J Appl Genet 48(2), 2007, pp.

157–166

Review

Chromosome abnormalities without phenotypic consequences

Ma³gorzata Kowalczyk1, Ma³gorzata Srebniak2, Agnieszka Tomaszewska1

1
Department of Medical Genetics, Medical University of Silesia, Sosnowiec, Poland
2
Clinical Genetics, Erasmus Medical Center, Rotterdam

Abstract. Some changes in chromosome morphology, detected during cytogenetic analysis, are not associated
with clinical defects. Therefore a proper discrimination of harmless variants from true abnormalities, especially
during prenatal diagnosis, is crucial to allow precise counseling. In this review we described chromosome vari-
ants and examples of chromosome anomalies that are considered to be unrelated to phenotypic consequences.
The correlation between the presence of marker chromosomes and a risk of clinical signs is also discussed. Struc-
tural rearrangements of heterochromatic material, satellite polymorphism, or fragile sites, are well-known exam-
ples of common chromosome variation. However, the absence of clinical effects has also been reported in some
cases of chromosome abnormalities concerning euchromatin. Such euchromatic anomalies were divided into
2 categories: unbalanced chromosome abnormalities (UBCAs), such as deletions or duplications,
and euchromatic variants (EVs). Recently so-called molecular karyotyping, especially whole-genome screening
by the use of high-resolution array-CGH technique, contributed to revealing a high number of previously un-
known small genomic variations, which seem to be asymptomatic, as they are present in phenotypically normal
individuals.

Keywords: cytogenetic diagnosis, euchromatic variants (EVs), heteromorphism, molecular karyotyping,

supernumerary marker chromosomes (SMCs), unbalanced euchromatic abnormalities (UBCAs).

Introduction of the present case with other cases reported be-

Some changes in chromosome morphology,
which are detected in cytogenetic diagnostics, are
not associated with clinical defects. There are
chromosomal regions that show a large degree of
variability. A proper discrimination of harmless
variants from true abnormalities, especially during
prenatal diagnosis, is crucial to allow precise
counseling. First of all, in cases where fetal
karyotype shows some chromosome rearrange-
ments, control analysis of parental chromosomes
should be performed. It will be helpful to distin-
guish a harmless congenital variation (if the same
change is found in phenotypically normal parents)
from a true abnormality causing clinical anoma-
lies. Therefore a complete characterization of the
detected abnormality by the use of all available
standard and molecular methods is necessary for
proper genetic counseling. Moreover, comparison
fore should also give additional information about
the clinical outcome.
According to Wyandt and Tonk (2004),
heteromorphisms “represent microscopically visi-
ble regions on chromosomes that are variable in
size, morphology and staining properties in differ-
ent individuals”. There are also 2 other terms used
with the same meaning: variants and
polymorphisms. The term polymorphism, how-
ever, is more correctly used in de context of genes
and molecules. The terms variant or
heteromorphism remain more correct for chromo-
somes.
Here we describe chromosome variants and ex-
amples of chromosome anomalies that are consid-
ered not to be associated with phenotypic
consequences. There are also some difficulties
discussed and a review of the literature is pre-
sented.

Received: June 12, 2006. Revised: March 7, 2007. Accepted: March 19, 2007.
Correspondence: M. Srebniak, Clinical Genetics, Erasmus Medical Centre, Rotterdam, Dr. Molewaterplein 50, 3015 GE Rot-
terdam; e-mail: m.srebniak@erasmusmc.nl or srebna@poczta.onet.pl
158 M. Kowalczyk et al.
Variants and structural rearrangements of
harmless material (heterochromatin, NORs,
fragile sites)
Heteromorphism of chromosomes (variant chro-
mosomes) is an example of genetic polymor-
phism. Variants differ according to frequency.
Some rare variants are even considered as private
variants, because they are found in just a single
family (Gardner and Sutherland 2004). Among all
chromosomes, the highest variability is demon-
strated by chromosome Y: heterochromatin,
pericentric inversions, satellited Y chromosomes
(Yqs), and Y heterochromatin translocations
(Connor and Ferguson- Smith 1998; Gardner and
Sutherland 2004).
