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MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype–phenotype study

Authors

  • P Makrythanasis,

    1. Departement of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
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    • These authors contributed equally.
  • BW van Bon,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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    • These authors contributed equally.
  • M Steehouwer,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • B Rodríguez-Santiago,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Unitat de Genètica, Universitat Pompeu Fabra
    3. Hospital del Mas Medical Research Institute (IMIM)
    4. Quantitative Genomic Medicine Laboratories, Ltd (qGenomics), Barcelona, Spain
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  • M Simpson,

    1. Hospital de Santa Maria, Serviço de Genética Médica, Lisbon, Portugal
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  • P Dias,

    1. Hospital de Santa Maria, Serviço de Genética Médica, Lisbon, Portugal
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  • BM Anderlid,

    1. Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet
    2. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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  • P Arts,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • M Bhat,

    1. Centre for Human Genetics, Bangalore, India
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  • B Augello,

    1. Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo
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  • E Biamino,

    1. Dipartimento di Scienze Pediatriche, Università di Torino, Torino, Italy
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  • EMHF Bongers,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • M del Campo,

    1. Unitat de Genètica, Universitat Pompeu Fabra
    2. Hospital del Mas Medical Research Institute (IMIM)
    3. Quantitative Genomic Medicine Laboratories, Ltd (qGenomics), Barcelona, Spain
    4. CIBER de enfermedades raras (CIBERER)
    5. Programa de Medicina Molecular y Genética, Hospital Vall d'Hebron
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  • I Cordeiro,

    1. Hospital de Santa Maria, Serviço de Genética Médica, Lisbon, Portugal
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  • AM Cueto-González,

    1. Programa de Medicina Molecular y Genética, Hospital Vall d'Hebron
    2. Pediatric Service, Hospital Universitari Mútua de Terrassa, Terrassa (Barcelona), Spain
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  • I Cuscó,

    1. Unitat de Genètica, Universitat Pompeu Fabra
    2. Hospital del Mas Medical Research Institute (IMIM)
    3. Quantitative Genomic Medicine Laboratories, Ltd (qGenomics), Barcelona, Spain
    4. CIBER de enfermedades raras (CIBERER)
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  • C Deshpande,

    1. Clinical Genetics, Guy's Hospital, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, London, UK
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  • E Frysira,

    1. Laboratory of Medical Genetics, Medical School, University of Athens, Athens, Greece
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  • L Izatt,

    1. Servicio de Genética, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain
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  • R Flores,

    1. Unitat de Genètica, Universitat Pompeu Fabra
    2. Hospital del Mas Medical Research Institute (IMIM)
    3. Quantitative Genomic Medicine Laboratories, Ltd (qGenomics), Barcelona, Spain
    4. CIBER de enfermedades raras (CIBERER)
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  • E Galán,

    1. Servicio de Genética, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain
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  • B Gener,

    1. Clinical Genetics Unit, Hospital de Cruces, Barakaldo, Bizkaia, Spain
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  • C Gilissen,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • SM Granneman,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • J Hoyer,

    1. Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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  • HG Yntema,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • CM Kets,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • DA Koolen,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • CL Marcelis,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • A Medeira,

    1. Hospital de Santa Maria, Serviço de Genética Médica, Lisbon, Portugal
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  • L Micale,

    1. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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  • S Mohammed,

    1. Clinical Genetics, Guy's Hospital, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, London, UK
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  • SA de Munnik,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • A Nordgren,

    1. Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet
    2. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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  • S Psoni,

    1. Laboratory of Medical Genetics, Medical School, University of Athens, Athens, Greece
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  • W Reardon,

    1. National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Dublin 12, Ireland
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  • N Revencu,

    1. Centre for Human Genetics, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
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  • T Roscioli,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. School of Women's and Children's Health, Sydney Children's Hospital, University of New South Wales, Sydney, Australia
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  • M Ruiterkamp-Versteeg,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • HG Santos,

    1. Hospital de Santa Maria, Serviço de Genética Médica, Lisbon, Portugal
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  • J Schoumans,

