International Journal of Molecular Sciences

Research

18 pages, 7153 KiB

Open AccessArticle

Genetic Variants in the TBC1D2B Gene Are Associated with Ramon Syndrome and Hereditary Gingival Fibromatosis

by Thatphicha Kularbkaew, Tipaporn Thongmak, Phan Sandeth, Callum S. Durward, Pichai Vittayakittipong, Paul Duke, Anak Iamaroon, Sompid Kintarak, Worrachet Intachai, Chumpol Ngamphiw, Sissades Tongsima, Peeranat Jatooratthawichot, Timothy C. Cox, James R. Ketudat Cairns and Piranit Kantaputra

Int. J. Mol. Sci. 2024, 25(16), 8867; https://doi.org/10.3390/ijms25168867 - 15 Aug 2024

Viewed by 794

Abstract

Ramon syndrome (MIM 266270) is an extremely rare genetic syndrome, characterized by gingival fibromatosis, cherubism-like lesions, epilepsy, intellectual disability, hypertrichosis, short stature, juvenile rheumatoid arthritis, and ocular abnormalities. Hereditary or non-syndromic gingival fibromatosis (HGF) is also rare and considered to represent a heterogeneous [...] Read more.

Ramon syndrome (MIM 266270) is an extremely rare genetic syndrome, characterized by gingival fibromatosis, cherubism-like lesions, epilepsy, intellectual disability, hypertrichosis, short stature, juvenile rheumatoid arthritis, and ocular abnormalities. Hereditary or non-syndromic gingival fibromatosis (HGF) is also rare and considered to represent a heterogeneous group of disorders characterized by benign, slowly progressive, non-inflammatory gingival overgrowth. To date, two genes, ELMO2 and TBC1D2B, have been linked to Ramon syndrome. The objective of this study was to further investigate the genetic variants associated with Ramon syndrome as well as HGF. Clinical, radiographic, histological, and immunohistochemical examinations were performed on affected individuals. Exome sequencing identified rare variants in TBC1D2B in both conditions: a novel homozygous variant (c.1879_1880del, p.Glu627LysfsTer61) in a Thai patient with Ramon syndrome and a rare heterozygous variant (c.2471A>G, p.Tyr824Cys) in a Cambodian family with HGF. A novel variant (c.892C>T, p.Arg298Cys) in KREMEN2 was also identified in the individuals with HGF. With support from mutant protein modeling, our data suggest that TBC1D2B variants contribute to both Ramon syndrome and HGF, although variants in additional genes might also contribute to the pathogenesis of HGF. Full article

(This article belongs to the Special Issue Recent Advances in Human Genetics)

► Show Figures

Figure 1

12 pages, 2009 KiB

Open AccessArticle

Evaluating the Transition from Targeted to Exome Sequencing: A Guide for Clinical Laboratories

by Kevin Yauy, Charles Van Goethem, Henri Pégeot, David Baux, Thomas Guignard, Corinne Thèze, Olivier Ardouin, Anne-Françoise Roux, Michel Koenig, Anne Bergougnoux and Mireille Cossée

Int. J. Mol. Sci. 2023, 24(8), 7330; https://doi.org/10.3390/ijms24087330 - 15 Apr 2023

Viewed by 1883

Abstract

The transition from targeted to exome or genome sequencing in clinical contexts requires quality standards, such as targeted sequencing, in order to be fully adopted. However, no clear recommendations or methodology have emerged for evaluating this technological evolution. We developed a structured method [...] Read more.

The transition from targeted to exome or genome sequencing in clinical contexts requires quality standards, such as targeted sequencing, in order to be fully adopted. However, no clear recommendations or methodology have emerged for evaluating this technological evolution. We developed a structured method based on four run-specific sequencing metrics and seven sample-specific sequencing metrics for evaluating the performance of exome sequencing strategies to replace targeted strategies. The indicators include quality metrics and coverage performance on gene panels and OMIM morbid genes. We applied this general strategy to three different exome kits and compared them with a myopathy-targeted sequencing method. After having achieved 80 million reads, all-tested exome kits generated data suitable for clinical diagnosis. However, significant differences in the coverage and PCR duplicates were observed between the kits. These are two main criteria to consider for the initial implementation with high-quality assurance. This study aims to assist molecular diagnostic laboratories in adopting and evaluating exome sequencing kits in a diagnostic context compared to the strategy used previously. A similar strategy could be used to implement whole-genome sequencing for diagnostic purposes. Full article

(This article belongs to the Special Issue Recent Advances in Human Genetics)

► Show Figures

Figure 1

14 pages, 2716 KiB

Open AccessArticle

Accurate Prediction of Transcriptional Activity of Single Missense Variants in HIV Tat with Deep Learning

by Houssemeddine Derbel, Christopher J. Giacoletto, Ronald Benjamin, Gordon Chen, Martin R. Schiller and Qian Liu

Int. J. Mol. Sci. 2023, 24(7), 6138; https://doi.org/10.3390/ijms24076138 - 24 Mar 2023

Cited by 1 | Viewed by 2010

Abstract

Tat is an essential gene for increasing the transcription of all HIV genes, and affects HIV replication, HIV exit from latency, and AIDS progression. The Tat gene frequently mutates in vivo and produces variants with diverse activities, contributing to HIV viral heterogeneity as [...] Read more.

Tat is an essential gene for increasing the transcription of all HIV genes, and affects HIV replication, HIV exit from latency, and AIDS progression. The Tat gene frequently mutates in vivo and produces variants with diverse activities, contributing to HIV viral heterogeneity as well as drug-resistant clones. Thus, identifying the transcriptional activities of Tat variants will help to better understand AIDS pathology and treatment. We recently reported the missense mutation landscape of all single amino acid Tat variants. In these experiments, a fraction of double missense alleles exhibited intragenic epistasis. However, it is too time-consuming and costly to determine the effect of the variants for all double mutant alleles through experiments. Therefore, we propose a combined GigaAssay/deep learning approach. As a first step to determine activity landscapes for complex variants, we evaluated a deep learning framework using previously reported GigaAssay experiments to predict how transcription activity is affected by Tat variants with single missense substitutions. Our approach achieved a 0.94 Pearson correlation coefficient when comparing the predicted to experimental activities. This hybrid approach can be extensible to more complex Tat alleles for a better understanding of the genetic control of HIV genome transcription. Full article

(This article belongs to the Special Issue Recent Advances in Human Genetics)

► Show Figures

Figure 1

Review

Jump to: Research, Other

15 pages, 1401 KiB

Open AccessReview

Exploring the Role of Clustered Mutations in Carcinogenesis and Their Potential Clinical Implications in Cancer

by Yi Li, Rui Zhu, Jiaming Jin, Haochuan Guo, Jiaxi Zhang, Zhiheng He, Tingming Liang and Li Guo

Int. J. Mol. Sci. 2024, 25(12), 6744; https://doi.org/10.3390/ijms25126744 - 19 Jun 2024

Viewed by 988

Abstract

Abnormal cell proliferation and growth leading to cancer primarily result from cumulative genome mutations. Single gene mutations alone do not fully explain cancer onset and progression; instead, clustered mutations—simultaneous occurrences of multiple mutations—are considered to be pivotal in cancer development and advancement. These [...] Read more.

Abnormal cell proliferation and growth leading to cancer primarily result from cumulative genome mutations. Single gene mutations alone do not fully explain cancer onset and progression; instead, clustered mutations—simultaneous occurrences of multiple mutations—are considered to be pivotal in cancer development and advancement. These mutations can affect different genes and pathways, resulting in cells undergoing malignant transformation with multiple functional abnormalities. Clustered mutations influence cancer growth rates, metastatic potential, and drug treatment sensitivity. This summary highlights the various types and characteristics of clustered mutations to understand their associations with carcinogenesis and discusses their potential clinical significance in cancer. As a unique mutation type, clustered mutations may involve genomic instability, DNA repair mechanism defects, and environmental exposures, potentially correlating with responsiveness to immunotherapy. Understanding the characteristics and underlying processes of clustered mutations enhances our comprehension of carcinogenesis and cancer progression, providing new diagnostic and therapeutic approaches for cancer. Full article

(This article belongs to the Special Issue Recent Advances in Human Genetics)

► Show Figures

Figure 1

22 pages, 2312 KiB

Open AccessReview

Exploring the Role of Enhancer-Mediated Transcriptional Regulation in Precision Biology

by Xueyan Wang, Danli Liu, Jing Luo, Dashuai Kong and Yubo Zhang

Int. J. Mol. Sci. 2023, 24(13), 10843; https://doi.org/10.3390/ijms241310843 - 29 Jun 2023

Cited by 2 | Viewed by 1922

Abstract

The emergence of precision biology has been driven by the development of advanced technologies and techniques in high-resolution biological research systems. Enhancer-mediated transcriptional regulation, a complex network of gene expression and regulation in eukaryotes, has attracted significant attention as a promising avenue for [...] Read more.

The emergence of precision biology has been driven by the development of advanced technologies and techniques in high-resolution biological research systems. Enhancer-mediated transcriptional regulation, a complex network of gene expression and regulation in eukaryotes, has attracted significant attention as a promising avenue for investigating the underlying mechanisms of biological processes and diseases. To address biological problems with precision, large amounts of data, functional information, and research on the mechanisms of action of biological molecules is required to address biological problems with precision. Enhancers, including typical enhancers and super enhancers, play a crucial role in gene expression and regulation within this network. The identification and targeting of disease-associated enhancers hold the potential to advance precision medicine. In this review, we present the concepts, progress, importance, and challenges in precision biology, transcription regulation, and enhancers. Furthermore, we propose a model of transcriptional regulation for multi-enhancers and provide examples of their mechanisms in mammalian cells, thereby enhancing our understanding of how enhancers achieve precise regulation of gene expression in life processes. Precision biology holds promise in providing new tools and platforms for discovering insights into gene expression and disease occurrence, ultimately benefiting individuals and society as a whole. Full article

(This article belongs to the Special Issue Recent Advances in Human Genetics)

► Show Figures

Figure 1

16 pages, 1038 KiB

Open AccessReview

Narrative Review: Update on the Molecular Diagnosis of Fragile X Syndrome

by Cristian-Gabriel Ciobanu, Irina Nucă, Roxana Popescu, Lucian-Mihai Antoci, Lavinia Caba, Anca Viorica Ivanov, Karina-Alexandra Cojocaru, Cristina Rusu, Cosmin-Teodor Mihai and Monica-Cristina Pânzaru

Int. J. Mol. Sci. 2023, 24(11), 9206; https://doi.org/10.3390/ijms24119206 - 24 May 2023

Cited by 2 | Viewed by 4049

Abstract

The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet able to precisely identify the number of repeats, methylation status, level of mosaicism, and/or the presence of AGG [...] Read more.

The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet able to precisely identify the number of repeats, methylation status, level of mosaicism, and/or the presence of AGG interruptions. A high number of repeats (>200) in the fragile X messenger ribonucleoprotein 1 gene (FMR1) results in hypermethylation of promoter and gene silencing. The actual molecular diagnosis is performed using a Southern blot, TP-PCR (Triplet-Repeat PCR), MS-PCR (Methylation-Specific PCR), and MS-MLPA (Methylation-Specific MLPA) with some limitations, with multiple assays being necessary to completely characterise a patient with FXS. The actual gold standard diagnosis uses Southern blot; however, it cannot accurately characterise all cases. Optical genome mapping is a new technology that has also been developed to approach the diagnosis of fragile X syndrome. Long-range sequencing represented by PacBio and Oxford Nanopore has the potential to replace the actual diagnosis and offers a complete characterization of molecular profiles in a single test. The new technologies have improved the diagnosis of fragile X syndrome and revealed unknown aberrations, but they are a long way from being used routinely in clinical practice. Full article

