Severe intellectual disability and autistic features associated with microduplication 2q23.1

Abstract

We report on two patients with developmental delay, hypotonia, and autistic features associated with duplications of chromosome region 2q23.1-2q23.2 detected by chromosome microarray analysis. The duplications include one OMIM Morbid Map gene, MBD5, as well as seven known RefSeq genes (ACVR2A, ORC4L, EPC2, KIF5C, MIR1978, LYPD6B, and LYPD6). MBD5 lies in the minimum area of overlap of the 2q23.1 microdeletion syndrome. This report provides the first detailed clinical examination of two individuals with a duplication of this region and suggests that brain development and cognitive function may be affected by an increased dosage of the genes involved.

Figure 1

Facial dysmorphology in patients with duplication in 2q23.1. Clinical photographs of Patient 1 (a, b) showing arched eyebrows, bilateral ptosis, bulbous nasal tip, prominent lips, and mild retrognathia. Clinical photographs of Patient 2 (c, d) revealing subtle facial asymmetry with the right side slightly smaller than the left side, a tubular nose with prominent nasal tip, and somewhat prominent lips.

Figure 2

Array CGH and FISH analysis. Molecular cytogenetic investigations in patients 1 and 2 identified similar duplications within the long arm of chromosome 2. The estimated size of the duplications are 1.634 and 2 Mb, respectively, and both involve seven RefSeq genes including MBD5 and EPC2. (a, b) Chromosome and Gene views of the duplications obtained from DNA Analytics 4.0 (Agilent Technologies). (c) FISH analysis of lymphocytes from patient 1 using a FITC-labeled RP11-375H16 bacterial artificial chromosome probe (green) on DAPI-stained nuclei (blue) is consistent with a duplication. (d) Gene content displayed on the UCSC Genome Browser (NCBI 37/hg19).

Figure 3

Elevated expression of MBD5 and EPC2 in 2q23.1 duplication syndrome. qRT-PCR mRNA expression analysis of MBD5 (left) and EPC2 (right) in lymphoblastoid cell lines or fresh white blood cells from patient 1 with 2q23.1 duplication. Fresh white blood cells or lymphoblastoid cell lines from unaffected (absence of alteration of MBD5 or EPC2) subjects were used as normal controls. Results were normalized to GAPDH expression. Relative expression values are based on the ΔΔCt value. Expression of all controls was normalized to 1. Each bar represents the mean (±SEM) of values from three to five independent experiments. Data show increased MBD5 (left) and EPC2 (right) expression in Patient 1. ^aA previously published case, SMS185 (Williams et al), revealed a reduction of MBD5 and EPC2 due to haploinsufficiency (left).