Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles International Journal of Molecular Sciences Year : 2022

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

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]
Pratibha Bhai
Michael A Levy
  • Function : Author
  • PersonId : 1125501
Jennifer Kerkhof
Haley Mcconkey
Lucia Pedace
  • Function : Author
  • PersonId : 1125502
Solveig Heide
  • Function : Author
  • PersonId : 1012475
Eric Bieth
  • Function : Author
  • PersonId : 948825
Silvia Maitz


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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Dates and versions

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



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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