MED23-associated intellectual disability in a non-consanguineous family

Abstract

Intellectual disability (ID) is a heterogeneous condition arising from a variety of environmental and genetic factors. Among these causes are defects in transcriptional regulators. Herein, we report on two brothers in a nonconsanguineous family with novel compound heterozygous, disease-segregating mutations (NM_015979.3: [3656A > G];[4006C > T], NP_057063.2: [H1219R];[R1336X]) in MED23. This gene encodes a subunit of the Mediator complex that modulates the expression of RNA polymerase II-dependent genes. These brothers, who had profound ID, spasticity, congenital heart disease, brain abnormalities, and atypical electroencephalography, represent the first case of MED23-associated ID in a non-consanguineous family. They also expand upon the clinical features previously reported for mutations in this gene.

Keywords: MED23; intellectual disability (ID); mediator complex; whole exome sequencing (WES).

Figure 1

Mid-line sagittal T1-TFE (Turbo Field Echo) of patient 1 (age 11 years) and T1 of patient 2 (age 22 months) are shown in A and B respectively. Mild-to-moderate pontine hypoplasia was evident in both patients, though less severe in patient 2. Additionally, patient 2 showed mild thinning of the corpus callosum. Axial T2-weighted images of patient 1 (age 8 years) and patient 2 (age 5 years) are shown in C and D respectively. Hypomyelination, as evidenced by reduced gray/white matter differentiation in T2 signal intensity, was noted over the posterior and temporal white matter for both patients. This abnormality resolved by age 11 years in patient 1 (not shown).

Figure 2

A) Pedigree of the non-consanguineous family. Squares are males, and the circle is female. The black symbols represent the two affected siblings who presented with profound intellectual disability. B) Whole exome short-read alignments to a human reference genome (hg19) reveal novel MED23 mutations segregating with disease. The mother was heterozygous for a c.3656A>G (p.H1219R) change (highlighted in blue). The father was heterozygous for a c.4006C>T (p.R1336X) change (highlighted in green). Both affected siblings were compound heterozygous for the mutations. C) Graph showing steady state (mRNA)MED23 levels detected by qRT-PCR in unaffected control (Cnt) and in pooled patient (Pt) fibroblasts after normalization to GAPDH. Error bars represent the standard deviation of four independent experiments. D) Immunoblot detection of MED23 in nuclear lysates from unaffected control (Cnt) and patient fibroblasts. Histone H2B was used as a loading control. E) Plots showing the relative levels of (mRNA)FOS in cultured skin fibroblasts of Patient II-1 and an age and gender matched control (cnt). Measurements were made following 24 hours of serum starvation (time = 0) and 30 minutes after addition of serum to 10%. The mRNA levels of three independent replicates were standardized to GAPDH mRNA. Error bars represent one standard deviation. F) Plots showing the relative levels of (mRNA)JUN in cultured skin fibroblasts of Patient II-1 and an age and gender matched control (cnt). Measurements were made following 24 hours of serum starvation (time = 0) and 30 minutes after addition of serum to 10%. The mRNA levels of three independent replicates were standardized to GAPDH mRNA. Error bars represent one standard deviation.