Microduplication of 3p26.3 Implicated in Cognitive Development

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. 1. Introduction Anomalies of the distal portion of the short arm of chromosome 3 are rare and not yet fully understood. The most well-characterised anomalies are deletions. For the most part, they occur de novo, although a few familial cases have been reported [1–8]. These deletions range from one to several megabases, but the extent of the deletion does not correlate with phenotypic severity. The clinical syndrome includes intellectual disability, low birth weight, micro- and trigonocephaly, and characteristic facial features such as ptosis, telecanthus, downslanting palpebral fissures, and micrognathia. Many genes have been implicated to play a role: CRBN and CNTN4 have been suggested to cause typical 3p deletion syndrome [9, 10], and the CHL1 gene has been proposed to play an additional role in cognitive impairment [8, 11–13]. The involvement of the CHL1 gene has been reported in four previous case studies: three with deletions confined to 3p26.3 [6–8], including only the CHL1 gene, a translocation [12], and one novel microduplication [13] (Figure 1). In these cases the growth abnormalities and typical facial features of 3p deletion syndrome were absent. Nonspecific intellectual disability was the main trait. 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 [ 6– 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]. Interestingly, the previously reported 3p26.3 microduplication case manifested similar clinical features to those patients carrying a CHL1 gene deletion, namely, nonspecific intellectual disability and epilepsy [13]. Epilepsy was also present in one