A Common Molecular Mechanism Underlies Two Phenotypically Distinct 17p13.1 Microdeletion Syndromes

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.

Genotype–phenotype correlations in patients with retinoblastoma and interstitial 13q deletions

“…23 It was recognized that partial deletions of this gene lead to stronger cancer predisposition than full-length loss that include the first exon and intron, possibly because an aberrant function of this part of the TP53 accelerates tumorigenesis. 23 In patients with 13q13 microdeletions, however, the pattern of genotype-phenotype correlation is distinct in that full-length loss of only the RB1 gene is associated with bilateral retinoblastoma as are intragenic mutations that result in loss of function due to premature termination.…”

17p13.1 microdeletion: Genetic and clinical findings in a new patient with epilepsy and comparison with literature

“…Since the first report in 2009 [Adam et al, 2009], 15 patients with 17p.13.1 deletions have been described [Adam et al, 2009;Krepischi-Santos et al, 2009;Schluth-Bolard et al, 2010;Schwarzbraun et al, 2009;Komoike et al, 2010;Shlien et al, 2010;Zeesman et al, 2012]. In 10 patients, the deletion encompassed TP53 gene [Adam et al, 2009;Krepischi-Santos et al, 2009;Schwarzbraun et al, 2009;Schluth-Bolard et al, 2010;Shlien et al, 2010] which is involved in cancer predisposition; moreover, germline TP53 missense mutations predispose to an autosomal-cancer susceptibility condition known as Li-Fraumeni syndrome [Malkin et al, 1990].…”

“…In 10 patients, the deletion encompassed TP53 gene [Adam et al, 2009;Krepischi-Santos et al, 2009;Schwarzbraun et al, 2009;Schluth-Bolard et al, 2010;Shlien et al, 2010] which is involved in cancer predisposition; moreover, germline TP53 missense mutations predispose to an autosomal-cancer susceptibility condition known as Li-Fraumeni syndrome [Malkin et al, 1990].…”

Li-Fraumeni Syndrome

“…It is postulated from this work that the transforming events conferred by aberrant p53 expression in LFS result from qualitative abnormalities of the p53-expressed project rather than quantitative decrease in baseline expression. 47 Thus, while germline p53 mutations establish the baseline risk of tumor development in LFS, a complex interplay of modifying genetic cofactors likely defines the specific phenotypes of individual patients.…”