Submit to Genes Review for Genes Propose a Special Issue

Journal Menu

Journal Browser

Genetic and Phenotypic Correlation: Gene-Disease Validation

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

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 July 2023) | Viewed by 20144

Share This Special Issue

Special Issue Editors

Dr. Yu An

E-Mail Website
Guest Editor

Human Phenome Institute, Fudan University, Shanghai, China
Interests: genetics and genomics; developmental disorder; neurodevelopmental disorder; genetic counseling; translational medicine
Special Issues, Collections and Topics in MDPI journals

Dr. Tianyun Wang

E-Mail Website
Guest Editor

Department of Genome Sciences, University of Washington, Seattle, WA, USA
Interests: genetics; genomics; autism; neurodevelopmental disorders
Special Issues, Collections and Topics in MDPI journals

Dr. Hua Sun

E-Mail Website
Guest Editor

Stead Family Department of Pediatrics, The University of Iowa, Iowa City, IA 52242, USA
Interests: nephrology; urology, congenital anomalies; prenatal counseling; rare renal diseases

Dr. Junyu Zhang

E-Mail Website
Guest Editor

Department of Reproductive Genetics, Obstetrics and Gynecology Hospital of Tongji University, 2699 West Gaoke Road, Shanghai 201204, China
Interests: reproductive genetics; gene disease validity; variant interpretation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

With the increasing use of genomic sequencing technology, a significant number of genes contributing to Mendelian disorders can be rapidly identified. However, the clinical utility of this technology bottlenecks at variant interpretation. Substantial gaps in the knowledge base necessitate more information on gene disease validation, especially genetic or experimental evidence on variants of known genes, which can clarify the correlation between genotype and phenotype.

The “one-gene-one-disease” paradigm has been challenged by multiple disease traits caused by one gene or one locus in one gene. At times, face lumping and the splitting conundrum are necessary to evaluate the validity of a gene–disease relationship. However, variable expressivity and the incomplete penetrance of recurrent variants make genetic diagnosis challenging. More genetic and experimental evidence could enhance our understanding of the role of genetic etiology in diseases; filling this research gap constitutes the genetic basis for improving precision medicine.

This Special Issue welcomes a variety of research papers, including systematic reviews of the genotype–phenotype correlation, detailed studies on genetic and experimental evidence of gene alteration, and novel insights into the genetic mechanism of rare genetic diseases, involving both the modifier factor discovery and expanded clinical phenotype of genetic variants.

Dr. Yu An
Dr. Tianyun Wang
Dr. Hua Sun
Dr. Junyu Zhang
Guest Editors

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

developmental disorder
neurodevelopment
birth defect
genetic disorder
gene discovery
next-generation sequencing (NGS)
while exome/genome sequencing
molecular biology
animal modeling
genotype
phenotype
gene curation
pathogenesis
modifier
variant interpretation

Published Papers (9 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Other

16 pages, 5298 KiB

Open AccessArticle

A Missense Mutation c.1132G > A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata

by Yue Shi, Yan Xu, Chao Wang, Yiqing Chen, Xiaojun Ren, Yu Kang and Chao Wang

Genes 2023, 14(3), 744; https://doi.org/10.3390/genes14030744 - 18 Mar 2023

Cited by 1 | Viewed by 1930

Abstract

Background: HLRCC syndrome is a hereditary cancer predisposition syndrome caused by heterozygous germline pathogenic variant of the fumarate hydratase (FH) gene and characterized by cutaneous leiomyomas (CL), uterine leiomyomas (UL), and renal cell carcinoma (RCC). Loss of function variant of FH gene inactivates the Kreb’s cycle enzyme activity and predisposes individuals with such variant to the development of HLRCC. Methods: Next-generation sequencing (NGS) and Sanger confirmation were given to family members accessible. Following that, a functional study in vitro was performed to further confirm the pathogenicity of the variant. FH-Wild type (FH-WT) and FH-mutant (FH-MUT) (E378K) plasmid were constructed and transfected into 293T and uterine leiomyoma cell lines, respectively. Proliferation assessment was executed to show how this mutation affects the growth of uterine leiomyoma. qPCR and Western blotting were performed to investigate the change of transcription and translation of FH with mutation (E378K), and FH enzyme assay activity were tested in 293T cells with mutation and wild-type plasmids. Results: Here, we presented two families with the same missense variant (c.1132G > A) that has not been reported as a germline mutation in hereditary uterine leiomyomas before and classified as VUS in gene databases. Our in vitro experiments supported the pathogenicity of this missense variant, especially in uterine leiomyomata. Conclusions: According to the American College of Medical Genetics (ACMG) guideline, the E378K variant was classified as likely pathogenic (with evidence PS4_support, PS3_support, PM2_support, PP1, PP3 and PP4 evidence). Further insights into clinical management in uterine leiomyomata were discussed and should be practiced in gynecological clinical settings. Full article