    1. Department of Medical Genetics, Cancer Cytogenetic Unit, University Hospital of Lausanne, Lausanne, Switzerland
    2. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
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  • JHM Schuurs-Hoeijmakers,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • MC Silengo,

    1. Dipartimento di Scienze Pediatriche, Università di Torino, Torino, Italy
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  • L Toledo,

    1. Hospital Materno Infantil, Unidad de Neurologia Infantil, Las Palmas de Gran Canaria, Spain
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  • T Vendrell,

    1. Programa de Medicina Molecular y Genética, Hospital Vall d'Hebron
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  • I van der Burgt,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • B van Lier,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • C Zweier,

    1. Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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  • A Reymond,

    1. The Center for Integrative Genomics, University of Lausanne, Lausanne
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  • RC Trembath,

    1. Division of Genetics and Molecular Medicine, Guy's Hospital, King's College London School of Medicine, London, UK
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  • L Perez-Jurado,

    1. Unitat de Genètica, Universitat Pompeu Fabra
    2. Hospital del Mas Medical Research Institute (IMIM)
    3. Quantitative Genomic Medicine Laboratories, Ltd (qGenomics), Barcelona, Spain
    4. CIBER de enfermedades raras (CIBERER)
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  • J Dupont,

    1. Hospital de Santa Maria, Serviço de Genética Médica, Lisbon, Portugal
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  • BBA de Vries,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • HG Brunner,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • JA Veltman,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • G Merla,

    Corresponding author
    1. Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo
    • Corresponding authors: Giuseppe Merla, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Poliambulatorio Giovanni Paolo II, I-71013 San Giovanni Rotondo, Italy.

      Tel.: +39 882416350;

      fax: +39882411616;

      e-mail: g.merla@operapadrepio.it;

      Stylianos E Antonarakis, Department of Genetic Medicine and Development, University of Geneva, Geneva Switzerland and Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.

      Tel.: +41223795708;

      fax: +41223795706;

      e-mail: stylianos.antonarakis@unige.ch

      and

      Alexander Hoischen, Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

      Tel.: +31243668940;

      fax: +31243668752;

      e-mail: a.hoischen@gen.umcn.nl

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    • These authors contributed equally.
  • SE Antonarakis,

    Corresponding author
    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    2. Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
    • Corresponding authors: Giuseppe Merla, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Poliambulatorio Giovanni Paolo II, I-71013 San Giovanni Rotondo, Italy.

      Tel.: +39 882416350;

      fax: +39882411616;

      e-mail: g.merla@operapadrepio.it;

      Stylianos E Antonarakis, Department of Genetic Medicine and Development, University of Geneva, Geneva Switzerland and Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.

      Tel.: +41223795708;

      fax: +41223795706;

      e-mail: stylianos.antonarakis@unige.ch

      and

      Alexander Hoischen, Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

      Tel.: +31243668940;

      fax: +31243668752;

      e-mail: a.hoischen@gen.umcn.nl

    Search for more papers by this author
    • These authors contributed equally.
  • A Hoischen

    Corresponding author
    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    • Corresponding authors: Giuseppe Merla, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Poliambulatorio Giovanni Paolo II, I-71013 San Giovanni Rotondo, Italy.

      Tel.: +39 882416350;

      fax: +39882411616;

      e-mail: g.merla@operapadrepio.it;

      Stylianos E Antonarakis, Department of Genetic Medicine and Development, University of Geneva, Geneva Switzerland and Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.

      Tel.: +41223795708;

      fax: +41223795706;

      e-mail: stylianos.antonarakis@unige.ch

      and

      Alexander Hoischen, Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

      Tel.: +31243668940;

      fax: +31243668752;

      e-mail: a.hoischen@gen.umcn.nl

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    • These authors contributed equally.

  • Nothing to declare.

Abstract

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa–Kuroki) syndrome (MIM#147920). To further elucidate the genotype–phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0–10). Sequencing of the full coding region and intron–exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median ‘MLL2-Kabuki score’ of 6) as compared to the patients without MLL2 mutations (median ‘MLL2-Kabuki score’ of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.

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