Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

Lucia Micale, Bartolomeo Augello, Carmela Fusco, Angelo Selicorni, Maria N. Loviglio, Margherita Cirillo Silengo, Alexandre Reymond, Barbara Gumiero, Federica Zucchetti, Ester V. D'Addetta, Elga Belligni, Alessia Calcagn, Maria C. Digilio, Bruno Dallapiccola, Francesca Faravelli, Francesca Forzano, Maria Accadia, Aldo Bonfante, Maurizio Clementi, Cecilia DaolioSofia Douzgou, Paola Ferrari, Rita Fischetto, Livia Garavelli, Elisabetta Lapi, Teresa Mattina, Daniela Melis, Maria G. Patricelli, Manuela Priolo, Paolo Prontera, Alessandra Renieri, Maria A. Mencarelli, Gioacchino Scarano, Matteo Della Monica, Benedetta Toschi, Licia Turolla, Alessandra Vancini, Adriana Zatterale, Orazio Gabrielli, Leopoldo Zelante, Giuseppe Merla

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish
Article number38
JournalOrphanet Journal of Rare Diseases
Volume6
Issue number1
DOIs
Publication statusPublished - 2011

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Mutation
Intellectual Disability
Nucleotides
Genes
RNA Splice Sites
Frameshift Mutation
Nonsense Codon
Dermatoglyphics
Genetic Association Studies
Transferases
Computer Simulation
Histones
Introns
Exons
Peptides
Kabuki syndrome
DNA

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

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Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients. / Micale, Lucia; Augello, Bartolomeo; Fusco, Carmela; Selicorni, Angelo; Loviglio, Maria N.; Silengo, Margherita Cirillo; Reymond, Alexandre; Gumiero, Barbara; Zucchetti, Federica; D'Addetta, Ester V.; Belligni, Elga; Calcagn, Alessia; Digilio, Maria C.; Dallapiccola, Bruno; Faravelli, Francesca; Forzano, Francesca; Accadia, Maria; Bonfante, Aldo; Clementi, Maurizio; Daolio, Cecilia; Douzgou, Sofia; Ferrari, Paola; Fischetto, Rita; Garavelli, Livia; Lapi, Elisabetta; Mattina, Teresa; Melis, Daniela; Patricelli, Maria G.; Priolo, Manuela; Prontera, Paolo; Renieri, Alessandra; Mencarelli, Maria A.; Scarano, Gioacchino; Monica, Matteo Della; Toschi, Benedetta; Turolla, Licia; Vancini, Alessandra; Zatterale, Adriana; Gabrielli, Orazio; Zelante, Leopoldo; Merla, Giuseppe.

In: Orphanet Journal of Rare Diseases, Vol. 6, No. 1, 38, 2011.

Research output: Contribution to journalArticle

Micale, L, Augello, B, Fusco, C, Selicorni, A, Loviglio, MN, Silengo, MC, Reymond, A, Gumiero, B, Zucchetti, F, D'Addetta, EV, Belligni, E, Calcagn, A, Digilio, MC, Dallapiccola, B, Faravelli, F, Forzano, F, Accadia, M, Bonfante, A, Clementi, M, Daolio, C, Douzgou, S, Ferrari, P, Fischetto, R, Garavelli, L, Lapi, E, Mattina, T, Melis, D, Patricelli, MG, Priolo, M, Prontera, P, Renieri, A, Mencarelli, MA, Scarano, G, Monica, MD, Toschi, B, Turolla, L, Vancini, A, Zatterale, A, Gabrielli, O, Zelante, L & Merla, G 2011, 'Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients', Orphanet Journal of Rare Diseases, vol. 6, no. 1, 38. https://doi.org/10.1186/1750-1172-6-38
Micale, Lucia ; Augello, Bartolomeo ; Fusco, Carmela ; Selicorni, Angelo ; Loviglio, Maria N. ; Silengo, Margherita Cirillo ; Reymond, Alexandre ; Gumiero, Barbara ; Zucchetti, Federica ; D'Addetta, Ester V. ; Belligni, Elga ; Calcagn, Alessia ; Digilio, Maria C. ; Dallapiccola, Bruno ; Faravelli, Francesca ; Forzano, Francesca ; Accadia, Maria ; Bonfante, Aldo ; Clementi, Maurizio ; Daolio, Cecilia ; Douzgou, Sofia ; Ferrari, Paola ; Fischetto, Rita ; Garavelli, Livia ; Lapi, Elisabetta ; Mattina, Teresa ; Melis, Daniela ; Patricelli, Maria G. ; Priolo, Manuela ; Prontera, Paolo ; Renieri, Alessandra ; Mencarelli, Maria A. ; Scarano, Gioacchino ; Monica, Matteo Della ; Toschi, Benedetta ; Turolla, Licia ; Vancini, Alessandra ; Zatterale, Adriana ; Gabrielli, Orazio ; Zelante, Leopoldo ; Merla, Giuseppe. / Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients. In: Orphanet Journal of Rare Diseases. 2011 ; Vol. 6, No. 1.
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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.",
author = "Lucia Micale and Bartolomeo Augello and Carmela Fusco and Angelo Selicorni and Loviglio, {Maria N.} and Silengo, {Margherita Cirillo} and Alexandre Reymond and Barbara Gumiero and Federica Zucchetti and D'Addetta, {Ester V.} and Elga Belligni and Alessia Calcagn and Digilio, {Maria C.} and Bruno Dallapiccola and Francesca Faravelli and Francesca Forzano and Maria Accadia and Aldo Bonfante and Maurizio Clementi and Cecilia Daolio and Sofia Douzgou and Paola Ferrari and Rita Fischetto and Livia Garavelli and Elisabetta Lapi and Teresa Mattina and Daniela Melis and Patricelli, {Maria G.} and Manuela Priolo and Paolo Prontera and Alessandra Renieri and Mencarelli, {Maria A.} and Gioacchino Scarano and Monica, {Matteo Della} and Benedetta Toschi and Licia Turolla and Alessandra Vancini and Adriana Zatterale and Orazio Gabrielli and Leopoldo Zelante and Giuseppe Merla",
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T1 - Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

AU - Micale, Lucia

AU - Augello, Bartolomeo

AU - Fusco, Carmela

AU - Selicorni, Angelo

AU - Loviglio, Maria N.

AU - Silengo, Margherita Cirillo

AU - Reymond, Alexandre

AU - Gumiero, Barbara

AU - Zucchetti, Federica

AU - D'Addetta, Ester V.

AU - Belligni, Elga

AU - Calcagn, Alessia

AU - Digilio, Maria C.

AU - Dallapiccola, Bruno

AU - Faravelli, Francesca

AU - Forzano, Francesca

AU - Accadia, Maria

AU - Bonfante, Aldo

AU - Clementi, Maurizio

AU - Daolio, Cecilia

AU - Douzgou, Sofia

AU - Ferrari, Paola

AU - Fischetto, Rita

AU - Garavelli, Livia

AU - Lapi, Elisabetta

AU - Mattina, Teresa

AU - Melis, Daniela

AU - Patricelli, Maria G.

AU - Priolo, Manuela

AU - Prontera, Paolo

AU - Renieri, Alessandra

AU - Mencarelli, Maria A.

AU - Scarano, Gioacchino

AU - Monica, Matteo Della

AU - Toschi, Benedetta

AU - Turolla, Licia

AU - Vancini, Alessandra

AU - Zatterale, Adriana

AU - Gabrielli, Orazio

AU - Zelante, Leopoldo

AU - Merla, Giuseppe

PY - 2011

Y1 - 2011

N2 - 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.

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