 1 are prototypical examples of human disorders caused by short tandem repeat variation, repetitive nucleotide stretches that are highly mutable both in the germline and somatic tissue. As short tandem repeats are unstable, they can expand, contract, and acquire and lose epigenetic marks in somatic tissue. This means within an individual, the genotype and epigenetic state at these loci can vary considerably from cell to cell. This somatic mosaicism may play a key role in clinical pathogenesis, and yet, our understanding of mosaicism in driving clinical phenotypes in short tandem repeat disorders is only just emerging. This review focuses on these three relatively well-studied examples where, given the advent of new technologies and bioinformatic approaches, a critical role for mosaicism is coming into focus both with respect to cellular physiology and clinical phenotypes. Full article
(This article belongs to the Special Issue Genomic Mosaicism in Human Development and Diseases)
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12 pages, 2422 KiB  
Review
The Clinical Spectrum of Mosaic Genetic Disease
by Hanabi Geiger, Yutaka Furuta, Suné van Wyk, John A. Phillips III and Rory J. Tinker
Genes 2024, 15(10), 1240; https://doi.org/10.3390/genes15101240 - 24 Sep 2024
Viewed by 3483
Abstract
Genetic mosaicism is defined as the presence of two or more cell lineages with different genotypes arising from a single zygote. Mosaicism has been implicated in hundreds of genetic diseases with diverse genetic etiologies affecting every organ system. Mosaic genetic disease (MDG) is [...] Read more.
Genetic mosaicism is defined as the presence of two or more cell lineages with different genotypes arising from a single zygote. Mosaicism has been implicated in hundreds of genetic diseases with diverse genetic etiologies affecting every organ system. Mosaic genetic disease (MDG) is a spectrum that, on the extreme ends, enables survival from genetic severe disorders that would be lethal in a non-mosaic form. On the milder end of the spectrum, mosaicism can result in little if any phenotypic effects but increases the risk of transmitting a pathogenic genotype. In the middle of the spectrum, mosaicism has been implicated in reducing the phenotypic severity of genetic disease. In this review will describe the spectrum of mosaic genetic disease whilst discussing the status of the detection and prevalence of mosaic genetic disease. Full article
(This article belongs to the Special Issue Genomic Mosaicism in Human Development and Diseases)
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