Complex chromosome 17p rearrangements associated with low-copy repeats in two patients with congenital anomalies |
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Authors: | L E L M Vissers P Stankiewicz S A Yatsenko E Crawford H Creswick V K Proud B B A de Vries R Pfundt C L M Marcelis J Zackowski W Bi A Geurts van Kessel J R Lupski J A Veltman |
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Institution: | (1) Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands;(2) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;(3) Sentara Hospital Laboratories, Norfolk, VA, USA;(4) Children’s Hospital of the King’s Daughters, Norfolk, VA, USA;(5) Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;(6) Texas Children’s Hospital, Houston, TX, USA |
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Abstract: | Recent molecular cytogenetic data have shown that the constitution of complex chromosome rearrangements (CCRs) may be more
complicated than previously thought. The complicated nature of these rearrangements challenges the accurate delineation of
the chromosomal breakpoints and mechanisms involved. Here, we report a molecular cytogenetic analysis of two patients with
congenital anomalies and unbalanced de novo CCRs involving chromosome 17p using high-resolution array-based comparative genomic
hybridization (array CGH) and fluorescent in situ hybridization (FISH). In the first patient, a 4-month-old boy with developmental
delay, hypotonia, growth retardation, coronal synostosis, mild hypertelorism, and bilateral club feet, we found a duplication
of the Charcot-Marie–Tooth disease type 1A and Smith-Magenis syndrome (SMS) chromosome regions, inverted insertion of the
Miller-Dieker lissencephaly syndrome region into the SMS region, and two microdeletions including a terminal deletion of 17p.
The latter, together with a duplication of 21q22.3-qter detected by array CGH, are likely the unbalanced product of a translocation
t(17;21)(p13.3;q22.3). In the second patient, an 8-year-old girl with mental retardation, short stature, microcephaly and
mild dysmorphic features, we identified four submicroscopic interspersed 17p duplications. All 17 breakpoints were examined
in detail by FISH analysis. We found that four of the breakpoints mapped within known low-copy repeats (LCRs), including LCR17pA,
middle SMS-REP/LCR17pB block, and LCR17pC. Our findings suggest that the LCR burden in proximal 17p may have stimulated the
formation of these CCRs and, thus, that genome architectural features such as LCRs may have been instrumental in the generation
of these CCRs. |
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