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

Wu DJ, Wang NJ, Driscoll J, Dorrani N, Liu D, Sigman M, Schanen NC - Mol Cytogenet (2009)

Bottom Line: Autism spectrum disorders have been associated with maternally derived duplications that involve the imprinted region on the proximal long arm of chromosome 15.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, University of Delaware, Newark, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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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.

Mentions: To further assess the dosage and BP position for the translocation event on chromosome 15, array CGH was performed using our custom BAC array, revealing dosage consistent with trisomy for the interval between BP1 and BP4 (clone AC087455) on chromosome 15q13.2 (Figure 2A and 2B) [18]. The position of the chromosome 9 BP was interrogated using array CGH with the Nimblegen platform. These analyses placed the proximal boundary of the translocation event on chromosome 9 at g 132,510,300 (Figure 2C and 2D). The 2 kb region flanking the translocation BP on chromosome 9 is composed of 52.6% short interspersed elements and 24.3% long interspersed elements. We performed a BLAST search comparing a 2 kb region flanking the translocation BP on chromosome 9 with the two clones flanking the BP on chromosome 15 as well as the intervening sequence and detected two primary blocks of homology. For BAC AC087455, a 283 bp sequence (g 28,082,283 - 28,082,562) with 87% identity to the chromosome 9 BP sequence (g 132,510,495-132,510,776) lies near the telomeric end of the BAC clone. Similarly, a 283 bp region with 90% identity was detected between clone AC120045 (g 28,136,197-28,136,479) and the chromosome 9 sequence. Either of these regions of sequence homology may have facilitated a non-homologous allelic recombination event that gave rise to the original translocation chromosome. Subsequently, a 3:1 segregation error in the paternal germline led to aneusomy for the der(15) in the proband.


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

Wu DJ, Wang NJ, Driscoll J, Dorrani N, Liu D, Sigman M, Schanen NC - Mol Cytogenet (2009)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2803171&req=5

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.
Mentions: To further assess the dosage and BP position for the translocation event on chromosome 15, array CGH was performed using our custom BAC array, revealing dosage consistent with trisomy for the interval between BP1 and BP4 (clone AC087455) on chromosome 15q13.2 (Figure 2A and 2B) [18]. The position of the chromosome 9 BP was interrogated using array CGH with the Nimblegen platform. These analyses placed the proximal boundary of the translocation event on chromosome 9 at g 132,510,300 (Figure 2C and 2D). The 2 kb region flanking the translocation BP on chromosome 9 is composed of 52.6% short interspersed elements and 24.3% long interspersed elements. We performed a BLAST search comparing a 2 kb region flanking the translocation BP on chromosome 9 with the two clones flanking the BP on chromosome 15 as well as the intervening sequence and detected two primary blocks of homology. For BAC AC087455, a 283 bp sequence (g 28,082,283 - 28,082,562) with 87% identity to the chromosome 9 BP sequence (g 132,510,495-132,510,776) lies near the telomeric end of the BAC clone. Similarly, a 283 bp region with 90% identity was detected between clone AC120045 (g 28,136,197-28,136,479) and the chromosome 9 sequence. Either of these regions of sequence homology may have facilitated a non-homologous allelic recombination event that gave rise to the original translocation chromosome. Subsequently, a 3:1 segregation error in the paternal germline led to aneusomy for the der(15) in the proband.

Bottom Line: Autism spectrum disorders have been associated with maternally derived duplications that involve the imprinted region on the proximal long arm of chromosome 15.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, University of Delaware, Newark, USA.

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.

No MeSH data available.


Related in: MedlinePlus