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A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia caused by runt-related transcription factor 2 (RUNX2) mutations. In addition to the regular missense, small or large fragment deletions are the common mutation types of RUNX2. This study aimed to find the rules of deletion...

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Autores principales: Zhang, Yanli, Duan, Xiaohong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322484/
https://www.ncbi.nlm.nih.gov/pubmed/35885911
http://dx.doi.org/10.3390/genes13071128
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author Zhang, Yanli
Duan, Xiaohong
author_facet Zhang, Yanli
Duan, Xiaohong
author_sort Zhang, Yanli
collection PubMed
description Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia caused by runt-related transcription factor 2 (RUNX2) mutations. In addition to the regular missense, small or large fragment deletions are the common mutation types of RUNX2. This study aimed to find the rules of deletions in RUNX2. The clinical information of one Chinese CCD family was collected. Genomic DNA was extracted for whole-exome sequencing (WES). Bioinformatics analyzed the pathogenicity of the variants. Polymerase chain reaction (PCR) and Sanger sequencing were carried out using specific primers. RT-PCR and Q-PCR were also used to detect the mRNA level of RUNX2. The CCD studies related with deletions in RUNX2 from 1999 to 2021 from HGMD and PubMed were collected and analyzed for the relationship between the phenotypes and the length of deleted fragments. The proband presented typical CCD features, including delayed closure of cranial sutures, clavicle dysplasia, abnormal teeth. WES, PCR with specific primers and Sanger sequencing revealed a novel heterozygous 90-kbp deletion in RUNX2 (NG_008020.2 g.103671~193943), which caused a substitution (p.Asn183Ile) and premature termination (p.Asp184*). In addition, the mRNA expression of RUNX2 was decreased by 75.5% in the proband. Herein, 31 types of deletions varying from 2 bp to 800 kbp or covering the whole gene of RUNX2 were compared and the significant phenotypic difference was not found among these deletions. The CCD phenotypes were related with the final effects of RUNX2 mutation instead of the length of deletion. WES has the defects in identifying large indels, and direct PCR with specific primers and Sanger sequencing could make up for the shortcoming.
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spelling pubmed-93224842022-07-27 A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia Zhang, Yanli Duan, Xiaohong Genes (Basel) Article Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia caused by runt-related transcription factor 2 (RUNX2) mutations. In addition to the regular missense, small or large fragment deletions are the common mutation types of RUNX2. This study aimed to find the rules of deletions in RUNX2. The clinical information of one Chinese CCD family was collected. Genomic DNA was extracted for whole-exome sequencing (WES). Bioinformatics analyzed the pathogenicity of the variants. Polymerase chain reaction (PCR) and Sanger sequencing were carried out using specific primers. RT-PCR and Q-PCR were also used to detect the mRNA level of RUNX2. The CCD studies related with deletions in RUNX2 from 1999 to 2021 from HGMD and PubMed were collected and analyzed for the relationship between the phenotypes and the length of deleted fragments. The proband presented typical CCD features, including delayed closure of cranial sutures, clavicle dysplasia, abnormal teeth. WES, PCR with specific primers and Sanger sequencing revealed a novel heterozygous 90-kbp deletion in RUNX2 (NG_008020.2 g.103671~193943), which caused a substitution (p.Asn183Ile) and premature termination (p.Asp184*). In addition, the mRNA expression of RUNX2 was decreased by 75.5% in the proband. Herein, 31 types of deletions varying from 2 bp to 800 kbp or covering the whole gene of RUNX2 were compared and the significant phenotypic difference was not found among these deletions. The CCD phenotypes were related with the final effects of RUNX2 mutation instead of the length of deletion. WES has the defects in identifying large indels, and direct PCR with specific primers and Sanger sequencing could make up for the shortcoming. MDPI 2022-06-23 /pmc/articles/PMC9322484/ /pubmed/35885911 http://dx.doi.org/10.3390/genes13071128 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Yanli
Duan, Xiaohong
A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia
title A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia
title_full A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia
title_fullStr A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia
title_full_unstemmed A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia
title_short A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia
title_sort novel 90-kbp deletion of runx2 associated with cleidocranial dysplasia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322484/
https://www.ncbi.nlm.nih.gov/pubmed/35885911
http://dx.doi.org/10.3390/genes13071128
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