Morphological variations of constitutive
heterochromatin are frequently detected during
routine cytogenetic analysis. Most often, chromo-
somes vary in size and position of
heterochromatin in the following regions: 1qh,
9qh, and 16qh. Some variants are sometimes re-
ferred as inversions of heterochromatin (Gardner
and Sutherland 2004). Inversions of only
heterochromatic regions are considered not to
cause phenotypic abnormalities. On the other
hand, carriers of inversions involving
a euchromatic segment are liable to produce un-
balanced gametes. Among polymorphic inver-
sions, the most popular is inv(9)(p11q12). Partial
inversions of the qh region of chromosome 1 are
also frequently noticed, but total inversion
inv(1)(p13p21) is a rare variant (Gardner and
Sutherland 2004).
Variations of the C-band material can be seen
in other chromosomes, as well. Zaslav et al.
(2004) demonstrated a rare heterochromatic vari-
ant of chromosome 4 (with an extra dark band
at the terminal part of the long arm). This inherited
variant was reported not to be associated with any
risk of phenotypic abnormalities. Hetero-
morphism 18ph+ was also described previously
(Tabet et al. 2001).
Variation in length of the short arm of
acrocentric chromosomes is commonly seen. It is
due to different amounts of tandemly repeated
DNA sequences: satellites I, II, III and IV, rRNA
genes, and b satellite, which are located in p11,
p12 and p13 bands, respectively (Willat et al.
2001; Gardner and Sutherland 2004). It was
shown by Benzacken et al. (2001) and recently by
Starke et al. (2005) that in cases of suspiciously
large acrocentric short arms (especially in prenatal
diagnostics) the detailed analysis by using an ade-
quate method should be performed. Especially
when the fetus exhibits clinical abnormalities, ver-
ification of such a polymorphism, also by parental
chromosome analysis, is necessary in order to ex-
clude the occurrence of cryptic abnormalities.
In the first report mentioned above, Benzacken
et al. (2001) described a case of Beckwith-
Wiedemann syndrome (BWS) due to an unbal-
anced translocation between short arms of chro-
mosomes 11 and 14. Previous banding analysis
(during pregnancy) revealed normal karyotype ex-
cept for an enlarged satellite stalk of one chromo-
some 14. The detailed cytogenetic diagnosis
(G, R, C-banding, silver-staining and FISH with
specific telomeric probes) performed later in the
newborn, showed the presence of material derived
from chromosome 11 on the top of the short arm of
chromosome 14. So it was in fact a case of partial
trisomy 11p instead of 14p+ polymorphism.
The second mentioned report (Starke et al. 2005)
describes 3 cases. In each example, banding analy-
sis revealed a very large short arm of an
acrocentric chromosome. However, after applying
M-FISH and microdissection techniques, it turned
out that in 2 cases the rearrangements were not
polymorphisms but partial trisomies. Materials
derived from chromosomes 6 and 19 were found
within the enlarged short arms. Those cases
strongly suggest that enlarged acrocentric p arms
need to be carefully examined and in some cases
comparison to parental chromosomes seems nec-
essary.
So-called NOR-translocations, i.e. transfer of
nucleolus organizing region (NOR) material from
an acrocentric chromosome onto another chromo-
some, may also lead to creation of new variant
chromosomes, which are often inherited through
many generations. An example of such polymor-
phism is chromosome 12 with NOR localized on
the short arm (12ps) (Willat et al. 2001). This sat-
ellited chromosome was recorded in 3 families
as a heritable variant, which does not influence the
phenotype of the carriers. The 4qs chromosome
may serve as another example. It was observed in
a fetus and 2 normal individuals of the same fam-
ily: father and grandfather (Miller et al. 1995). In-
terstitially satellited chromosomes were reported
by Reddy and Sulcova (1998): chromosome 21
with additional material on its short arm, chromo-
some 7 with NOR insertion in the p arm, and chro-
mosome 2 with satellites at the end of the q arm.