(This article belongs to the Special Issue Genetic and Phenotypic Correlation: Gene-Disease Validation)

► Show Figures

Figure 1

15 pages, 2180 KiB

Open AccessArticle

Pathogenicity Analysis of a Novel Variant in GTPBP3 Causing Mitochondrial Disease and Systematic Literature Review

by Qin Zhang, Qianqian Ouyang, Jingjing Xiang, Hong Li, Haitao Lv and Yu An

Genes 2023, 14(3), 552; https://doi.org/10.3390/genes14030552 - 22 Feb 2023

Cited by 2 | Viewed by 1808

Abstract

Defect of GTPBP3, the human mitochondrial tRNA-modifying enzyme, can lead to Combined Oxidative Phosphorylation Deficiency 23 (COXPD23). Up to now, about 20 different variants of the GTPBP3 gene have been reported; however, genotype–phenotype analysis has rarely been described. Here, we reported a 9-year-old boy with COXPD23 who presented with hyperlactatemia, hypertrophic cardiomyopathy, seizures, feeding difficulties, intellectual disability and motor developmental delay, and abnormal visual development. Biallelic pathogenic variants of the GTPBP3 gene were identified in this boy, one novel variant c.1102dupC (p. Arg368Profs*22) inherited from the mother and the other known variant c.689A>C (p. Gln230Pro) inherited from father. We curated 18 COXPD23 patients with GTPBP3 variants to investigate the genotype–phenotype correlation. We found that hyperlactatemia and cardiomyopathy were critical clinical features in COXPD23 and the average onset age was 1.7 years (3 months of age for the homozygote). Clinical classification of COXPD23 for the two types, severe and mild, was well described in this study. We observed arrhythmia and congestive heart failure frequently in the severe type with early childhood mortality, while developmental delay was mainly observed in the mild type. The proportion of homozygous variants (71.4%) significantly differed from that of compound heterozygous variants (18.1%) in the severe type. Compared with the variants in gnomAD, the proportion of LOFVs in GTPBP3 was higher in COXPD23 patients (48.6% versus 8.9%, p < 0.0001 ****), and 31% of them were frameshift variants, showing the LOF mechanism of GTPBP3. Additionally, the variants in patients were significantly enriched in the TrmE-type G domain, indicating that the G domain was crucial for GTPBP3 protein function. The TrmE-type G domain contained several significant motifs involved in the binding of guanine nucleotides and Mg²⁺, the hydrolysis of GTP, and the regulation of the functional status of GTPases. In conclusion, we reported a mild COXPD23 case with typical GTPBP3-related symptoms, including seizures and abnormal visual development seldom observed previously. Our study provides novel insight into understanding the clinical diagnosis and genetic counseling of patients with COXPD23 by exploring the genetic pathogenesis and genotype–phenotype correlation of COXPD23. Full article

(This article belongs to the Special Issue Genetic and Phenotypic Correlation: Gene-Disease Validation)

► Show Figures

Figure 1

14 pages, 2247 KiB

Open AccessArticle

Genotype–Phenotype Correlations in 2q37-Deletion Syndrome: An Update of the Clinical Spectrum and Literature Review

by Eva-Cristiana Gavril, Irina Nucă, Monica-Cristina Pânzaru, Anca Viorica Ivanov, Cosmin-Teodor Mihai, Lucian-Mihai Antoci, Cristian-Gabriel Ciobanu, Cristina Rusu and Roxana Popescu

