Microduplication of 3p26.3 implicated in cognitive development

Abstract

We report here a 34-month-old boy with global developmental delay referred for molecular karyotyping and fragile X studies. Molecular karyotype analysis revealed a microduplication in the 3p26.3 region involving part of the CHL1 and CNTN6 genes. Several deletions, one translocation, and one duplication have previously been described in this region of chromosome 3. The CHL1 gene has been proposed as a dosage-sensitive gene with a central role in cognitive development, and so the microduplication reported here appears to be implicated in our patient's phenotype.

Figure 1

Schematic of chromosome 3p26.3 showing microdeletions and microduplications. (a) Shows the ideogram of chromosome 3, together with the region encompassing microdeletions and microduplications (red box). (b) Shows the location and extent of the microdeletions and microduplications detected in the proband reported here and other cases reported in the literature [–8, 13], BAC probes used in the FISH studies, and RefSeq genes that lie within this region of chromosome 3. These graphics were taken from the UCSC genome browser [14].

Figure 2

FISH analysis of metaphase cells using two BAC probes. The fluorescent signals identify the two homologues of chromosome 3 in cells of the proband. The orange and green signals (indicated by the yellow arrow head) show hybridisation of the BAC clones RP11-203L11 and RP11-739I20, respectively, to their normal sequences. The lower homolog shows a yellow signal, created from the combination of orange and green signals (indicated by a white arrow head), which is consistent with two tandem duplications on the same homologue.

Figure 3

Schematic of hypothetical meiotic and mitotic recombination events leading to the observed allelic and copy number imbalances in the proband. (a) Shows a possible exchange between homologous chromosomes at meiosis that could lead to a copy number gain in two neighbouring genes (labelled G1 and G2); the coloured boxes represent flanking alleles of a repetitive sequence. (b) Shows the homologous chromosomes 3 of the proband at conception. (c) Shows a possible early mitotic event (between homologous copies of chromosome 3) during development of the proband that would give rise to interstitial segmental isodisomy in the region bounded by genes 1 and 2. The contribution of this cell line with that of the cell line represented in (b) would be consistent with the allelic imbalance and copy number data of the proband.