Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Nov 12;87(5):631-42.
doi: 10.1016/j.ajhg.2010.10.007.

A common molecular mechanism underlies two phenotypically distinct 17p13.1 microdeletion syndromes

Adam Shlien  1 , Berivan Baskin, Maria Isabel W Achatz, Dimitrios J Stavropoulos, Kim E Nichols, Louanne Hudgins, Chantal F Morel, Margaret P Adam, Nataliya Zhukova, Lianne Rotin, Ana Novokmet, Harriet Druker, Mary Shago, Peter N Ray, Pierre Hainaut, David Malkin
Affiliations

A common molecular mechanism underlies two phenotypically distinct 17p13.1 microdeletion syndromes

Adam Shlien et al. Am J Hum Genet. .

Abstract

DNA copy-number variations (CNVs) underlie many neuropsychiatric conditions, but they have been less studied in cancer. We report the association of a 17p13.1 CNV, childhood-onset developmental delay (DD), and cancer. Through a screen of over 4000 patients with diverse diagnoses, we identified eight probands harboring microdeletions at TP53 (17p13.1). We used a purpose-built high-resolution array with 93.75% breakpoint accuracy to fine map these microdeletions. Four patients were found to have a common phenotype including DD, hypotonia, and hand and foot abnormalities, constituting a unique syndrome. Notably, these patients were not affected with cancer. Moreover, none of the TP53-deletion patients affected with cancer (n = 4) had neurocognitive impairments. DD patients have larger deletions, which encompass but do not disrupt TP53, whereas cancer-affected patients harbor CNVs with at least one breakpoint within TP53. Most 17p13.1 deletions arise by Alu-mediated nonallelic homologous recombination. Furthermore, we identify a critical genomic region associated with DD and containing six underexpressed genes. We conclude that, although they overlap, 17p13.1 CNVs are associated with distinct phenotypes depending on the position of the breakpoint with respect to TP53. Further, detailed characterization of breakpoints revealed a common formation signature. Future studies should consider whether other loci in the genome also give rise to phenotypically distinct disorders by means of a common mechanism, resulting in a similar formation signature.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Discovery of a 17p13.1 CNV Leading to Two Distinct Phenotypes (A) FISH experiments using TP53 (red) and 17ptel (green) probes. The fluorescent signals in this representative family trio confirm a de novo hemizygous TP53 deletion in the child's metaphase and interphase nuclei. Two hundred nuclei were scored, and no evidence of mosaicism for the CNV was observed. TP53 microdeletions were not observed by conventional Giemsa banded karyotyping. (B) Results of MLPA, qPCR, and clinical array revealed two isoforms of the 17p13.1 CNV. Among DD patients, the CNV includes and extends past TP53 in the telomeric and centromeric directions (n = 4; top); Among the cancer-affected patients, the 17p13.1 CNV deletes some—but not all—of TP53's exons. TP53 is transcribed off of the minus DNA strand; therefore, its introns and exons are drawn from last to first.
Figure 2
Figure 2
Breakpoint Maps, Sequence Resolution, and Inferred Mechanism of DD-Associated 17p13.1 CNVs We developed an ultrahigh-resolution CGH array (see Figure S3) to obtain breakpoint-level information on 17p13.1 CNVs. Shown are the array results for all four DD patients. Log2 ratios from the array are shown, each dot representing one probe and deletions indicated in green. The proximal and distal breakpoints were determined for all samples, revealing that all DD patients shared a critical region including TP53 and 23 other genes (red). The precise breakpoint positions, their sizes, and the nucleotide sequence of the disrupted regions are shown. The presence of two Alu elements (orange arrows and orange-colored nucleotides) at the junctions is consistent with the formation of the CNV by Alu-Alu-mediated NAHR (patients 3026, 3148, and 3354). The percentage of homology between directly oriented Alus is indicated for NAHR CNVs. In one instance an NHEJ signature could be seen at the at the breakpoint sequence: Four additional base pairs incorporated at the junction (patient 2723).
