An update on genetic variants of the<i>NKX2‐5</i>

Kolomenski, Jorge E.; Delea, Marisol; Simonetti, Leandro; Fabbro, Mónica; Espeche, Lucía D.; Taboas, Melisa; Nadra, Alejandro D.; Bruque, Carlos David; Daín, Liliana

doi:10.1002/humu.24030

Cited by 11 publications

(8 citation statements)

References 139 publications

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“…A pathogenic genetic variant in NKX2-5 was the first found to be associated with CHDs ( 3 ). Gade et al screened 39 CHD families for NKX2-5 mutations.…”

Section: Discussionmentioning

confidence: 99%

Case Report: A Novel NKX2-5 Mutation in a Family With Congenital Heart Defects, Left Ventricular Non-compaction, Conduction Disease, and Sudden Cardiac Death

Morlanes-Gracia

Antoniutti

Alvarez-Rubio

et al. 2021

Front. Cardiovasc. Med.

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The NKX2-5 gene encodes for a transcription factor crucial for cardiac cell differentiation and proliferation. It was the first gene associated with congenital heart disease (CHD) in humans and has been linked to conduction disorders or cardiomyopathies. However, an overlapping phenotype is not frequent in the literature. We describe a family with a novel missense mutation in the NKX2-5 gene (p.Gln181Pro) with numerous antecedents with atrial septal defect (ASD), left ventricular non-compaction (LVNC), conduction disease, and sudden cardiac death (SCD).

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“…A pathogenic genetic variant in NKX2-5 was the first found to be associated with CHDs ( 3 ). Gade et al screened 39 CHD families for NKX2-5 mutations.…”

Section: Discussionmentioning

confidence: 99%

Case Report: A Novel NKX2-5 Mutation in a Family With Congenital Heart Defects, Left Ventricular Non-compaction, Conduction Disease, and Sudden Cardiac Death

Morlanes-Gracia

Antoniutti

Alvarez-Rubio

et al. 2021

Front. Cardiovasc. Med.

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“…These included a molecular homology modeling (MHM) approach and structural analysis of the mutated proteins. The line protein graphs in figures were generated with the PyGame library in the Python 2.7 programming language ( http://www.python.org ) 47 .…”

Section: Methodsmentioning

confidence: 99%

Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches

Buonfiglio

Bruque²,

Lotersztein

et al. 2022

Sci Rep

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Hearing loss is a heterogeneous disorder. Identification of causative mutations is demanding due to genetic heterogeneity. In this study, we investigated the genetic cause of sensorineural hearing loss in patients with severe/profound deafness. After the exclusion of GJB2-GJB6 mutations, we performed whole exome sequencing in 32 unrelated Argentinean families. Mutations were detected in 16 known deafness genes in 20 patients: ACTG1, ADGRV1 (GPR98), CDH23, COL4A3, COL4A5, DFNA5 (GSDDE), EYA4, LARS2, LOXHD1, MITF, MYO6, MYO7A, TECTA, TMPRSS3, USH2A and WSF1. Notably, 11 variants affecting 9 different non-GJB2 genes resulted novel: c.12829C > T, p.(Arg4277*) in ADGRV1; c.337del, p.(Asp109*) and c.3352del, p.(Gly1118Alafs*7) in CDH23; c.3500G > A, p.(Gly1167Glu) in COL4A3; c.1183C > T, p.(Pro395Ser) and c.1759C > T, p.(Pro587Ser) in COL4A5; c.580 + 2 T > C in EYA4; c.1481dup, p.(Leu495Profs*31) in LARS2; c.1939 T > C, p.(Phe647Leu), in MYO6; c.733C > T, p.(Gln245*) in MYO7A and c.242C > G, p.(Ser81*) in TMPRSS3 genes. To predict the effect of these variants, novel protein modeling and protein stability analysis were employed. These results highlight the value of whole exome sequencing to identify candidate variants, as well as bioinformatic strategies to infer their pathogenicity.

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“…( 43 ) The line protein graphs in figures were generated with the PyGame library in the Python 2.7 programming language (Python Software Foundation, Troisdorf, Germany; http://www.python.org). ( 44 )…”

Section: Methodsmentioning

confidence: 99%

Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci

et al. 2022

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Osteoporosis is the most common bone disease, characterized by a low bone mineral density (BMD) and increased risk of fracture. At the other end of the BMD spectrum, some individuals present strong, fracture‐resistant, bones. Both osteoporosis and high BMD are heritable and their genetic architecture encompasses polygenic inheritance of common variants and some cases of monogenic highly penetrant variants in causal genes. We have investigated the genetics of high BMD in a family segregating this trait in an apparently Mendelian dominant pattern. We searched for rare causal variants by whole‐exome sequencing in three affected and three nonaffected family members. Using this approach, we have identified 38 rare coding variants present in the proband and absent in the three individuals with normal BMD. Although we have found four variants shared by the three affected members of the family, we have not been able to relate any of these to the high‐BMD phenotype. In contrast, we have identified missense variants in two genes, VAV3 and ADGRE5, each shared by two of out of three affected members, whose loss of function fits with the phenotype of the family. In particular, the proband, a woman displaying the highest BMD (sum Z‐score = 7), carries both variants, whereas the other two affected members carry one each. VAV3 encodes a guanine‐nucleotide‐exchange factor with an important role in osteoclast activation and function. Although no previous cases of VAV3 mutations have been reported in humans, Vav3 knockout (KO) mice display dense bones, similarly to the high‐BMD phenotype present in our family. The ADGRE5 gene encodes an adhesion G protein‐coupled receptor expressed in osteoclasts whose KO mouse displays increased trabecular bone volume. Combined, these mouse and human data highlight VAV3 and ADGRE5 as novel putative high‐BMD genes with additive effects, and potential therapeutic targets for osteoporosis. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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An update on genetic variants of theNKX2‐5

Cited by 11 publications

References 139 publications

Case Report: A Novel NKX2-5 Mutation in a Family With Congenital Heart Defects, Left Ventricular Non-compaction, Conduction Disease, and Sudden Cardiac Death

Case Report: A Novel NKX2-5 Mutation in a Family With Congenital Heart Defects, Left Ventricular Non-compaction, Conduction Disease, and Sudden Cardiac Death

Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches

Genetic Analysis in a Familial Case With High Bone Mineral Density Suggests Additive Effects at Two Loci

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