A case of interstitially satellited 6ps chromosome
was reported by Chen et al. (2004).
 Chromosome abnormalities without consequences
A fragile site (abbreviated fra) is a region of
chromosome particularly liable to chromatid
breaks. Most of fragile sites associated with spe-
cific chromosome bands can occur as harmless
variants, except for fra(X)(q27.3) and fra(X)(q28),
which are connected with specific diseases. Many
authors tried to find a correlation between an ab-
normal phenotype and other fragile sites, but later
it appeared that fragile sites are common
heteromorphisms.
Marker chromosomes
Extra structurally abnormal chromosomes found
in pre- and postnatal diagnostics are defined as su-
pernumerary marker chromosomes (SMCs).
SMCs make serious problems for genetic counsel-
ing, especially in prenatal diagnosis. This is due to
the fact that the presence of markers can be associ-
ated with a risk of phenotypic abnormalities de-
pending on the amount of euchromatin contents in
the derivative chromosome and the chromosomal
origin (Eggermann et al. 2002). Different degrees
of mosaicism or parental origin may also influence
the patient’s phenotype (Hou and Wang 1998).
SMCs cannot be called heteromorphisms or vari-
ants, as they are extra chromosomes that normally
do not exist in a human karyotype. However, some
SMCs have apparently no phenotypic conse-
quences and these are worth being discussed here.
The majority of SMCs are derived from
acrocentric chromosomes (Langer et al. 2001).
Published data suggest that very small satellited
markers derived from chromosomes 13, 14, 15
and 21 are associated with a low risk of an abnor-
mal phenotype, in contrast to satellited markers
originating from chromosome 22, which cause se-
rious phenotypic effects (Callen et al. 1992). De-
rivatives of chromosome 15 are the most common,
with a frequency of about 50% (Eggermann et al.
2002). Therefore SMCs(15) are widely discussed
in the literature. Published reports – suggest that
patients with a SMC(15) containing only the
heterochromatin or little euchromatin (i.e. with
breakpoints at 15q11.1) may have a normal pheno-
type. However, larger SMCs(15), containing at
least the 15q12 band, cause various phenotypic ab-
normalities (Eggermann et al. 2002).
Only 15% of all SMCs are of non-acrocentric
origin and the risk of phenotypic defects is esti-
mated to be about 28% (Trimborn et al. 2005).
SMCs consisting of pericentric heterochromatin
of chromosomes 1, 9 and 16 exert no influence on
the carrier’s phenotype (Callen et al. 1990). About
1/3 of SMCs cases could be correlated to 4 clinical
159
syndromes: Pallister-Killian syndrome, isochro-
mosome 18p, derivative chromosome
22 [der(22)t(11;22)(q23;q11.2)], and the cat-eye
syndrome [inv dup(22q)] (Liehr et al. 2004a). Half
of the carriers of SMC(15) had no clinical prob-
lems, but only 8% of the carriers of SMCs derived
from all other chromosomes were healthy. Re-
cently it has been shown that each SMC can have
unique breakpoints, even if they seem to be
cytogenetically identical. That is probably the rea-
son why it is so difficult to build a correct pheno-
type- genotype correlation for each marker, and
family studies are necessary to determine whether
the marker is harmless or not. Liehr et al. (2006)
conclude from their study that partial trisomies or
polysomies of the centromeric heterochromatin of
chromosomes X, 9, 14, 16 and 20 are not associ-
ated with clinical abnormalities. Also gains of the
heterochromatin of chromosomes 1, 2, 4, 5, 6, 7, 8,
15, 17, 18, 21, and 22 plus a proximal region of
this band are not associated with clinical abnor-
malities. The chromosome regions are as follows:
1p12®p11.2, 1q21.1 (prb), 2q12, 4p13~12, 5q12
(prb), 6q11.2, 7p11.2, 8p11.21 (prb), 15q12 (prb),
17p11.2 (prb), 18p11.21, 21q21.1 (prb) and
22q11.21 (proximal region of this band = prb).
In 1/3 of cases the SMCs are inherited. It is
considered that such familial marker chromo-
somes are usually harmless, especially when they
are present in karyotypes of phenotypically nor-
mal parents. Nevertheless, that is not true for all
cases. Eggermann et al. (2002) described a patient
who was referred for cytogenetic analysis because
of abnormal features, and a familial SMC(15) was
detected. Other family members, being carriers of
this marker, were phenotypically normal. Unfortu-
nately those authors did not explain the reason of
this phenomenon, but in that case the abnormal
features found in the patient might also be unre-
lated to the SMC(15) found in the family.
Small supernumerary marker chromosomes
cannot be fully identified by conventional banding
techniques. The most commonly used technique is
fluorescence in situ hybridization (FISH) with
band-specific DNA probes (Blennow et al. 1993;
Eggermann et al. 2002). However, this method
might be time-consuming, especially when sev-
eral series of different hybridizations are required.
Therefore more sophisticated approaches have
been developed. The application of micro-FISH
(Anderlid et al. 2001; Engelen et al. 2003;
Trimborn et al. 2005) and multicolor karyotyping
technologies, such as multiplex-FISH (M-FISH),
including centromere-specific multicolor FISH
160 M. Kowalczyk et al.
(cenM-FISH; Nietzel et al. 2001) or spectral
karyotyping (SKY) (Guanciali-Franchi et al.
2004) in analysis of marker chromosomes, was
demonstrated in the literature. Taking into account
that approximately 80% of all SMCs derive from
acrocentric chromosomes, Langer et al. (2001) de-
scribed a new strategy for their rapid and detailed
identification. It is based on the combination of
2 hybridizations. The first one is AcroM-FISHB,
with a special multicolor probe mix that consists
of 3 components: painting and centromeric probes
for all acrocentric chromosomes, and a rDNA
probe. It allows the complete characterization of
all SMCs containing material from
NOR-chromosomes. The second hybridization, by
using a multicolor technique (e.g. M-FISH),
should be performed if euchromatic origin is still
unknown after AcroM-FISH. According to the
published data, in some cases M-FISH analysis
alone was sufficient to reveal the origin of SMCs.
However, if the marker chromosome contains
heterochromatin, the fluorescence signal will be
negative after M-FISH because of unlabelled
blocking-DNA, which is added to the hybridiza-
tion mix to suppress repetitive sequences. So the
best strategy is, according to Langer et al. (2001),
a simultaneous use of both AcroM-FISH and
multicolor karyotyping technique. It enables to
shorten the time of analysis, which is particularly
important if de novo SMC was detected during
prenatal diagnostics.
Rearrangements of euchromatic material
The G-band pattern is a characteristic feature of
each chromosome, which enables to detect various
balanced or unbalanced aberrations in the
karyotype. Most of visible chromosome abnor-
malities concerning euchromatic regions have se-
rious phenotypic consequences. On the other
hand, the absence of phenotypic effects was re-
ported in some cases of euchromatic anomalies.
It is well-known that a chromosome abnormality
might be harmless if the same anomaly is detected
in a phenotypically normal parent. Therefore al-
most all recorded euchromatic abnormalities with-
out phenotypic consequences are inherited.
However, there is a group of familial anomalies
where a child had abnormal phenotype, whereas
its parent and other carriers in the family were
completely healthy. In such cases the detected ab-
normality may influence the carrier’s phenotype
because of, e.g., genomic imprinting, or it is only
a coincidental finding and the true cause of the
phenotypic abnormality remains unknown.
In such cases other microdeletions or gene mutations
must be considered in the affected region in the carrier
with abnormalities (see The Chromosome Anomaly
Register at the website of the School of Medicine, Uni-
versity of Southampton, http://www.som.
Soton.ac.uk/research/geneticsdiv/Anomaly%20Regiser
%20old/index.htm).
Barber (2005a) divided euchromatic anomalies
into 2 categories: (1) unbalanced chromosome ab-
normalities (UBCAs), such as deletions (del) or
duplications (dup), and (2) euchromatic variants
(EVs), mostly due to variation in copy number of
pseudogenes. About 200 cases of both UBCAs
and EVs were gathered by Barber. This Chromo-
some Anomaly Collection, accessible at the
website of the National Genetics Reference Labo-
ratory in Wessex (http://www.ngrl.org.uk/Wes-
sex/collection.htm), is constantly updated. We
present here only some of the examples of
euchromatic abnormalities.
