TY - JOUR
T1 - Missense MED12 variants in 22 males with intellectual disability
T2 - From nonspecific symptoms to complete syndromes
AU - Maia, Nuno
AU - Ibarluzea, Nekane
AU - Misra-Isrie, Mala
AU - Koboldt, Daniel C.
AU - Marques, Isabel
AU - Soares, Gabriela
AU - Santos, Rosário
AU - Marcelis, Carlo L. M.
AU - Keski-Filppula, Riikka
AU - Guitart, Miriam
AU - Gabau Vila, Elisabeth
AU - Lehman, April
AU - Hickey, Scott
AU - Mori, Mari
AU - Terhal, Paulien
AU - Valenzuela, Irene
AU - Lasa-Aranzasti, Amaia
AU - Cueto-González, Anna Maria
AU - Chhouk, Brian H.
AU - Yeh, Rebecca C.
AU - Neil, Jennifer E.
AU - Abu-Libde, Bassam
AU - Kleefstra, Tjitske
AU - Elting, Mariet W.
AU - Császár, Andrea
AU - Kárteszi, Judit
AU - Bessenyei, Beáta
AU - van Bokhoven, Hans
AU - Jorge, Paula
AU - van Hagen, Johanna M.
AU - de Brouwer, Arjan P. M.
N1 - Funding Information: Foundation for Science and Technology (FCT), Grant/Award Number: UIDB/00215/2020 UIDP/00215/2020 LA/P/0064/2020; Broad Institute; National Eye Institute; National Heart, Lung and Blood Institute, Grant/Award Number: UM1 HG008900; National Human Genome Research Institute, Grant/Award Number: R01 HG009141 Funding information Funding Information: Unit for Multidisciplinary Research in Biomedicine (UMIB) and ITR‐Laboratory for Integrative and Translational Research in Population Health, supported by national funds through the Foundation for Science and Technology (FCT) Portugal (grant numbers UIDB/00215/2020 UIDP/00215/2020 LA/P/0064/2020, respectively). The sequencing and analysis of Patient 12 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), which are funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. Publisher Copyright: © 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - MED12
KW - genotype
KW - intellectual disability
KW - phenotype
UR - http://www.scopus.com/inward/record.url?scp=85140230561&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ajmg.a.63004
DO - https://doi.org/10.1002/ajmg.a.63004
M3 - Article
C2 - 36271811
SN - 1552-4825
VL - 191
SP - 135
EP - 143
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 1
ER -