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Novel Splice Site Pathogenic Variant of EFTUD2 Is Associated with Mandibulofacial Dysostosis with Microcephaly and Extracranial Symptoms in Korea

Elongation factor Tu guanosine-5’-triphosphate (GTP) binding domain containing 2 (EFTUD2) encodes a major component of the spliceosomal GTPase and, if mutated, causes mandibulofacial dysostosis with microcephaly (MFDM; MIM#610536). Despite the increasing number of potentially pathogenic variants rep...

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Autores principales: Kim, So Young, Lee, Da-hye, Han, Jin Hee, Choi, Byung Yoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277841/
https://www.ncbi.nlm.nih.gov/pubmed/32408545
http://dx.doi.org/10.3390/diagnostics10050296
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author Kim, So Young
Lee, Da-hye
Han, Jin Hee
Choi, Byung Yoon
author_facet Kim, So Young
Lee, Da-hye
Han, Jin Hee
Choi, Byung Yoon
author_sort Kim, So Young
collection PubMed
description Elongation factor Tu guanosine-5’-triphosphate (GTP) binding domain containing 2 (EFTUD2) encodes a major component of the spliceosomal GTPase and, if mutated, causes mandibulofacial dysostosis with microcephaly (MFDM; MIM#610536). Despite the increasing number of potentially pathogenic variants reported in the literature, most previous studies have relied solely on in silico prediction of the pathogenic potential of EFTUD2 variants, which may result in misclassification of the variant’s pathogenicity. Given the importance of the functional verification of EFTUD2 variants, we identified a novel splice donor site variant, c.271+1G>A of EFTUD2, whose pathogenicity was clearly verified at the RNA level using a minigene assay. A child with MFDM, mixed hearing loss, microcephaly, and a congenital cardiac defect was identified with this variant, which arose in a de novo fashion. The minigene assay showed erroneous integration of the 118 bp IVS3 of EFTUD2 exclusively among the c.271+1G>A variant clone. We first applied the minigene assay to identify the splice function of a splice site variant of EFTUD2, thereby allowing for in vitro functional verification of splice site variants in EFTUD2.
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spelling pubmed-72778412020-06-12 Novel Splice Site Pathogenic Variant of EFTUD2 Is Associated with Mandibulofacial Dysostosis with Microcephaly and Extracranial Symptoms in Korea Kim, So Young Lee, Da-hye Han, Jin Hee Choi, Byung Yoon Diagnostics (Basel) Article Elongation factor Tu guanosine-5’-triphosphate (GTP) binding domain containing 2 (EFTUD2) encodes a major component of the spliceosomal GTPase and, if mutated, causes mandibulofacial dysostosis with microcephaly (MFDM; MIM#610536). Despite the increasing number of potentially pathogenic variants reported in the literature, most previous studies have relied solely on in silico prediction of the pathogenic potential of EFTUD2 variants, which may result in misclassification of the variant’s pathogenicity. Given the importance of the functional verification of EFTUD2 variants, we identified a novel splice donor site variant, c.271+1G>A of EFTUD2, whose pathogenicity was clearly verified at the RNA level using a minigene assay. A child with MFDM, mixed hearing loss, microcephaly, and a congenital cardiac defect was identified with this variant, which arose in a de novo fashion. The minigene assay showed erroneous integration of the 118 bp IVS3 of EFTUD2 exclusively among the c.271+1G>A variant clone. We first applied the minigene assay to identify the splice function of a splice site variant of EFTUD2, thereby allowing for in vitro functional verification of splice site variants in EFTUD2. MDPI 2020-05-12 /pmc/articles/PMC7277841/ /pubmed/32408545 http://dx.doi.org/10.3390/diagnostics10050296 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kim, So Young
Lee, Da-hye
Han, Jin Hee
Choi, Byung Yoon
Novel Splice Site Pathogenic Variant of EFTUD2 Is Associated with Mandibulofacial Dysostosis with Microcephaly and Extracranial Symptoms in Korea
title Novel Splice Site Pathogenic Variant of EFTUD2 Is Associated with Mandibulofacial Dysostosis with Microcephaly and Extracranial Symptoms in Korea
title_full Novel Splice Site Pathogenic Variant of EFTUD2 Is Associated with Mandibulofacial Dysostosis with Microcephaly and Extracranial Symptoms in Korea
title_fullStr Novel Splice Site Pathogenic Variant of EFTUD2 Is Associated with Mandibulofacial Dysostosis with Microcephaly and Extracranial Symptoms in Korea
title_full_unstemmed Novel Splice Site Pathogenic Variant of EFTUD2 Is Associated with Mandibulofacial Dysostosis with Microcephaly and Extracranial Symptoms in Korea
title_short Novel Splice Site Pathogenic Variant of EFTUD2 Is Associated with Mandibulofacial Dysostosis with Microcephaly and Extracranial Symptoms in Korea
title_sort novel splice site pathogenic variant of eftud2 is associated with mandibulofacial dysostosis with microcephaly and extracranial symptoms in korea
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277841/
https://www.ncbi.nlm.nih.gov/pubmed/32408545
http://dx.doi.org/10.3390/diagnostics10050296
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