CMT 1A: Complex chromosome 17p rearrangements associated with low-copy repeats i

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Hum Genet. 2007 Apr 25

Complex chromosome 17p rearrangements associated with low-copy

repeats in two patients with congenital anomalies.

Vissers LE, Stankiewicz P, Yatsenko SA, Crawford E, Creswick H,

Proud VK, de Vries BB, Pfundt R, Marcelis CL, Zackowski J, Bi W, van

Kessel AG, Lupski JR, Veltman JA.

Department of Human Genetics, Nijmegen Centre for Molecular Life

Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101,

6500 HB, Nijmegen, The Netherlands

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 -Magenis syndrome

(SMS) chromosome regions, inverted insertion of the -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.