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Functional Studies for Interpreting Genetic Variants Associated with Genetic Disorders

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

Deadline for manuscript submissions: closed (15 January 2022) | Viewed by 11616

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Special Issue Editor

Dr. Rodolfo Iuliano

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Guest Editor

Department of Health Sciences, Campus S. Venuta, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
Interests: gene variants; functional studies; signal transduction; gene regulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The new high performant sequencing techniques have generated a lot of data about human genome variation. In terms of pathogenicity or benignity, the classification of all gene variants is an important future goal for medical genetics and relevant efforts should be pursued to interpret gene variants associated with genetic disorders. The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) established guidelines for variant interpretation to help variant classification. Variant type, familial inheritance, variant frequency, and prediction tools are essential to assess a gene variant classification. One of the strong criteria included in the ACMG guidelines is based on the characterisation of gene variants by functional studies. Therefore, studies reporting experimental evidence that helps the interpretation and classification of gene variants are critical.

This Special Issue aims to collect research articles and reviews based on functional studies that support the classification of germline gene variants detected in human genetic diseases.

Prof. Dr. Rodolfo Iuliano
Guest Editor

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Keywords

Gene variants
Functional assay
Variant interpretation
Genetic disorders
Variant effect
Disease model
Gene regulation

Published Papers (4 papers)

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Research

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28 pages, 1508 KiB

Open AccessArticle

SOD-1 Variants in Amyotrophic Lateral Sclerosis: Systematic Re-Evaluation According to ACMG-AMP Guidelines

by Paola Ruffo, Benedetta Perrone and Francesca Luisa Conforti

Genes 2022, 13(3), 537; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13030537 - 18 Mar 2022

Cited by 5 | Viewed by 3477

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease whose causes are unclear. The first ALS gene associated with the autosomal dominant form of the disease was SOD1. This gene has a high rate of rare variants, and an appropriate classification is essential for a correct ALS diagnosis. In this study, we re-evaluated the classification of all previously reported SOD1 variants (n = 202) from ALSoD, project MinE, and in-house databases by applying the ACMG-AMP criteria to ALS. New bioinformatics analysis, frequency rating, and a thorough search for functional studies were performed. We also proposed adjusting criteria strength describing how to apply them to SOD1 variants. Most of the previously reported variants have been reclassified as likely pathogenic and pathogenic based on the modified weight of the PS3 criterion, highlighting how in vivo or in vitro functional studies are determining their interpretation and classification. Furthermore, this study reveals the concordance and discordance of annotations between open databases, indicating the need for expert review to adapt the study of variants to a specific disease. Indeed, in complex diseases, such as ALS, the oligogenic inheritance, the presence of genes that act as risk factors and the reduced penetration must be considered. Overall, the diagnosis of ALS remains clinical, and improving variant classification could support genetic data as diagnostic criteria. Full article

(This article belongs to the Special Issue Functional Studies for Interpreting Genetic Variants Associated with Genetic Disorders)

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Graphical abstract

10 pages, 1488 KiB

Open AccessArticle

A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions

by Valentina Bruni, Cristina Barbara Spoleti, Andrea La Barbera, Vincenzo Dattilo, Emma Colao, Carmela Votino, Emanuele Bellacchio, Nicola Perrotti, Sabrina Giglio and Rodolfo Iuliano

Genes 2021, 12(9), 1395; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091395 - 10 Sep 2021

Cited by 4 | Viewed by 2250

Abstract

Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1. Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of COL2A1 in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2_1269del located in intron 20/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a COL2A1 messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of COL2A1 cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in COL2A1 may be relevant in determining the phenotype of skeletal dysplasia. Full article

(This article belongs to the Special Issue Functional Studies for Interpreting Genetic Variants Associated with Genetic Disorders)

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15 pages, 4137 KiB

Open AccessArticle

Extended Phenotyping and Functional Validation Facilitate Diagnosis of a Complex Patient Harboring Genetic Variants in MCCC1 and GNB5 Causing Overlapping Phenotypes

by Zhuo Shao, Ikuo Masuho, Anupreet Tumber, Jason T. Maynes, Erika Tavares, Asim Ali, Stacy Hewson, Andreas Schulze, Peter Kannu, Kirill A. Martemyanov and Ajoy Vincent

Genes 2021, 12(9), 1352; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091352 - 29 Aug 2021

Cited by 2 | Viewed by 2167

Abstract

Identifying multiple ultra-rare genetic syndromes with overlapping phenotypes is a diagnostic conundrum in clinical genetics. This study investigated the pathogenicity of a homozygous missense variant in GNB5 (GNB5L; NM_016194.4: c.920T > G (p. Leu307Arg); GNB5S; NM_006578.4: c.794T > G (p. Leu265Arg)) identified through exome sequencing in a female child who also had 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (newborn screening positive) and hemoglobin E trait. The proband presented with early-onset intellectual disability, the severity of which was more in keeping with GNB5-related disorder than 3-MCC deficiency. She later developed bradycardia and cardiac arrest, and upon re-phenotyping showed cone photo-transduction recovery deficit, all known only to GNB5-related disorders. Patient-derived fibroblast assays showed preserved GNB5S expression, but bioluminescence resonance energy transfer assay showed abolished function of the variant reconstituted Gβ5S containing RGS complexes for deactivation of D2 dopamine receptor activity, confirming variant pathogenicity. This study highlights the need for precise phenotyping and functional assays to facilitate variant classification and clinical diagnosis in patients with complex medical conditions. Full article

(This article belongs to the Special Issue Functional Studies for Interpreting Genetic Variants Associated with Genetic Disorders)

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6 pages, 667 KiB

Open AccessOpinion

Chronic Pancreatitis: The True Pathogenic Culprit within the SPINK1 N34S-Containing Haplotype Is No Longer at Large

by Na Pu, Emmanuelle Masson, David N. Cooper, Emmanuelle Génin, Claude Férec and Jian-Min Chen

Genes 2021, 12(11), 1683; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111683 - 23 Oct 2021

Cited by 4 | Viewed by 2608

Abstract

A diverse range of loss-of-function variants in the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) has been identified in patients with chronic pancreatitis (CP). The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser or N34S) variant (rs17107315:T>C) is one of the most important heritable risk factors for CP as a consequence of its relatively high prevalence worldwide (population allele frequency ≈ 1%) and its considerable effect size (odds ratio ≈ 11). The causal variant responsible for this haplotype has been intensively investigated over the past two decades. The different hypotheses tested addressed whether the N34S missense variant has a direct impact on enzyme structure and function, whether c.101A>G could affect pre-mRNA splicing or mRNA stability, and whether another variant in linkage disequilibrium with c.101A>G might be responsible for the observed association with CP. Having reviewed the currently available genetic and experimental data, we conclude that c.-4141G>T (rs142703147:C>A), which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module located ∼4 kb upstream of the SPINK1 promoter, can be designated as the causal variant beyond reasonable doubt. This case illustrates the difficulties inherent in determining the identity of the causal variant underlying an initially identified disease association. Full article

(This article belongs to the Special Issue Functional Studies for Interpreting Genetic Variants Associated with Genetic Disorders)

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