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A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome

PURPOSE: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). METHODS: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, wer...

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Autores principales: Cuvertino, Sara, Hartill, Verity, Colyer, Alice, Garner, Terence, Nair, Nisha, Al-Gazali, Lihadh, Canham, Natalie, Faundes, Victor, Flinter, Frances, Hertecant, Jozef, Holder-Espinasse, Muriel, Jackson, Brian, Lynch, Sally Ann, Nadat, Fatima, Narasimhan, Vagheesh M., Peckham, Michelle, Sellers, Robert, Seri, Marco, Montanari, Francesca, Southgate, Laura, Squeo, Gabriella Maria, Trembath, Richard, van Heel, David, Venuto, Santina, Weisberg, Daniel, Stals, Karen, Ellard, Sian, Barton, Anne, Kimber, Susan J., Sheridan, Eamonn, Merla, Giuseppe, Stevens, Adam, Johnson, Colin A., Banka, Siddharth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200597/
https://www.ncbi.nlm.nih.gov/pubmed/31949313
http://dx.doi.org/10.1038/s41436-019-0743-3
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author Cuvertino, Sara
Hartill, Verity
Colyer, Alice
Garner, Terence
Nair, Nisha
Al-Gazali, Lihadh
Canham, Natalie
Faundes, Victor
Flinter, Frances
Hertecant, Jozef
Holder-Espinasse, Muriel
Jackson, Brian
Lynch, Sally Ann
Nadat, Fatima
Narasimhan, Vagheesh M.
Peckham, Michelle
Sellers, Robert
Seri, Marco
Montanari, Francesca
Southgate, Laura
Squeo, Gabriella Maria
Trembath, Richard
van Heel, David
Venuto, Santina
Weisberg, Daniel
Stals, Karen
Ellard, Sian
Barton, Anne
Kimber, Susan J.
Sheridan, Eamonn
Merla, Giuseppe
Stevens, Adam
Johnson, Colin A.
Banka, Siddharth
author_facet Cuvertino, Sara
Hartill, Verity
Colyer, Alice
Garner, Terence
Nair, Nisha
Al-Gazali, Lihadh
Canham, Natalie
Faundes, Victor
Flinter, Frances
Hertecant, Jozef
Holder-Espinasse, Muriel
Jackson, Brian
Lynch, Sally Ann
Nadat, Fatima
Narasimhan, Vagheesh M.
Peckham, Michelle
Sellers, Robert
Seri, Marco
Montanari, Francesca
Southgate, Laura
Squeo, Gabriella Maria
Trembath, Richard
van Heel, David
Venuto, Santina
Weisberg, Daniel
Stals, Karen
Ellard, Sian
Barton, Anne
Kimber, Susan J.
Sheridan, Eamonn
Merla, Giuseppe
Stevens, Adam
Johnson, Colin A.
Banka, Siddharth
author_sort Cuvertino, Sara
collection PubMed
description PURPOSE: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). METHODS: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. RESULTS: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition. CONCLUSION: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.
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spelling pubmed-72005972020-05-07 A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome Cuvertino, Sara Hartill, Verity Colyer, Alice Garner, Terence Nair, Nisha Al-Gazali, Lihadh Canham, Natalie Faundes, Victor Flinter, Frances Hertecant, Jozef Holder-Espinasse, Muriel Jackson, Brian Lynch, Sally Ann Nadat, Fatima Narasimhan, Vagheesh M. Peckham, Michelle Sellers, Robert Seri, Marco Montanari, Francesca Southgate, Laura Squeo, Gabriella Maria Trembath, Richard van Heel, David Venuto, Santina Weisberg, Daniel Stals, Karen Ellard, Sian Barton, Anne Kimber, Susan J. Sheridan, Eamonn Merla, Giuseppe Stevens, Adam Johnson, Colin A. Banka, Siddharth Genet Med Article PURPOSE: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). METHODS: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. RESULTS: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition. CONCLUSION: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism. Nature Publishing Group US 2020-01-17 2020 /pmc/articles/PMC7200597/ /pubmed/31949313 http://dx.doi.org/10.1038/s41436-019-0743-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Cuvertino, Sara
Hartill, Verity
Colyer, Alice
Garner, Terence
Nair, Nisha
Al-Gazali, Lihadh
Canham, Natalie
Faundes, Victor
Flinter, Frances
Hertecant, Jozef
Holder-Espinasse, Muriel
Jackson, Brian
Lynch, Sally Ann
Nadat, Fatima
Narasimhan, Vagheesh M.
Peckham, Michelle
Sellers, Robert
Seri, Marco
Montanari, Francesca
Southgate, Laura
Squeo, Gabriella Maria
Trembath, Richard
van Heel, David
Venuto, Santina
Weisberg, Daniel
Stals, Karen
Ellard, Sian
Barton, Anne
Kimber, Susan J.
Sheridan, Eamonn
Merla, Giuseppe
Stevens, Adam
Johnson, Colin A.
Banka, Siddharth
A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome
title A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome
title_full A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome
title_fullStr A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome
title_full_unstemmed A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome
title_short A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome
title_sort restricted spectrum of missense kmt2d variants cause a multiple malformations disorder distinct from kabuki syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200597/
https://www.ncbi.nlm.nih.gov/pubmed/31949313
http://dx.doi.org/10.1038/s41436-019-0743-3
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