MED12-Related Disease in a Chinese Girl: Clinical Characteristics and Underlying Mechanism

Abstract

The RNA polymerase II transcription subunit 12 homolog (MED12) is a member of the mediator complex, which plays a critical role in RNA transcription. Mutations in MED12 cause X-linked intellectual disability and other anomalies collectively grouped as MED12related disorders. While MED12 mutations have been most commonly reported in male patients, we present the case of a 1-year-old girl with clinical characteristics similar to MED12-related disorders. To explore the clinical characteristics of the condition and its possible pathogenesis, we analyzed the patient's clinical data; genetic testing by wholeexome sequencing revealed a de novo heterozygous mutation (c.1249-1G > C) in MED12. Further cDNA experiments revealed that the patient had an abnormal splicing at the skipping of exon9, which may have produced a truncated protein. qPCR showed decreased MED12 gene expression level in the patient, and an X-chromosome inactivation test confirmed a skewed inactivation of the X-chromosome. The lymphoblast transcription levels of the genes involved in the Gli3-dependent sonic hedgehog (SHH) signaling pathway, namely, CREB5, BMP4, and NEUROG2, were found to be significantly elevated compared with those of her parents and sex-and age-matched controls. Our results support the view that MED12 mutations may dysregulate the SHH signaling pathway, which may have accounted for the aberrant craniofacial morphology of our patient.

De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females

“…15 Secondly, a de novo splice variant that is identical to the one identified in individual 1 in this study, was reported in a one year old female with a similar phenotype comprising developmental delay, facial dysmorphism, cleft lip and palate and a thin corpus callosum. 31 For the two novel splice-variants we identified, we could not detect an aberrant transcript.…”

“…Similarly to previously reported missense variants found in males, the de novo missense variants identified in females in this study were distributed all over the protein. Previously, only two missense variants, p.(Glu172Gln) 29 and p.(Arg521His), 31 have been reported in females with comparable phenotypes.…”

“…12,13 Additionally, variants in MED12 have been implicated in non-specific NDDs in males. 11,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Though carrier females in these families are usually not affected, three females with inherited MED12 variants, 15,17,25 p.(Ser1967Glnfs*84), p.(Arg1148His) and p.(Ile771Thr), and three females with de novo MED12 variants, [29][30][31] p.(Glu172Gln), c.1249-1G>C and p.(Arg521His), were reported to have NDDs with variable cognitive impairment.…”

Insights into the regulatory role and clinical relevance of mediator subunit, MED12, in human diseases

“…The girl showed clinical features very similar to those affected from Opitz-Kaveggia and Lujan syndrome (macrocephaly, dysgenesis of the corpus callosum, hypotonia, development delay, long and thin face, hyper nasal voice, high nasal root, repaired cleft lip and palate, short philtrum, and hyperextensible digits). The mutation lead to deregulated sonic hedgehog signalling which might have caused the diseased phenotype(Wang et al, 2020).4.1.2 | Ohdo syndrome, Maat-Kievit-Brunner typeThe Maat-Kievit-Brunner type of intellectual disability is a kind of mental retardation that happens usually in males and is X chromosome linked. Other than intellectual disability, certain physical features are typical of the disease and includes narrowing of the eye opening, droopy eyelids, prominent cheeks, broad nasal bridge, nose with a rounded tip, large space between the nose and upper lip, and a narrow mouth.…”

A novel nonsense variant in MED12 associated with malformations in a female fetus

“…Interestingly, the X‐chromosome inactivation profile in blood cells from the two sisters showed no correlation with clinical outcomes as previously reported in symptomatic female carriers of an X‐linked disease 8 . Likewise, an intronic splice variant causing exon 9 skipping in MED12 was recently reported in a girl with generalized hypotonia, cleft lip and palate, facial dysmorphism and pulmonary stenosis 9 . The clinical spectrum of MED12‐related disorders was further expanded when de novo loss of function variants in MED12 was shown to be associated with Hardikar syndrome (OMIM 612726) in females 10 .…”