TY - JOUR
T1 - A common molecular mechanism underlies two phenotypically distinct 17p13.1 microdeletion syndromes
AU - Shlien, Adam
AU - Baskin, Berivan
AU - Achatz, Maria Isabel W.
AU - Stavropoulos, Dimitrios J.
AU - Nichols, Kim E.
AU - Hudgins, Louanne
AU - Morel, Chantal F.
AU - Adam, Margaret P.
AU - Zhukova, Nataliya
AU - Rotin, Lianne
AU - Novokmet, Ana
AU - Druker, Harriet
AU - Shago, Mary
AU - Ray, Peter N.
AU - Hainaut, Pierre
AU - Malkin, David
PY - 2010/11/12
Y1 - 2010/11/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78249286208&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2010.10.007
DO - 10.1016/j.ajhg.2010.10.007
M3 - Article
C2 - 21056402
AN - SCOPUS:78249286208
SN - 0002-9297
VL - 87
SP - 631
EP - 642
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -