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Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome
Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presenta...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836705/ https://www.ncbi.nlm.nih.gov/pubmed/35163737 http://dx.doi.org/10.3390/ijms23031815 |
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author | Foroutan, Aidin Haghshenas, Sadegheh Bhai, Pratibha Levy, Michael A. Kerkhof, Jennifer McConkey, Haley Niceta, Marcello Ciolfi, Andrea Pedace, Lucia Miele, Evelina Genevieve, David Heide, Solveig Alders, Mariëlle Zampino, Giuseppe Merla, Giuseppe Fradin, Mélanie Bieth, Eric Bonneau, Dominique Dieterich, Klaus Fergelot, Patricia Schaefer, Elise Faivre, Laurence Vitobello, Antonio Maitz, Silvia Fischetto, Rita Gervasini, Cristina Piccione, Maria van de Laar, Ingrid Tartaglia, Marco Sadikovic, Bekim Lebre, Anne-Sophie |
author_facet | Foroutan, Aidin Haghshenas, Sadegheh Bhai, Pratibha Levy, Michael A. Kerkhof, Jennifer McConkey, Haley Niceta, Marcello Ciolfi, Andrea Pedace, Lucia Miele, Evelina Genevieve, David Heide, Solveig Alders, Mariëlle Zampino, Giuseppe Merla, Giuseppe Fradin, Mélanie Bieth, Eric Bonneau, Dominique Dieterich, Klaus Fergelot, Patricia Schaefer, Elise Faivre, Laurence Vitobello, Antonio Maitz, Silvia Fischetto, Rita Gervasini, Cristina Piccione, Maria van de Laar, Ingrid Tartaglia, Marco Sadikovic, Bekim Lebre, Anne-Sophie |
author_sort | Foroutan, Aidin |
collection | PubMed |
description | Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease. |
format | Online Article Text |
id | pubmed-8836705 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88367052022-02-12 Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome Foroutan, Aidin Haghshenas, Sadegheh Bhai, Pratibha Levy, Michael A. Kerkhof, Jennifer McConkey, Haley Niceta, Marcello Ciolfi, Andrea Pedace, Lucia Miele, Evelina Genevieve, David Heide, Solveig Alders, Mariëlle Zampino, Giuseppe Merla, Giuseppe Fradin, Mélanie Bieth, Eric Bonneau, Dominique Dieterich, Klaus Fergelot, Patricia Schaefer, Elise Faivre, Laurence Vitobello, Antonio Maitz, Silvia Fischetto, Rita Gervasini, Cristina Piccione, Maria van de Laar, Ingrid Tartaglia, Marco Sadikovic, Bekim Lebre, Anne-Sophie Int J Mol Sci Article Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease. MDPI 2022-02-05 /pmc/articles/PMC8836705/ /pubmed/35163737 http://dx.doi.org/10.3390/ijms23031815 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 Foroutan, Aidin Haghshenas, Sadegheh Bhai, Pratibha Levy, Michael A. Kerkhof, Jennifer McConkey, Haley Niceta, Marcello Ciolfi, Andrea Pedace, Lucia Miele, Evelina Genevieve, David Heide, Solveig Alders, Mariëlle Zampino, Giuseppe Merla, Giuseppe Fradin, Mélanie Bieth, Eric Bonneau, Dominique Dieterich, Klaus Fergelot, Patricia Schaefer, Elise Faivre, Laurence Vitobello, Antonio Maitz, Silvia Fischetto, Rita Gervasini, Cristina Piccione, Maria van de Laar, Ingrid Tartaglia, Marco Sadikovic, Bekim Lebre, Anne-Sophie Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome |
title | Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome |
title_full | Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome |
title_fullStr | Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome |
title_full_unstemmed | Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome |
title_short | Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome |
title_sort | clinical utility of a unique genome-wide dna methylation signature for kmt2a-related syndrome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836705/ https://www.ncbi.nlm.nih.gov/pubmed/35163737 http://dx.doi.org/10.3390/ijms23031815 |
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