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. 2023 Jan;191(1):135-143.
doi: 10.1002/ajmg.a.63004. Epub 2022 Oct 22.

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

Nuno Maia  1 , Nekane Ibarluzea  2 , Mala Misra-Isrie  3 , Daniel C Koboldt  4   5 , Isabel Marques  1 , Gabriela Soares  6 , Rosário Santos  1 , Carlo L M Marcelis  7 , Riikka Keski-Filppula  8 , Miriam Guitart  9 , Elisabeth Gabau Vila  9 , April Lehman  5   10 , Scott Hickey  5   10 , Mari Mori  10   11 , Paulien Terhal  12 , Irene Valenzuela  13 , Amaia Lasa-Aranzasti  13 , Anna Maria Cueto-González  13 , Brian H Chhouk  14 , Rebecca C Yeh  14 , Jennifer E Neil  14 , Bassam Abu-Libde  15 , Tjitske Kleefstra  7 , Mariet W Elting  3 , Andrea Császár  16 , Judit Kárteszi  17 , Beáta Bessenyei  18 , Hans van Bokhoven  7 , Paula Jorge  1 , Johanna M van Hagen  3 , Arjan P M de Brouwer  7
Affiliations

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

Nuno Maia et al. Am J Med Genet A. 2023 Jan.

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: MED12; genotype; intellectual disability; phenotype.

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Conflict of interest statement

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Figures

FIGURE 1
FIGURE 1
Clinical aspects of patients with a MED12 variant. Clearly visible are the different phenotypes. For instance, Patient 21 has a completely normal face, whereas Patient 1 presented with multiple congenital anomalies such as severe prenatal craniosynostosis, tall prominent forehead, hypertelorism, down‐slanting palpebrae, high narrow palate, maxillary hypoplasia, low‐set ears, and a cloverleaf skull.
FIGURE 2
FIGURE 2
MED12 protein structure and reported ID‐causing variants. (a) Variants found in this study. (b) Variants reported in females by Polla et al., . (c) All pathogenic and likely pathogenic variants were reported to ClinVar as of September 19, 2021. The latter include the variants by Polla et al. M, Med12 domain. Blue dots represent the missense variants; in red the nonsense variants are given; pink dots indicate the splice site variants; and orange dots signify frameshift variants. Gene diagrams were created using lollipops v1.5.3 using UniProt ID Q93074.
See this image and copyright information in PMC

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