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Missense MED12 variants in 22 males with intellectual disability: From nonspecific symptoms to complete syndromes |
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| Authors: | Nuno Maia Nekane Ibarluzea Mala Misra-Isrie Daniel C. Koboldt Isabel Marques Gabriela Soares Rosário Santos Carlo L. M. Marcelis Riikka Keski-Filppula Miriam Guitart Elisabeth Gabau Vila April Lehman Scott Hickey Mari Mori Paulien Terhal Irene Valenzuela Amaia Lasa-Aranzasti Anna Maria Cueto-González Brian H. Chhouk Rebecca C. Yeh Jennifer E. Neil Bassam Abu-Libde Tjitske Kleefstra Mariet W. Elting Andrea Császár Judit Kárteszi Beáta Bessenyei Hans van Bokhoven Paula Jorge Johanna M. van Hagen Arjan P. M. de Brouwer |
| Affiliation: | 1. Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto de Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto);2. Unit for Multidisciplinary Research In Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), and ITR - Laboratory for Integrative and Translational Research in Population Health, University of Porto, Porto, Portugal;3. Biocruces Bizkaia Health Research Institute, Barakaldo, Spain;4. Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands;5. Steve and Cindy Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA;6. Unidade de Genética Médica, Centro de Genética Médica Doutor Jacinto de Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal;7. Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands;8. Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu, Finland;9. Paediatric Unit, ParcTaulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, I3PTUniversitat Autònoma de Barcelona, Sabadell, Spain;10. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA Division of Genetic & Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA;11. Division of Genetic & Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA;12. Division Laboratories, Pharmacy and Biomedical Genetics, Wilhelmina Children's Hospital, Utrecht, The Netherlands;13. Department of Clinical and Molecular Genetics, Vall d'Hebron University Hospital and Medicine Genetics Group, Vall d'Hebron Research Institute, Barcelona, Spain;14. Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA;15. Makassed Hospital, Jerusalem, Israel;16. Paediatric Ward, Hospital of Zala County, Zalaegerszeg, Hungary;17. Genetic Counselling, Hospital of Zala County, Zalaegerszeg, Hungary;18. Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary |
| Abstract: | We describe the phenotype of 22 male patients (20 probands) carrying a hemizygous missense variant in MED12. The phenotypic spectrum is very broad ranging from nonspecific intellectual disability (ID) to the three well-known syndromes: Opitz–Kaveggia syndrome, Lujan–Fryns syndrome, or Ohdo syndrome. The identified variants were randomly distributed throughout the gene (p = 0.993, χ2 test), but mostly outside the functional domains (p = 0.004; χ2 test). Statistical analyses did not show a correlation between the MED12-related phenotypes and the locations of the variants (p = 0.295; Pearson correlation), nor the protein domain involved (p = 0.422; Pearson correlation). In conclusion, establishing a genotype–phenotype correlation in MED12-related diseases remains challenging. Therefore, we think that patients with a causative MED12 variant are currently underdiagnosed due to the broad patients' clinical presentations. |
| Keywords: | intellectual disability MED12 phenotype genotype |