8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

Abstract

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.

Keywords: 8p23.2-pter microdeletion; 8p23.3; ARGHEF10; DLGAP2; behavior disorder; candidate region; chromosomal microarray analysis (CMA); critical microdeletion region (CR); developmental delay; small deletions.

Figure 1

Physical map of the 8p23.2-pter region (nucleotides 1 to 6,000,000 GRCh37/hg19) adapted from the UCSC Genome Browser [20]: differently colored bars indicate the different genomic regions involved in the microdeletions of: our seven patients (RED bars), patients reported in the literature (GREEN bars), patients described in the DECIPHER database (BLACK bars). All curated and predicted NCBI RefSeq genes included in this region are annotated. Genes included in the candidate region are indicated below with BLUE bars. DARK GREEN bars point to OMIM-disease genes, whereas LIGHT GREY bars indicate genes not associated to any OMIM phenotype [17].

Figure 2

Protein-protein interaction in STRING database [57]. (A) DLGAP2 network, (B) ARHGEF10 network (C) ARHGEF10 and DLGAP2 common network. The top ten interactors for each gene are shown. Colored lines indicate different kinds of interactions. Blue: known interaction from curated databases; violet: known interaction experimentally determined; green: predicted interaction for gene neighborhood; red: predicted interaction for gene fusion; dark blue: predicted interaction for gene co-occurrence; yellow: interaction based on text mining; black: interaction based on gene-expression; light blue: interaction based on protein homology.

Figure 3

Topological associated domains (TADs) in 8p23.2-pter region based on Hi-C data performed by YUE Lab website [72].