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American Journal of Medical Genetics 83:361–364 (1999)
Duplication Within Chromosome 5q Characterized
by Fluorescence In Situ Hybridization
David Mowat,1* Anna Jauch,2 Lisa Robson,3 and Arabella Smith3
1
Department of Clinical Genetics, Sydney Children’s Hospital, Sydney, Australia
Institut für Humangenetik und Anthropologie, Heidelberg, Germany
3
Department of Cytogenetics, Western Sydney Genetics Program, Royal Alexandra Hospital for Children,
Westmead, Australia
2
We present a 16-month-old boy with developmental delay, minor anomalies, small penis, and lymphedema of the upper limbs.
Routine cytogenetic analysis suspected a
duplication of 5q. Fluorescent in situ hybridization (FISH) with a cosmid probe
(MCC at the 5q22 APC region) showed tandemly duplicated fluorescent signals on one
of chromosomes 5, whereas FISH with three
YAC probes (TYAC12 at 5q35, HTY3182 at
5q34, and TYAC139 at 5q31) did not give duplicated signals. These findings indicate a
duplication of 5q22 band in one chromosome 5. The boy we describe here is the first
case of a pure partial duplication of 5q to be
proven by FISH techniques. A review of previously reported cases of putative partial 5q
duplication showed no consistent phenotype. Am. J. Med. Genet. 83:361–364, 1999.
© 1999 Wiley-Liss, Inc.
KEY WORDS: chromosome 5; partial duplication of 5q; mental retardation; FISH; lymphedema
INTRODUCTION
Attempts at phenotype-karyotype correlation of partial trisomy for the long arm of chromosome 5 have
been hampered because patients represent a heterogeneous group and their partial 5q duplications are of
different lengths. Most cases were the result of an inherited unbalanced translocation, and therefore do not
have pure partial trisomy for 5q [Ferguson-Smith et
al., 1973; Jalbert et al., 1975; Osztovics and Kiss, 1975;
*Correspondence to: Dr. David Mowat, Department of Medical
Genetics, Sydney Children’s Hospital, Randwick, Sydney, NSW
2031, Australia. E-mail: d.mowat@unsw.edu.au
Received 19 December 1997; Accepted 17 December 1998
© 1999 Wiley-Liss, Inc.
Watanabe et al., 1977; Bartsch-Sandhoff and Liersch,
1977; Zabel et al., 1978; Curry et al., 1979; Jones et al.,
1979; Rodewald et al., 1980]. There were three cases of
apparently pure duplications of 5q, whose breakpoints
had been determined cytogenetically [Kessel and
Pfeiffer, 1979; Gilgenkrantz et al., 1981; Martin et al.,
1985].
We describe a boy with de novo duplication for 5q15q23.1 that was confirmed by a combination of chromosome painting with fluorescent in situ hybridization
(FISH) using probes from various regions of 5q. The
boy had quite a different phenotype from that of previously reported patients with a similar chromosome
abnormality.
CLINICAL REPORT
The patient was the fourth child of healthy nonconsanguineous Caucasian parents and was born when
the mother was 25 years and the father 26 years old.
After an uneventful pregnancy, he was delivered at
term by normal vaginal delivery with a birth weight of
3,440 g (75th centile), length of 51 cm (50th centile) and
occipitofrontal circumference (OFC) of 35 cm (50th centile). He was a quiet baby and fed well. At age 4
months, he was noted to have a squint and to be delayed in his motor development. He had a normal computed tomographic scan and underwent grommet surgery for a glue ear. When re-examined at age 16
months, he was noted to have significant global delay
with a developmental level between 7 to 9 months. His
length was 81 cm (50th centile), weight 11 kg (25th
centile), and OFC 45.7 cm (10th centile). He had blond
hair, blue eyes, bitemporal narrowing, flat nasal
bridge, broad nasal tip with horizontal nasal alae, long
philtrum, protruding lower lip, low-set relatively large
ears, with over-folding of the right helix, and a convergent squint (Fig. 1). He had lymphedema of the upper
limbs distal to the midshaft of both humeri, which is
slowly resolving in time. He had a small penis (<2 SD
below the mean) and his testes were normal in size. He
had mild truncal hypotonia over and above that expected for his developmental delay.
362
Fig. 1.
Mowat et al.
Patient at age 16 months, showing his broad nasal tip (A, C), relatively large ears (A–C), upper limb edema (C, D) and small penis (E).
