Missense MED12 Variants in 22 Males with Intellectual Disability: From Nonspecific Symptoms to Complete Syndromes

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, χ test), but mostly outside the functional domains (p = 0.004; χ 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.

Citing Articles

MED12 Loss-of-Function Variants as a Cause of Congenital Diaphragmatic Hernia in Females With Hardikar Syndrome and Nonspecific Intellectual Disability.

Kao E, Mizerik E, Bacino C, Dai H, Vossaert L, Scott D Am J Med Genet A. 2024; 197(1):e63868.

PMID: 39215511 PMC: 11637953. DOI: 10.1002/ajmg.a.63868.

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

Maia N, Ibarluzea N, Misra-Isrie M, Koboldt D, Marques I, Soares G Am J Med Genet A. 2022; 191(1):135-143.

PMID: 36271811 PMC: 10092556. DOI: 10.1002/ajmg.a.63004.

References

Yamamoto T, Shimojima K . A novel MED12 mutation associated with non-specific X-linked intellectual disability. Hum Genome Var. 2016; 2:15018. PMC: 4785543. DOI: 10.1038/hgv.2015.18. View

Zhou H, Pang X . Electrostatic Interactions in Protein Structure, Folding, Binding, and Condensation. Chem Rev. 2018; 118(4):1691-1741. PMC: 5831536. DOI: 10.1021/acs.chemrev.7b00305. View

Graham Jr J, Superneau D, Rogers R, Corning K, Schwartz C, Dykens E . Clinical and behavioral characteristics in FG syndrome. Am J Med Genet. 1999; 85(5):470-5. View

Vulto-van Silfhout A, de Vries B, van Bon B, Hoischen A, Ruiterkamp-Versteeg M, Gilissen C . Mutations in MED12 cause X-linked Ohdo syndrome. Am J Hum Genet. 2013; 92(3):401-6. PMC: 3591845. DOI: 10.1016/j.ajhg.2013.01.007. View

Srivastava S, Niranjan T, May M, Tarpey P, Allen W, Hackett A . Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders. Mol Genet Genomic Med. 2019; 7(4):e00569. PMC: 6465656. DOI: 10.1002/mgg3.569. View

Callier P, Aral B, Hanna N, Lambert S, Dindy H, Ragon C . Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability. Clin Genet. 2013; 84(6):507-21. DOI: 10.1111/cge.12094. View

Schwartz C, Tarpey P, Lubs H, Verloes A, May M, Risheg H . The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet. 2007; 44(7):472-7. PMC: 2597996. DOI: 10.1136/jmg.2006.048637. View

Martinez F, Caro-Llopis A, Rosello M, Oltra S, Mayo S, Monfort S . High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. J Med Genet. 2016; 54(2):87-92. DOI: 10.1136/jmedgenet-2016-103964. View

Risheg H, Graham Jr J, Clark R, Rogers R, Opitz J, Moeschler J . A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat Genet. 2007; 39(4):451-3. DOI: 10.1038/ng1992. View

10.

Lin M, Guo J . New insights into protein-DNA binding specificity from hydrogen bond based comparative study. Nucleic Acids Res. 2019; 47(21):11103-11113. PMC: 6868434. DOI: 10.1093/nar/gkz963. View

11.

Clark A, Oldenbroek M, Boyer T . Mediator kinase module and human tumorigenesis. Crit Rev Biochem Mol Biol. 2015; 50(5):393-426. PMC: 4928375. DOI: 10.3109/10409238.2015.1064854. View

12.

Khan S, Vihinen M . Spectrum of disease-causing mutations in protein secondary structures. BMC Struct Biol. 2007; 7:56. PMC: 1995201. DOI: 10.1186/1472-6807-7-56. View

13.

Charzewska A, Maiwald R, Kahrizi K, Oehl-Jaschkowitz B, Dufke A, Lemke J . The power of the Mediator complex-Expanding the genetic architecture and phenotypic spectrum of MED12-related disorders. Clin Genet. 2018; 94(5):450-456. DOI: 10.1111/cge.13412. View

14.

Schalock R, Luckasson R, Tasse M . An Overview of Intellectual Disability: Definition, Diagnosis, Classification, and Systems of Supports (12th ed.). Am J Intellect Dev Disabil. 2021; 126(6):439-442. DOI: 10.1352/1944-7558-126.6.439. View

15.

Maia N, Ibarluzea N, Misra-Isrie M, Koboldt D, Marques I, Soares G . Missense MED12 variants in 22 males with intellectual disability: From nonspecific symptoms to complete syndromes. Am J Med Genet A. 2022; 191(1):135-143. PMC: 10092556. DOI: 10.1002/ajmg.a.63004. View

16.

Hu H, Haas S, Chelly J, Van Esch H, Raynaud M, de Brouwer A . X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry. 2015; 21(1):133-48. PMC: 5414091. DOI: 10.1038/mp.2014.193. View

17.

Patil S, Somashekar P, Shukla A, Siddaiah S, Bhat V, Girisha K . Clinical Variability in Familial X-Linked Ohdo Syndrome-Maat-Kievit-Brunner Type with Mutation. J Pediatr Genet. 2017; 6(3):198-204. PMC: 5548526. DOI: 10.1055/s-0037-1602386. View

18.

Lubs H, Stevenson R, Schwartz C . Fragile X and X-linked intellectual disability: four decades of discovery. Am J Hum Genet. 2012; 90(4):579-90. PMC: 3322227. DOI: 10.1016/j.ajhg.2012.02.018. View

19.

Au P, You J, Caluseriu O, Schwartzentruber J, Majewski J, Bernier F . GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK. Hum Mutat. 2015; 36(10):1009-1014. PMC: 4589226. DOI: 10.1002/humu.22837. View

20.

Shen L, Ji H . Mutational Spectrum Analysis of Neurodegenerative Diseases and Its Pathogenic Implication. Int J Mol Sci. 2015; 16(10):24295-301. PMC: 4632750. DOI: 10.3390/ijms161024295. View