Genes 2023, 14(2), 465; https://doi.org/10.3390/genes14020465 - 11 Feb 2023

Cited by 2 | Viewed by 2594

Abstract

2q37 microdeletion/deletion syndrome (2q37DS) is one of the most common subtelomeric deletion disorders, caused by a 2q37 deletion of variable size. The syndrome is characterized by a broad and diverse spectrum of clinical findings: characteristic facial dysmorphism, developmental delay/intellectual disability (ID), brachydactyly type E, short stature, obesity, hypotonia in infancy, and abnormal behavior with autism spectrum disorder. Although numerous cases have been described so far, the exact mapping of the genotype and phenotype have not yet been achieved. Materials and Methods: In this study we analyzed nine newly diagnosed cases with 2q37 deletion (3 male/6 female, aged between 2 and 30 years old), and followed up at the Iasi Regional Medical Genetics Centre. All patients were tested first with MLPA using combined kits P036/P070 subtelomeric screening mix and follow-up mix P264; after, the deletion size and location were confirmed via CGH-array. We compared our findings with the data of other cases reported in the literature. Results: From nine cases, four had pure 2q37 deletions of variable sizes, and five presented deletion/duplication rearrangements (with chromosomes 2q, 9q, and 11p). In most cases, characteristic phenotypic aspects were observed: 9/9 facial dysmorphism, 8/9 global developmental delay and ID, 6/9 hypotonia, 5/9 behavior disorders, and 8/9 skeletal anomalies—especially brachydactyly type E. Two cases had obesity, one case had craniosynostosis, and four had heart defects. Other features found in our cases included translucent skin and telangiectasias (6/9), and a hump of fat on the upper thorax (5/9). Conclusions: Our study enriches the literature data by describing new clinical features associated with 2q37 deletion, and possible genotype–phenotype correlations. Full article

(This article belongs to the Special Issue Genetic and Phenotypic Correlation: Gene-Disease Validation)

► Show Figures

Figure 1

7 pages, 1283 KiB

Open AccessArticle

Anterior Umbilication of Lens in a Family with Congenital Cataracts Associated with a Missense Mutation of MIP Gene

by Zhixing Cheng, Xun Wang, Qiwei Wang, Xulin Zhang, Dongni Wang, Weiming Huang, Meimei Dongye, Xiaocheng Feng, Danying Zheng and Haotian Lin

Genes 2022, 13(11), 1987; https://doi.org/10.3390/genes13111987 - 31 Oct 2022

Viewed by 1227

Abstract

Congenital cataracts (CCs) have significant genotypic and phenotypic heterogeneity. The major intrinsic protein (MIP) gene, one of the causative genes of CCs, plays a vital role in maintaining the homeostasis and transparency of the lens. In this study, we identified a unique phenotype of anterior umbilication of the lens in a four-generation pedigree with CCs. All patients in the observed family had nystagmus, nuclear cataracts, and elongated axial lengths compared with their healthy counterparts except for patient I:2, whose axial length was unavailable, and patientII:4, who had total cataracts. We confirmed, using Sanger sequencing based on whole-exon sequencing (WES) data, that all patients carried a heterozygous variant NM_012064.4:c.97C > T (NP_036196.1:p.R33C) in their MIP gene. To our knowledge, 29 variants of the human MIP gene and the relative phenotypes associated with CCs have been identified. Nevertheless, this is the first report on the anterior umbilication of the lens with nuclear or total opacity caused by the c.97C > T (p.R33C) variant in the MIP gene. These results also provide evidence that the elongated axial length might be associated with this variant. This study further confirms the phenotypic heterogeneity of CCs. Full article

(This article belongs to the Special Issue Genetic and Phenotypic Correlation: Gene-Disease Validation)

► Show Figures

Figure 1

12 pages, 269 KiB

Open AccessArticle

The Benefits of Family Screening in Rare Diseases: Genetic Testing Reveals 165 New Cases of Fabry Disease among At-Risk Family Members of 83 Index Patients

by Sergey Moiseev, Ekaterina Tao, Alexey Moiseev, Nikolay Bulanov, Ekaterina Filatova, Victor Fomin and Dominique P. Germain

Genes 2022, 13(9), 1619; https://doi.org/10.3390/genes13091619 - 09 Sep 2022

Cited by 3 | Viewed by 2009

Abstract

Background: Fabry disease (FD, OMIM #301500) is a rare, progressive, X-linked, inherited genetic disease caused by a functional deficiency of lysosomal α-galactosidase, leading to the accumulation of glycosphingolipids in virtually all of the body’s cell types and fluids. Patients with rare genetic diseases and non-specific symptoms often experience substantial diagnostic delays, which can negatively impact the prompt initiation of treatment. If FD is not treated specifically, end organ damage (such as chronic renal failure, hypertrophic cardiomyopathy with arrhythmia, and strokes) impairs quality of life and reduces life expectancy. Patients and Methods: For 83 consecutive patients with FD referred to the Russian reference center for lysosomal storage diseases, family trees were built and genetic testing (cascade genotyping) was offered to family members. Results: The pathogenic GLA variant associated with FD was identified for all 83 probands. Family testing using cascade genotyping enabled the identification of 165 additional cases of FD among the tested 331 at-risk family members. Discussion: This is the first study to have described family screening in a large Russian cohort of patients with FD and chronic kidney disease. Raising awareness of FD among clinicians is important for earlier diagnosis and specific treatment. Full article

(This article belongs to the Special Issue Genetic and Phenotypic Correlation: Gene-Disease Validation)

13 pages, 2046 KiB

Open AccessArticle

Prenatal Cases Reflect the Complexity of the COL1A1/2 Associated Osteogenesis Imperfecta

by Kai Yang, Yan Liu, Jue Wu, Jing Zhang, Hua-ying Hu, You-sheng Yan, Wen-qi Chen, Shu-fa Yang, Li-juan Sun, Yong-qing Sun, Qing-qing Wu and Cheng-hong Yin

Genes 2022, 13(9), 1578; https://doi.org/10.3390/genes13091578 - 02 Sep 2022

Cited by 1 | Viewed by 1997

Abstract

Introduction: Osteogenesis imperfecta (OI) is a rare mendelian skeletal dysplasia with autosomal dominant or recessive inheritance pattern, and almost the most common primary osteoporosis in prenatal settings. The diversity of clinical presentation and genetic etiology in prenatal OI cases presents a challenge to counseling yet has seldom been discussed in previous studies. Methods: Ten cases with suspected fetal OI were enrolled and submitted to a genetic detection using conventional karyotyping, chromosomal microarray analysis (CMA), and whole-exome sequencing (WES). Sanger sequencing was used as the validation method for potential diagnostic variants. In silico analysis of specific missense variants was also performed. Results: The karyotyping and CMA results of these cases were normal, while WES identified OI-associated variants in the COL1A1/2 genes in all ten cases. Six of these variants were novel. Additionally, four cases here exhibited distinctive clinical and/or genetic characteristics, including the situations of intrafamilial phenotypic variability, parental mosaicism, and “dual nosogenesis” (mutations in collagen I and another gene). Conclusion: Our study not only expands the spectrum of COL1A1/2-related OI, but also highlights the complexity that occurs in prenatal OI and the importance of clarifying its pathogenic mechanisms. Full article

(This article belongs to the Special Issue Genetic and Phenotypic Correlation: Gene-Disease Validation)

► Show Figures

Figure 1

15 pages, 1914 KiB

Open AccessArticle

Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the ZC4H2 Gene

by Jing-Jing Sun, Qin Cai, Miao Xu, Yan-Na Liu, Wan-Rui Li, Juan Li, Li Ma, Cheng Cai, Xiao-Hui Gong, Yi-Tao Zeng, Zhao-Rui Ren and Fanyi Zeng

Genes 2022, 13(9), 1558; https://doi.org/10.3390/genes13091558 - 29 Aug 2022

Cited by 3 | Viewed by 3560

Abstract

Pathogenic variants of zinc finger C4H2-type containing (ZC4H2) on the X chromosome cause a group of genetic diseases termed ZC4H2-associated rare disorders (ZARD), including Wieacker-Wolff Syndrome (WRWF) and Female-restricted Wieacker-Wolff Syndrome (WRWFFR). In the current study, a de novo c.352C>T (p.Gln118*) mutation in ZC4H2 (NM_018684.4) was identified in a female neonate born with severe arthrogryposis multiplex congenita (AMC) and Pierre-Robin sequence (cleft palate and micrognathia). Plasmids containing the wild-type (WT), mutant-type (MT) ZC4H2, or GFP report gene (N) were transfected in 293T cell lines, respectively. RT-qPCR and western blot analysis showed that ZC4H2 protein could not be detected in the 293T cells transfected with MT ZC4H2. The RNA seq results revealed that the expression profile of the MT group was similar to that of the N group but differed significantly from the WT group, indicating that the c.352C>T mutation resulted in the loss of function of ZC4H2. Differentially expressed genes (DEGs) enrichment analysis showed that c.352C>T mutation inhibited the expression levels of a series of genes involved in the oxidative phosphorylation pathway. Subsequently, expression levels of ZC4H2 were knocked down in neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) by lentiviral-expressed small hairpin RNAs (shRNAs) against ZC4H2. The results also demonstrated that decreasing the expression of ZC4H2 significantly reduced the growth of NSCs by affecting the expression of genes related to the oxidative phosphorylation signaling pathway. Taken together, our results strongly suggest that ZC4H2 c.352C>T (p.Gln118*) mutation resulted in the loss of protein function and caused WRWFFR. Full article

