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Journal Articles International Journal of Molecular Sciences Year : 2022

Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

Aidin Foroutan (1, 2) , Sadegheh Haghshenas (1, 2) , Pratibha Bhai (2) , Michael A Levy (2) , Jennifer Kerkhof (2) , Haley Mcconkey (2) , Marcello Niceta (3) , Andrea Ciolfi (3) , Lucia Pedace (3) , Evelina Miele (3) , David Genevieve (4) , Solveig Heide (5) , Mariëlle Alders (6, 7) , Giuseppe Zampino (8, 9) , Giuseppe Merla (10, 11) , Mélanie Fradin (12) , Eric Bieth (13) , Dominique Bonneau (14) , Klaus Dieterich (15) , Patricia Fergelot (16) , Elise Schaefer (17) , Laurence Faivre (18, 19) , Antonio Vitobello (18, 19) , Silvia Maitz (20) , Rita Fischetto (21) , Cristina Gervasini (22) , Maria Piccione (23) , Ingrid van de Laar (24) , Marco Tartaglia (3) , Bekim Sadikovic (1, 2) , Anne-Sophie Lebre (25, 26)
1 UWO - University of Western Ontario
2 LHSC - London Health Sciences Center
3 IRCCS Ospedale Pediatrico Bambino Gesù [Roma]
4 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
5 CHU Pitié-Salpêtrière [AP-HP]
6 Amsterdam UMC - Amsterdam University Medical Center
7 UvA - University of Amsterdam [Amsterdam]
8 Fondazione Policlinico Universitario Agostino Gemelli IRCCS
9 Unicatt - Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
10 University of Naples Federico II = Università degli studi di Napoli Federico II
11 FC2S - Fondazione Casa Sollievo della Sofferenza [San Giovanni Rotondo, Italy]
12 Service de génétique clinique [Rennes]
13 Service de génétique [Angers]
14 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
15 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
16 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
17 Les Hôpitaux Universitaires de Strasbourg (HUS)
18 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
19 FHU TRANSLAD (CHU de Dijon)
20 SGH - San Gerardo Hospital [Monza, Italy]
21 Hosp P Giovanni XXIII - Hospital Papa Giovanni XXIII
22 UNIMI - Università degli Studi di Milano = University of Milan
23 Università degli studi di Palermo - University of Palermo
24 Erasmus MC - Erasmus University Medical Center [Rotterdam]
25 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris
26 Service de génétique [Reims]
Aidin Foroutan
  • Function : Author
  • PersonId : 1140915
University of Western Ontario
London Health Sciences Center
Sadegheh Haghshenas
University of Western Ontario
London Health Sciences Center
Pratibha Bhai
London Health Sciences Center
Michael A Levy
  • Function : Author
  • PersonId : 1125501
London Health Sciences Center
Jennifer Kerkhof
London Health Sciences Center
Haley Mcconkey
London Health Sciences Center
Marcello Niceta
  • Function : Author
  • PersonId : 1140918
IRCCS Ospedale Pediatrico Bambino Gesù [Roma]
Andrea Ciolfi
IRCCS Ospedale Pediatrico Bambino Gesù [Roma]
Lucia Pedace
  • Function : Author
  • PersonId : 1125502
IRCCS Ospedale Pediatrico Bambino Gesù [Roma]
Evelina Miele
IRCCS Ospedale Pediatrico Bambino Gesù [Roma]
David Genevieve
  • Function : Author
  • PersonId : 907874
Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
Solveig Heide
  • Function : Author
  • PersonId : 1012475
CHU Pitié-Salpêtrière [AP-HP]
Mariëlle Alders
  • Function : Author
  • PersonId : 1125503
Amsterdam UMC - Amsterdam University Medical Center
University of Amsterdam [Amsterdam]
Giuseppe Zampino
  • Function : Author
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
Giuseppe Merla
  • Function : Author
  • PersonId : 1140920
University of Naples Federico II = Università degli studi di Napoli Federico II
Fondazione Casa Sollievo della Sofferenza [San Giovanni Rotondo, Italy]
Mélanie Fradin
Service de génétique clinique [Rennes]
Eric Bieth
  • Function : Author
  • PersonId : 948825
Service de génétique [Angers]
Dominique Bonneau
  • Function : Author
  • PersonId : 867786
MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
Klaus Dieterich
  • Function : Author
  • PersonId : 856417
Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
Patricia Fergelot
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
Elise Schaefer
  • Function : Author
  • PersonId : 1125504
Les Hôpitaux Universitaires de Strasbourg (HUS)
Laurence Faivre
  • Function : Author
  • PersonId : 856301
Lipides - Nutrition - Cancer [Dijon - U1231]
FHU TRANSLAD (CHU de Dijon)
Antonio Vitobello
  • Function : Author
  • PersonId : 1140922
Lipides - Nutrition - Cancer [Dijon - U1231]
FHU TRANSLAD (CHU de Dijon)
Silvia Maitz
San Gerardo Hospital [Monza, Italy]
Rita Fischetto
  • Function : Author
Hospital Papa Giovanni XXIII
Cristina Gervasini
  • Function : Author
  • PersonId : 1140924
Università degli Studi di Milano = University of Milan
Maria Piccione
  • Function : Author
Università degli studi di Palermo - University of Palermo
Ingrid van de Laar
  • Function : Author
  • PersonId : 1140925
Erasmus University Medical Center [Rotterdam]
Marco Tartaglia
IRCCS Ospedale Pediatrico Bambino Gesù [Roma]
Bekim Sadikovic
  • Function : Author
  • PersonId : 1103091
University of Western Ontario
London Health Sciences Center
Anne-Sophie Lebre
Institut de psychiatrie et neurosciences de Paris
Service de génétique [Reims]

Abstract

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.

Domains

Cellular Biology Neurons and Cognition [q-bio.NC]
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https://www.hal.inserm.fr/inserm-03561254

Submitted on : Tuesday, February 8, 2022-10:27:01 AM

Last modification on : Tuesday, May 23, 2023-3:59:31 PM

Long-term archiving on: Monday, May 9, 2022-6:29:30 PM

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inserm-03561254 , version 1 (08-02-2022)

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Aidin Foroutan, Sadegheh Haghshenas, Pratibha Bhai, Michael A Levy, Jennifer Kerkhof, et al.. Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome. International Journal of Molecular Sciences, 2022, 23 (3), pp.1815. ⟨10.3390/ijms23031815⟩. ⟨inserm-03561254⟩

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