(This article belongs to the Special Issue Recent Advances in Human Genetics)

► Show Figures

Figure 1

Other

Jump to: Research, Review

11 pages, 620 KiB

Open AccessBrief Report

The Rationale of Complement Blockade of the MCP_ggaac Haplotype following Atypical Hemolytic Uremic Syndrome of Three Southeastern European Countries with a Literature Review

by Daniel Turudic, Danka Pokrajac, Velibor Tasic, Dino Kasumovic, Zoltan Prohaszka and Danko Milosevic

Int. J. Mol. Sci. 2023, 24(17), 13041; https://doi.org/10.3390/ijms241713041 - 22 Aug 2023

Viewed by 1289

Abstract

We present eight cases of the homozygous MCPggaac haplotype, which is considered to increase the likelihood and severity of atypical hemolytic uremic syndrome (aHUS), especially in combination with additional risk aHUS mutations. Complement blockade (CBT) was applied at a median age of 92 [...] Read more.

We present eight cases of the homozygous MCPggaac haplotype, which is considered to increase the likelihood and severity of atypical hemolytic uremic syndrome (aHUS), especially in combination with additional risk aHUS mutations. Complement blockade (CBT) was applied at a median age of 92 months (IQR 36–252 months). The median number of relapses before CBT initiation (Eculizumab) was two. Relapses occurred within an average of 22.16 months (median 17.5, minimum 8 months, and maximum 48 months) from the first subsequent onset of the disease (6/8 patients). All cases were treated with PI/PEX, and rarely with renal replacement therapy (RRT). When complement blockade was applied, children had no further disease relapses. Children with MCPggaac haplotype with/without additional gene mutations can achieve remission through renal replacement therapy without an immediate need for complement blockade. If relapse of aHUS occurs soon after disease onset or relapses are repeated frequently, a permanent complement blockade is required. However, the duration of such a blockade remains uncertain. If complement inhibition is not applied within 4–5 relapses, proteinuria and chronic renal failure will eventually occur. Full article

(This article belongs to the Special Issue Recent Advances in Human Genetics)

► Show Figures

Figure 1

6 pages, 509 KiB

Open AccessCommentary

Synonymous Variants of Uncertain Silence

by Christopher J. Giacoletto, Jerome I. Rotter, Wayne W. Grody and Martin R. Schiller

Int. J. Mol. Sci. 2023, 24(13), 10556; https://doi.org/10.3390/ijms241310556 - 23 Jun 2023

Viewed by 1789

Abstract

Synonymous variants, traditionally regarded as silent mutations due to their lack of impact on protein sequence, structure and function, have been the subject of increasing scrutiny. This commentary explores the emerging evidence challenging the notion of synonymous variants as functionally inert. Analysis of [...] Read more.

Synonymous variants, traditionally regarded as silent mutations due to their lack of impact on protein sequence, structure and function, have been the subject of increasing scrutiny. This commentary explores the emerging evidence challenging the notion of synonymous variants as functionally inert. Analysis of the activity of 70 synonymous variants in the HIV Tat transcription factor revealed that 50% of the variants exhibited significant deviations from wild-type activity. Our analysis supports previous work and raises important questions about the broader impact of non-silent synonymous variants in human genes. Considering the potential functional implications, the authors propose classifying such variants as “synonymous variants of uncertain silence” (sVUS), highlighting the need for cautious interpretation and further investigations in clinical and genetic testing settings. Full article

(This article belongs to the Special Issue Recent Advances in Human Genetics)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Recent Advances in Human Genetics

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (8 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI