Special Issue "Functional Studies for Interpreting Genetic Variants Associated with Genetic Disorders"

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

Deadline for manuscript submissions: 15 January 2022.

Special Issue Editor

Prof. Dr. Rodolfo Iuliano
E-Mail Website
Guest Editor
Dipartimento di Medicina Sperimentale e Clinica, Università “Magna Graecia” di Catanzaro, 88100 Catanzaro, Italy
Interests: gene variants; functional studies; signal transduction; gene regulation

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

Manuscript Submission Information

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Keywords

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

Published Papers (2 papers)

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Research

Article
A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions
Genes 2021, 12(9), 1395; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091395 - 10 Sep 2021
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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. [...] Read more.
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
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Article
Extended Phenotyping and Functional Validation Facilitate Diagnosis of a Complex Patient Harboring Genetic Variants in MCCC1 and GNB5 Causing Overlapping Phenotypes
Genes 2021, 12(9), 1352; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091352 - 29 Aug 2021
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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 [...] Read more.
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
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