Euchromatic variants (EVs)
There are 5 variants considered as euchromatic
variants (EVs): 8p23.1, 9p12, 9q12, 15q11.2 and
16p11.2. An additional band containing an in-
creased copy number of paralogous gene and
pseudogene cassettes can be visible in these chro-
mosome regions (Barber 2005a). This extra band
is detectable only when the amplification exceeds
a specific level; small duplications may remain
submicroscopic.
Duplication including the 8p23.1 region was
widely discussed in the literature. However, the
influence of this segmental aneuploidy on pheno-
type carrier still remains unclear. Barber et al.
(1998) described duplication of chromosome 8
at band 8p23.1 in 7 independent families. This
anomaly has been studied in 3 of the 7 families by
the use of FISH with whole chromosome 8 paint-
ing probe and with a YAC HTY3020, which maps
to 8p23.1. The difference in YAC signal size be-
tween homologue chromosomes proved the dupli-
cation. Gain of the distal 8p material was also
detected by comparative genomic hybridization
(CGH). Taking into account the transmission of
this segmental aneuploidy within 4 recorded fami-
lies (all carriers were phenotypically normal),
those authors suggested that it is in fact
a euchromatic variant without clinical effects.
However, Gibbons et al. (1999) reported a patient
and her 2 daughters with minimal dysmorphology
and the same small duplications 8p23.1 character-
ized by FISH with specific probes. This example
shows that dup(8)(p23.1p23.1) may be associated
 Chromosome abnormalities without consequences 161

with a mild phenotypic effect. Other published Euchromatic variation of 16p11.2 was pre-
data suggest that duplication 8p23.1 might be also sented by Barber et al. (1999). FISH with cosmids
the cause of serious clinical defects, including specific for this region revealed that extra material
mental retardation, short stature, heart defects, or contains only a pseudogene cassette consisting of
hypotonia, as in cases reported by Tsai et al. non-functional sequences originating from chro-
(2002). Some phenotypic differences between pa- mosomes 14 and X. Heteromorphism 16p was pre-
tients with dup 8p23.1 may result from variation in viously described also by Jalal et al. (1990).
copy number and nature of the duplicated material
(Tsai et al. 2002). Barber et al. (2005b) have re- Unbalanced euchromatic abnormalities
cently shown that distinguishing duplications of (UBCAs)
8p23.1 associated with phenotypic abnormalities Deletions
from the ones that are only harmless copy number
variants is possible at the molecular level. Although monosomy of euchromatic material usu-
There are 2 euchromatic variants of chromo- ally causes an abnormal phenotype, there are some
some 9: short-arm variant and long-arm variant. documented chromosome deletions (mainly inher-
According to the literature, both variants are con- ited), which seem to be asymptomatic. Most of the
sidered to have no clinical effects, as they are ob-
served in phenotypically normal persons (Gardner Table 1. Unbalanced chromosome abnormalities
and Sutherland 2004). The first variant has an ad- observed in phenotypically normal individuals.
ditional material inserted into the 9p12 band; re- All demonstrated instances were chosen from the
ported, e.g., by Webb et al. (1989). The second one Chromosome Anomaly Collection (http://www.ngrl.
has an extra dark G-band located within the q12 org.uk/Wessex/collection.htm) except a case from
(qh) region (Docherty and Hulten 1993; von Beust Di Giacomo et al. (2004)a.
