Missense MED12 variants in 22 males with intellectual disability: From nonspecific symptoms to complete syndromes

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. YehJennifer 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

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)135-143
Number of pages9
JournalAmerican Journal of Medical Genetics, Part A
Issue number1
Early online date2022
Publication statusPublished - Jan 2023


  • MED12
  • genotype
  • intellectual disability
  • phenotype

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