CYTOGENETIC STUDIES
Routine chromosome analysis was performed on a
72-hour–cultured peripheral blood lymphocytes. Fragile X was excluded in 50 cells. All metaphase cells
showed additional material on 5q. GTG-banding
showed that the breakpoints were considered to be between 5q15 and 5q31 with a duplication of part of band
5q22 and all of band 5q23 (Fig. 2). Karyotypes from his
parents were both normal. Chromosome slides for
FISH were obtained using a cell suspension retained
after routine cytogenetic harvest. The following seven
probes were used for the characterization of the 5q rearrangement: three painting probes (CHR5B-Cambio
for the whole chromosome 5 paint, a probe for partial
chromosome 5p paint, and a microdissection probe for
the whole 5q paint), one cosmid probe (the MCC probe
at 5q22-APC region), and three YAC probes (TYAC12
at 5q35, HTY3182 at 5q34, and TYAC139 at 5q31).
The chromosome painting with CHR5B or the 5pspecific probe showed that the additional material on
5q was derived from chromosome 5, and no chromosome 5 material was inserted anywhere else, confirming a pure duplication of 5q. The 5q microdissection
probe and the 5q subtelomere probe (TYAC12) were
used simultaneously. As a result, only a single twinsignal appeared on both chromosomes 5 (Fig. 3a). Likewise, hybridization with two other YAC probes also
showed a single signal on both chromosomes 5 (Fig.
3b). These results indicated that the regions at which
the probes are located are not duplicated. The MCC
5q Duplication Identified by FISH
363
Fig. 2. GTG-banded karyotype with a derivative chromosome 5 on the
right. Arrowheads indicate proximal and distal breakpoints, and arrows
indicate the MCC locus at q22.
cosmid probe showed two twin-signals on one chromosome 5, indicating a duplication involving the 5q22 region (Fig. 3c). The very close proximity of the MCC
signals also indicated the breakpoint to be just distal to
5q22, and an inverted duplication at 5q23.1 as the distal breakpoint. More proximal probes were not available and the proximal breakpoint was considered to be
5q15 from the routine cytogenetic findings.
DISCUSSION
The patient we have described is the first case of a
pure partial 5q duplication to be studied and confirmed
by FISH. He had a phenotype milder than that of three
previously reported live-born patients with a similar
duplication of 5q (Table 1). They were associated with
growth failure, severe psychomotor retardation, microcephaly, and a variety of minor facial anomalies [Kessel and Pfeiffer, 1979; Gilgenkrantz et al., 1981; Martin
et al., 1985], whereas our patient has normal growth,
only minimal facial abnormality, mild-to-moderate
psychomotor retardation, and a normal head size. In
addition, our patient had a broad nasal tip, small penis,
and unusual distribution of non-pitting lymphedema of
the upper limbs, which is resolving. The pattern of
lymphedema and clinical manifestations seen in our
patient are different from those of known lymphedema
syndromes, e.g., Ullrich-Turner syndrome [Jones,
1997], hereditary lymphedema types I and II, Milroy
disease, lymphedema and microcephaly, and lymphedema and cerebral arteriovenous anomaly [Online
Mendelian Inheritance in Man, 1996]. Thus, there is no
phenotype apparently characteristic for the pure interstitial 5q duplication.
A duplication detected cytogenetically should first be
examined with specific library probes. If the whole
chromosome is painted, as here, one can proceed to a
chromosome-arm probe and/or breakpoint mapping
Fig. 3. FISH on chromosomes 5 of the patient. Two-color FISH by the
simultaneous use of Cy5-labeled 5q-microdissection painting probe and
FITC-labeled subtelomeric probe TYAC12 (a), and that using the same
painting probe and FITC-labeled TYAC139 probe (b) show single twinFITC-signal both on normal and derivative chromosomes 5, indicating that
the regions where the probes are located are not duplicated. Two twinsignals (larger arrowhead) appear on the derivative chromosome 5 when
using the MCC probe at 5q22, while a single twin-signal (smaller arrowhead) is seen on normal chromosome 5 (c).
with unique sequence probes from the putative region.
Limitations to this approach include the availability of
probes. In our patient, we could not ascertain the proximal boundary of the duplication with FISH. DNA techniques and probes, which may render breakpoints accurate, are not readily available in all laboratories.
Nevertheless, our case illustrates that there is a new
phase in phenotype-karyotype correlation using FISH
techniques to accurately confirm the cytogenetic findings. This should prevent the inclusion of cases with a
different chromosomal abnormality into a clinical phe-
364
Mowat et al.
