Open Access Research

Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

Lucia Micale1, Bartolomeo Augello1, Carmela Fusco1, Angelo Selicorni2, Maria N Loviglio1, Margherita Cirillo Silengo3, Alexandre Reymond4, Barbara Gumiero2, Federica Zucchetti2, Ester V D'Addetta1, Elga Belligni3, Alessia Calcagnì1, Maria C Digilio5, Bruno Dallapiccola5, Francesca Faravelli6, Francesca Forzano6, Maria Accadia7, Aldo Bonfante8, Maurizio Clementi9, Cecilia Daolio9, Sofia Douzgou10, Paola Ferrari11, Rita Fischetto12, Livia Garavelli13, Elisabetta Lapi14, Teresa Mattina15, Daniela Melis16, Maria G Patricelli17, Manuela Priolo18, Paolo Prontera19, Alessandra Renieri20, Maria A Mencarelli20, Gioacchino Scarano21, Matteo della Monica21, Benedetta Toschi22, Licia Turolla23, Alessandra Vancini24, Adriana Zatterale25, Orazio Gabrielli26, Leopoldo Zelante1 and Giuseppe Merla1*

Author Affiliations

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

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Orphanet Journal of Rare Diseases 2011, 6:38  doi:10.1186/1750-1172-6-38

Published: 9 June 2011

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.