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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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