TABLE I. Comparison of Cases With Putative Pure 5q Duplication*
Kessel and Pfeiffer,
1979
Gilgenkrantz
et al., 1981
Martin et al.,
1985
This
report
6 years
F
33
2,800
?
+
+
+
?
Bulbous
?
?
+
?
+
q13-q22
4 years
F
22
2,300
46
+
+
+
−
Bulbous
+
+
+
?
?
q13-q22
4 months
M
20
2,290
47.5
+
+
+
−
Bulbous
?
?
?
?
+
q22-q33
16 months
M
25
3,440
51
−
+
−
+
Broad tip
+
+
−
+
−
q15-q23.1
Age
Sex
Maternal age (years)
Birth weight (g)
Birth length (cm)
Microcephaly
Psychomotor retardation
Growth delay
Strabismus
Nose
Large ears
Hypotonia
Scoliosis
Edema
Congenital heart defect
Duplication
*?, Not reported; +, present; −, absent.
notype and provide more accurate descriptions of clinical syndromes.
ACKNOWLEDGMENTS
We are grateful to Ms. Jo Hasselaar for routine cytogenetic analysis, Dr. Brian Kearney at NCH for referring the patient, Dr. Helen Donis-Keller at Washington University for providing the YAC clones,
TYAC12 and TYAC139, Dr. Jeffrey Trent at NIH for
the chromosome-arm specific microdissection probes,
Dr. D. Koorey at Royal Prince Alfred Hospital, Sydney,
for the MCC probe, and to the family for their cooperation.
REFERENCES
Bartsch-Sandhoff M, Liersch R. 1977. Partial duplication 5q syndrome.
Phenotypic similarity in two sisters with identical karyotype (partial
duplication 5q33-5qter and partial deficiency 8p23-pter). Ann Genet
20:179–184.
Curry C Jr, Loughman W, Francke U, Bryan D, Golbus M, Derstine J,
Epstein C. 1979. Partial trisomy for the distal long arm of chromosome
5 (region q34-qter). A new clinically recognizable syndrome. Clin Genet
15:154–461.
Ferguson-Smith M, Newman B, Ellis P, Thomson D, Riley I. 1973. Assignment by deletion of human red cell acid phosphatase gene locus to the
short arm of chromosome 2. Nature 243:271–274.
Gilgenkrantz S, Dulucq P, Bresson J, Gouget A, Pernat C, Gregoire M.
1981. Partial proximal trisomy of the long arm of chromosome 5 (q13q22) resulting from maternal insertion der ins(10;5). J Med Genet 18:
465–480.
Jalbert P, Jalbert H, Sele B, Mouriquand C, Malka J, Boucharlat J, Pison
H. 1975. Partial trisomy for the long arms of chromosome No 5 due to
insertion and further “aneusomie de recombinaison.” J Med Genet 12:
418–423.
Jones KL. 1997. Smith’s recognizable patterns of human malformations.
5th ed. Philadelphia: W.B. Saunders. p 81, 326.
Jones L, Jordan D, Taysi K, Strauss A, Toth J. 1979. Partial duplication of
the long arm of chromosome 5: a case due to balanced paternal translocation and review of the literature. Hum Genet 51:37–42.
Kessel E, Pfeiffer R. 1979. Tandem duplication (5q13-22) in a mentally
deficient girl. Hum Genet 52:217–220.
Martin N, Cartwright D, Harvey P. 1985. Duplication 5q (5q22-5q33) from
an intrachromosomal insertion. Am J Med Genet 20:57–62.
Online Mendelian Inheritance in Man (OMIM). 1996. Baltimore: Center
for Medical Genetics, Johns Hopkins University; and Bethesda, MD:
National Center for Biotechnology Information, National Library of
Medicine.
Osztovics M, Kiss P. 1975. Familial translocation t(2;5)(p28;q31). Clin
Genet 8:112–116.
Rodewald A, Kankl M, Gley E, Zang K. 1980. Partial trisomy 5q: three
different phenotypes depending on different duplication segments.
Hum Genet 55:191–198.
Watanabe G, Kiyoio, Takeyama I, Kawana S, Yamamoto H. 1977. Inherited chromosomal translocation in two families t(4q−;13q+) and
t(5q−;13q+). Tohoku J Exp Med 121:179–184.
Zabel B, Baumann W, Gehler J, Conrad G. 1978. Partial trisomy for short
and long arm of chromosome no. 5. Two cases of two possible syndromes. J Med Genet 15:143–147.
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