Congenital heart defects in molecularly proven Kabuki syndrome patients

• Published in: American journal of medical genetics. Part A Vol. 173; no. 11; pp. 2912 - 2922
• Main Authors: Digilio, Maria Cristina, Gnazzo, Maria, Lepri, Francesca, Dentici, Maria Lisa, Pisaneschi, Elisa, Baban, Anwar, Passarelli, Chiara, Capolino, Rossella, Angioni, Adriano, Novelli, Antonio, Marino, Bruno, Dallapiccola, Bruno
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.11.2017
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - physiopathology; Aortic arch; Aortic Coarctation - complications; Aortic Coarctation - genetics; Aortic Coarctation - physiopathology; Aortic valve; Aortic Valve - abnormalities; Aortic Valve - physiopathology; Aortic Valve Stenosis - complications; Aortic Valve Stenosis - genetics; Aortic Valve Stenosis - physiopathology; Congenital defects; congenital heart defect; Defects; DNA-Binding Proteins - genetics; Echocardiography; Face - abnormalities; Face - physiopathology; Female; Health risk assessment; Heart; Heart Defects, Congenital - complications; Heart Defects, Congenital - genetics; Heart Defects, Congenital - physiopathology; Heart Septal Defects, Atrial - genetics; Heart Septal Defects, Atrial - physiopathology; Heart Septal Defects, Ventricular - genetics; Heart Septal Defects, Ventricular - physiopathology; Heart Valve Diseases - genetics; Heart Valve Diseases - physiopathology; Hematologic Diseases - complications; Hematologic Diseases - genetics; Hematologic Diseases - physiopathology; Histone Demethylases - genetics; Humans; Kabuki syndrome; KDM6A gene; KMT2D gene; Male; Neoplasm Proteins - genetics; Nuclear Proteins - genetics; Ventricle; Vestibular Diseases - complications; Vestibular Diseases - genetics; Vestibular Diseases - physiopathology; KMT2D gene; Kabuki syndrome; KDM6A gene; congenital heart defect
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.38417

The prevalence of congenital heart defects (CHD) in Kabuki syndrome ranges from 28% to 80%. Between January 2012 and December 2015, 28 patients had a molecularly proven diagnosis of Kabuki syndrome. Pathogenic variants in KMT2D (MLL2) were detected in 27 patients, and in KDM6A gene in one. CHD was diagnosed in 19/27 (70%) patients with KMT2D (MLL2) variant, while the single patient with KDM6A change had a normal heart. The anatomic types among patients with CHD included aortic coarctation (4/19 = 21%) alone or associated with an additional CHD, bicuspid aortic valve (4/19 = 21%) alone or associated with an additional CHD, perimembranous subaortic ventricular septal defect (3/19 = 16%), atrial septal defect ostium secundum type (3/19 = 16%), conotruncal heart defects (3/19 = 16%). Additional CHDs diagnosed in single patients included aortic dilatation with mitral anomaly and hypoplastic left heart syndrome. We also reviewed CHDs in patients with a molecular diagnosis of Kabuki syndrome reported in the literature. In conclusion, a CHD is detected in 70% of patients with KMT2D (MLL2) pathogenic variants, most commonly left‐sided obstructive lesions, including multiple left‐sided obstructions similar to those observed in the spectrum of the Shone complex, and septal defects. Clinical management of Kabuki syndrome should include echocardiogram at the time of diagnosis, with particular attention to left‐sided obstructive lesions and mitral anomalies, and annual monitoring for aortic arch dilatation.