(This article belongs to the Special Issue Genetic and Phenotypic Correlation: Gene-Disease Validation)

► Show Figures

Figure 1

13 pages, 1256 KiB

Open AccessArticle

Novel Loss-of-Function Variants in CHD2 Cause Childhood-Onset Epileptic Encephalopathy in Chinese Patients

by Xu Wang, Di Cui, Changhong Ding, Chunhong Chen, Xiaohui Wang, Fang Fang, Hong Jin and Xiaotun Ren

Genes 2022, 13(5), 908; https://doi.org/10.3390/genes13050908 - 19 May 2022

Cited by 1 | Viewed by 2111

Abstract

Developmental and epileptic encephalopathy-94 (DEE94) is a severe form of epilepsy characterized by a broad spectrum of neurodevelopmental disorders. It is caused by pathogenic CHD2 variants. While only a few pathogenic CHD2 variants have been reported with detailed clinical phenotypes, most of which lack molecular analysis. In this study, next-generation sequencing (NGS) was performed to identify likely pathogenic CHD2 variants in patients with epilepsy. Three likely pathogenic variants were finally identified in different patients. The seizure onset ages were from two years to six years. Patients 1 and 2 had developmental delays before epilepsy, while patient 3 had intellectual regression after the first seizure onset. The observed seizures were myoclonic, febrile, and generalized tonic-clonic, which had been controlled by different combinations of antiepileptic drugs. Two de novo (c.1809_1809+1delGGinsTT, p.? and c.3455+2_3455+3insTG, p.?) and one maternal (c.3783G>A, p.W1261*) variant were identified, which were all predicted to be pathogenic/likely pathogenic. Molecular analysis was performed in patient 1, and we detected aberrantly spliced products, proving the pathogenicity of this CHD2 variant. New cases with novel variants, along with a detailed clinical and molecular analysis, are important for a better understanding of CHD2-related epileptic encephalopathy. Full article

(This article belongs to the Special Issue Genetic and Phenotypic Correlation: Gene-Disease Validation)

► Show Figures

Figure 1

Other

Jump to: Research

12 pages, 2445 KiB

Open AccessBrief Report

Novel Exon 7 Deletions in TSPAN12 in a Three-Generation FEVR Family: A Case Report and Literature Review

by Zixuan Jiang and Panfeng Wang

Genes 2023, 14(3), 587; https://doi.org/10.3390/genes14030587 - 25 Feb 2023

Cited by 2 | Viewed by 1444

Abstract

Familial exudative vitreoretinopathy (FEVR) is a severe clinically and genetically heterogeneous disease that is characterized by vascular disorder. FEVR exhibits strikingly variable clinical phenotypes, ranging from asymptomatic to total blindness. In this case, we present a patient who was first treated as having high myopia and retinopathy but was finally diagnosed with FEVR caused by the heterozygous deletion of exon 7 in TSPAN12 with the aid of whole genome sequencing (WGS). Typical vascular changes, including vascular leakage and an avascular zone in the peripheral retina, were observed in the proband using fundus fluorescein angiography (FFA), and the macular dragging was shown to be progressing in the follow-up visit. Furthermore, the proband showed unreported TSPAN12-related phenotypes of FEVR: ERG (full-field electroretinogram) abnormalities and retinoschisis. Only mild vascular changes were exhibited in the FFA for the other three family members who carried the same deletion of exon 7 in TSPAN12. This case expands our understanding of the phenotype resulting from TSPAN12 mutations and signifies the importance of combining both clinical and molecular analysis approaches to establish a complete diagnosis. Full article

(This article belongs to the Special Issue Genetic and Phenotypic Correlation: Gene-Disease Validation)

► Show Figures

Journal Menu

Journal Browser

Genetic and Phenotypic Correlation: Gene-Disease Validation

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (9 papers)

Research

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI