Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients
- Equal contributors
1 Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, 71013 San Giovanni Rotondo, Italy
2 Ambulatorio Genetica Clinica Pediatrica, Clinica Pediatrica Università Milano Bicocca, Fondazione MBBM AOS Gerardo Monza, Italy
3 Dipartimento di Scienze Pediatriche, Università di Torino, Italy
4 Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
5 Medical Genetics, Bambino Gesù Paediatric Hospital, IRCCS, Rome, Italy
6 Division of Medical Genetics, Galliera Hospital, Genova, Italy
7 Laboratory of Medical Genetics, "V.Fazzi" Hospital, Lecce, Italy
8 Medical Genetics Unit, St. Bassiano Hospital, Bassano del Grappa, Italy
9 Dipartimento Pediatria, Genetica Clinica, Padova, Italy
10 Department of Genetics, Institute of Child Health, "Aghia Sophia" Children's Hospital, Athens, Greece
11 Dipartimento Materno Infantile, Università degli studi Modena, Italy
12 U.O. Malattie Metaboliche PO Giovanni XXIII, AOU Policlinico Consorziale, Bari, Italy
13 Clinical Genetics Unit, S.Maria Nuova Hospital Reggio Emilia, Italy
14 Medical Genetics Unit, Children's Hospital Anna Meyer, Firenze, Italy
15 Genetica Medica, Università di Catania, Catania, Italy
16 Area Funzionale di Genetica Clinica Pediatrica, Dipartimento di Pediatria, Università degli Studi di Napoli "Federico II", Italy
17 Biologia Molecolare e Citogenetica, Diagnostica e Ricerca San Raffaele, Milano, Italy
18 Unita' Operativa di Genetica Medica, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, Italy
19 Medical Genetics Unit, University of Perugia, "S. Maria della Misericordia" Hospital, Perugia, Italy
20 Medical Genetics Section, Biotechnology Department, University of Siena, Italy. UOC Genetica Medica, Dipartimento di Emergenza Urgenza e dei Servizi Diagnostici, Azienda Ospedaliera Universitaria Senese, Siena, Italy
21 UOC Genetica Medica, Azienda Ospedaliera RN "G.Rummo", Benevento, Italy
22 Medical Genetics Section, Cytogenetics and Molecular Genetics Unit, Santa Chiara University Hospital, Pisa, Italy
23 Ambulatorio di Genetica Medica, Azienda ULSS 9, Treviso, Italy
24 Newborn Intensive Care Unit, Maggiore Hospital, Bologna, Italy
25 Servizio di Genetica, ASL NAPOLI 1 P.S.I. Elena d'Aosta Napoli, Italy
26 Stituto di Scienze Materno-Infantili, Università Politecnica delle Marche, Ancona, Italy
Orphanet Journal of Rare Diseases 2011, 6:38 doi:10.1186/1750-1172-6-38Published: 9 June 2011
Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause.
Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools.
We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site.
This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management.