Figure 3
Figure 3
Breakpoint Maps, Sequence Resolution, and Inferred Mechanism of Cancer-Associated 17p13.1 CNVs An ultrahigh-resolution CGH array (see Figure S3) was used to obtain breakpoint-level information on 17p13.1 CNVs in two cancer-affected patients. Log2 ratios from the array are shown, each dot representing one probe and deletions indicated in green. The precise breakpoint positions, their sizes, and the nucleotide sequence of the disrupted regions are shown. The presence of two Alu elements (orange arrows and orange-colored nucleotides) at the junctions is consistent with the formation of the CNV by Alu-Alu-mediated NAHR (patient 3332 and brother). The percentage of homology between directly oriented Alus is indicated for NAHR CNVs. The proximal and distal breakpoints were always either intronic in TP53 or intragenic, never disrupting other genes besides TP53 or leading to gene fusions. Using high-quality DNA from one patient's frozen tumor, we observed a second deletion on the opposite allele, conforming to the classical two-hit hypothesis of tumorigenesis (patient 2760). This custom array was used to test for the presence of the CNV in two asymptomatic siblings of an index case affected with cancer (patient 3332). One sibling (shown) was found to harbor the identical deletion.
Figure 4
Figure 4
Gene-Expression Differences Distinguish between Cancer-Affected an DD Patients with 17p13.1 Deletions We used Affymetrix exon arrays to look for gene-expression differences in available blood-derived RNA. We first evaluated which of the 24 genes in our critical region (commonly deleted in patients with DD) is significantly under- or overexpressed. Twenty of these 24 genes could be assayed with the array and are shown. On the y axis is depicted the significance of each gene's expression change relative to controls (plotted in reverse order). The red dotted line represents the p value threshold of 0.01, above which all significant changes in gene expression are highlighted (black dots). (A) Among patients with small 17p13.1 CNV only TP53's expression is significantly changed (p = 6.82 × 10−3; fold change = −1.9). (B) Notably, a similar analysis of RNA from a DD patient did not show TP53 underexpression, despite the gene being fully deleted in a large 17p13.1 CNV. There are, however, six significantly changed genes (all underexpressed). As shown, these are TRAPPC1 (p = 2.90 × 10−5, fold change = −2.3), FXR2 (p = 3.47 × 10−3, fold change = −1.6), LSMD1 (p = 4.88 × 10−3, fold change = −2.2), KDM6B (p = 6.98 × 10−3, fold change = −6.4), CYB5D1 (p = 8.80 × 10−3, fold change = −1.6), and MPDU1 (p = 9.78 × 10−3, fold change = −1.8). In a separate analysis (Figure S6), TRAPPC1 was found to be the most significantly underexpressed gene in the transcriptome.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Stefansson H., Rujescu D., Cichon S., Pietiläinen O.P., Ingason A., Steinberg S., Fossdal R., Sigurdsson E., Sigmundsson T., Buizer-Voskamp J.E., GROUP Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:232–236. - PMC - PubMed
    1. International Schizophrenia Consortium Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455:237–241. - PMC - PubMed
    1. Greenway S.C., Pereira A.C., Lin J.C., DePalma S.R., Israel S.J., Mesquita S.M., Ergul E., Conta J.H., Korn J.M., McCarroll S.A. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat. Genet. 2009;41:931–935. - PMC - PubMed
    1. Diskin S.J., Hou C., Glessner J.T., Attiyeh E.F., Laudenslager M., Bosse K., Cole K., Mossé Y.P., Wood A., Lynch J.E. Copy number variation at 1q21.1 associated with neuroblastoma. Nature. 2009;459:987–991. - PMC - PubMed
    1. Mefford H.C., Sharp A.J., Baker C., Itsara A., Jiang Z., Buysse K., Huang S., Maloney V.K., Crolla J.A., Baralle D. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N. Engl. J. Med. 2008;359:1685–1699. - PMC - PubMed

Publication types