and Bink 1999; Ozikinay et al. 2005). Type of rear- Affected chromo- References
Duplication of proximal 15q, excluding the rangement some regions
Prader-Willi/Angelman critical region, is gener- 2p12-p12 Barber et al. 2005
ally interpreted as a harmless variant. Fantes et al. 2q13-q14.1 Sumption and Barber
(2002) showed that variations in the copy number 2001
3p25-pter Knight et al. 1993
of 4 pseudogenes (NF1, IgH D, GABRA5, and 5p13.1-p14.2 Barber 2000
BCL8) are responsible for a detectable elongation 5p14-p14 Overhauser et al. 1986
5p14.1-p14.3* Hand et al. 2000
of the 15q11.2-q13 region in some individuals. 7p22-pter* Mascarello et al. 1991
A detailed analysis of the amplification NF1 and 8p23.1/2-pter Reddy 1999
Deletion
8q24.13-q24.22 Batanian et al. 2001
IgH D within the pseudogene cassette was per- 9p21.2-p22.1 Pelly et al. 1992
formed by use of the FISH technique with specific 10q11.2-q21.2 Davis et al. 1999
11p12-p12 Barber et al. 1991
clones. The study was conducted for both 11q14.3-q21* Li et al. 2002
cytogenetically normal controls (20 cases) and 8 13q21-q21 Couturier et al. 1985
16q13-q22 Hand et al. 2000
individuals with a proximal 15q duplication. Hy- 16q21-q21 Witt et al. 1988
bridization on metaphase chromosomes revealed a 18p11.3-pter Rigola et al. 2001
difference in signal size between chromosome 15 1p21-p31 Zaslav et al. 1993
homologues, not only in carriers of such a seg- 1q11-q22* Chan et al. 2002
1q42.11-q42.12* Bortotto et al. 1990
mental aneuploidy. Moreover, interphase FISH 3q25-q25* Fryburg et al. 1994
mapping enabled to determine the copy number of 3q28-q29 Millard et al. 1998
4q31.3-q33* Maltby et al. 1999
NF1 and IgH D, as DNA in an interphase nucleus 5q15-q21* Li et al. 1998
is less condensed and the distance between signals 6q24.2-q24.2* Barber 2000
is increased, so the duplication is easier to detect. 8p22-p22 Chan et al. 2003
Duplication
8p23.1-p23.3 Engelen et al. 2000
The copy number for NF1 ranged from 1 to 4 in 8p23.2-p23.2* Harada et al. 2002
a normal population and from 5 to 10 in the dupli- 9p12-p21.3 Stumm et al. 2002
9p11.2-p13.1a Di Giacomo et al. 2004
cated region. The copy number of the NF1 10p13-p14 Saxe et al. 2003
pseudogene in both studied groups was also 14q24.3-q31* Robin et al. 1997
15q11-q13* Cook et al. 1997
slightly increased. Ritchie et al. (1998) in an ear- 16q12.1-q12.1* Verma et al. 1997
lier report showed that another pseudogene 18p11.2-pter Wolff et al. 1991
(GABRA5) was also represented by multiple cop- * familial cases in which the child is abnormal, but parents with the
ies (8–20) at the 15q11.2-q13 segment. same chromosome abnormality are unaffected.
162 M. Kowalczyk et al.
recorded cases are presented in Table 1 (after Bar-
ber).
A chromosome 2 deletion involving the
q13-q14.1 region, demonstrated by Sumption and
Barber (2001), is a good example. FISH with YAC
probes allowed to determine the breakpoints and
subsequently to estimate the extent of euchromatic
loss at 4.5–6.0 Mb. Microscopic deletion of
8q24.13-q24.22 was revealed in an unaffected
mother and her fetus after a precise cytogenetic
analysis, i.e. FISH with specific probes (Batanian
et al. 2001). A rare interstitial deletion of
11q14.3-q21 was identified in 5 individuals repre-
senting 3 generations of kindred. Only 1 carrier
showed mild clinical features, which were proba-
bly unrelated to the deletion. The accurate descrip-
tion of 11q partial monosomy including the size
and gene content was possible by performing
FISH with BAC probes mapping to the deleted re-
gion (Li et al. 2002).
There are several postulated alternative theo-
ries, which can help to explain the lack of clinical
consequences in the case of large euchromatic de-
letions. One of them assumes a low density of
genes in the deleted region or that the lost material
is entirely non-essential. Deletion may also be
harmless if the genes located in the deleted part of
chromosome are haplosufficient, which means
that cells with a single copy function normally.
