Autistic disorder associated with a paternally derived unbalanced translocation leading to duplication of chromosome 15pter-q13.2: a case report

Abstract

Autism spectrum disorders have been associated with maternally derived duplications that involve the imprinted region on the proximal long arm of chromosome 15. Here we describe a boy with a chromosome 15 duplication arising from a 3:1 segregation error of a paternally derived translocation between chromosome 15q13.2 and chromosome 9q34.12, which led to trisomy of chromosome 15pter-q13.2 and 9q34.12-qter. Using array comparative genome hybridization, we localized the breakpoints on both chromosomes and sequence homology suggests that the translocation arose from non-allelic homologous recombination involving the low copy repeats on chromosome 15. The child manifests many characteristics of the maternally-derived duplication chromosome 15 phenotype including developmental delays with cognitive impairment, autism, hypotonia and facial dysmorphisms with nominal overlap of the most general symptoms found in duplications of chromosome 9q34. This case suggests that biallelically expressed genes on proximal 15q contribute to the idic(15) autism phenotype.

Figure 1

Quantitative Southern Blot analysis of the SNRPN exon α locus to determine gene dosage and methylation status. Southern blot analysis was performed using the SNRPN exon α probe, which detects a methylated maternal band at 4.2 kb and unmethylated paternal band at 0.8 kb. Densitometry was performed on the blot, which indicated that the proband (P) shows increased dosage of the paternal unmethylated allele when compared to the parental samples (F: Father, M: Mother) with a ratio of 1.47:1, consistent with paternal methylation of the der(15) chromosome. This was further supported by methylation specific PCR, which showed paternal:maternal ratio of 1.8:1 (not shown).

Figure 2

Log₂ T/R ratio plots for comparative genome hybridization. A) Custom BAC Array CGH of chromosome 15 shows trisomy up to BP4. FISH probes used are circled in red. Notably, FISH probe pDJ204m06 was not used on the array thus is not shown. Clones used for BLAST search for homology against chromsome 9 BP are circled in green. B) Schematic of chromosome 15q11.1-13.3 showing the position of genes based on the UCSC genome browser. Highlighted in red are maternally expressed transcripts, and paternally expressed transcripts in black. (Below) The relative positions of the 5 BP clusters are shown with sequence homology indicated by color, blue indicating regions of homology to HERC2, green indicating regions of homology to GOLGA8E, yellow indicating regions of homology between CHRNA7. The black and white hatching indicates the heteromorphic region near the centromere that includes a number of pseudogenes and can expand in the normal population. Above the breakpoint schematic is the Affymetrix 6.0 whole genome array that shows the density of SNP coverage for this region with notable gaps at the positions of the common BPs, although not all probes for detecting copy number variations are shown in the UCSC browser. C) Nimble CGH Array of chromosome 9 shows trisomy distal to position 132,510,300 (Build 36.1) in 9q34.1. D) Duplicated genes in chromosome 9 based on the UCSC genome browser.

Figure 3

Characterization of translocation chromosomes by metaphase FISH. The two der(15) chromosomes revealed hybridization signals for clones up to BP4 and no signal distal to BP5. Der(9) chromosome revealed hybridization signal for pDJ184n23, which is distal to BP5. A) Schematic representation of chromosomes 9, 15 and the derivative chromosomes. In panels B-F, red signals represent pcm15, a chromosome 15 centromere probe. The positions of the other clones used for FISH are shown in Figure 2A. Chromosomes 9, 15 and the derivative chromosomes are indicated in each panel. B) Green signals represent clone 770c6, which lies in proximal to BP2. C) Green signals represent clone pDJ437h9, which lies in the BP2-BP3 interval. D) Green signals represent clone pDJ9i9, a BP2-BP3 probe that lies just proximal to BP3. E) Green signals represent clone pDJ204m06, which lies between BP3-BP4. F) Green signals represent clone pDJ184n23, which lies distal to BP5.