For instance, the 11q14.3-q21 region is considered
to be functionally haplosufficient. It is also possi-
ble that some deleted genes have additional cop-
ies, situated in a different place of the genome, and
those can compensate for the loss. Finally there is
a probability that the deleted chromosome region
was (before the deletion) inactivated as a result of
genomic imprinting, leading to expression of only
maternal or only paternal genes (Li et al. 2002), so
the loss of inactive material is harmless.
Duplications
In 2004, Di Giacomo et al. identified a duplication
of 9p11.2-p13.1, which is an example of a still
growing group of harmless euchromatic duplica-
tions (Table 1). Duplication of this region was
identified in 2 unrelated fetuses and in their
phenotypically normal mothers. Additionally, in
1 family this variant appeared in 3 generations.
FISH experiments with BACs containing se-
quences complementary to the amplified segment
were performed to exclude 9p duplication syn-
drome, associated with an additional copy of the
9p21.3 band. Moreover, on the basis of double
BAC signals, the breakpoints and the size of the
duplicated region were precisely defined. Despite
the fact that the implicated region is relatively
large (5 or 5.2-Mb), a low density of the genes may
explain the lack of phenotypic effects.
An unusual case of segmental trisomy
9p12-p21.3, derived from insertion ins(5;9)
(p13.3;p12p21.3), was reported by Stumm et al.
(2002). This anomaly has been transmitted
through 3 generations of normal individuals.
The lack of phenotypic abnormalities is striking,
especially that the size of the trisomic segment is
about 21 Mb. However, according to the published
data, one can expect characteristic clinical symp-
toms if the “critical” 9p22-p24 region is engaged
in the partial trisomy. So it may explain the lack of
abnormal features of 9p duplication syndrome in
the proband.
Chan et al. (2002) described a case of inherited
duplication of 1q11-q22 in a boy with
T lymphoblastic lymphoma. Duplication region
was to a large degree heterochromatic, while the
euchromatic gain involved only 1q21-22 bands.
The same karyotypic alternation was observed in
the unaffected parent and sister. Another example
of a harmless 1q duplication, spanning
1q42.11-42.12, was recorded by Bortotto et al.
(1990). Moreover, Zaslav et al. (1993) reported
a transmitted duplication of 1p21-p31 material
that causes no phenotypic effect.
So far, most of the reported cases of harmless
unbalanced euchromatic abnormalities have been
detected first during G-banding analysis and after-
wards characterized in detail by the use of molecu-
lar methods. Therefore, one can presume that such
a polymorphism might be much more frequent, as
recently the so-called molecular karyotyping has
started to play a very important role in clinical ge-
netics. Microaberrations are now revealed in pa-
tients previously karyotyped and assumed as
chromosomally normal. Some molecular tech-
niques – e.g. subtelomeric FISH, multicolor-
FISH, or comparative genomic hybridization
(CGH) – were demonstrated to be useful tools de-
tecting small chromosome rearrangements. But
none of these methods is sufficiently sensitive to
detect very subtle changes. Introduction of
high-resolution array CGH for whole-genome
screening has made it possible. Oostlander et al.
(2004) published a review article about advan-
tages of array-CGH in comparison with other ap-
proaches, and also its application in the diagnostic
process. First of all, replacing metaphase chromo-
somes by cloned DNA fragments increased the
resolution from 5–10 Mb (conventional CGH) to
1–5 Mb, or even up to 40 kb (by adding more
clones to the array). Moreover, array-CGH en-
ables mapping of the submicroscopic unbalanced
 Chromosome abnormalities without consequences
abnormalities in a single test. Schoumans et al.
(2004) additionally suggested that array-CGH
would allow to detect previously unknown cryptic
chromosome rearrangements, and new syndromes
correlated with these disorders would be defined.
This has already come true (e.g. CHARGE syn-
drome). Screening of the whole genome by ar-
ray-CGH may also contribute to finding new
imbalances, which might seem not to be associ-
ated with any clinical features. One of such exam-
ples is the case lately described by Caignec et al.
(2005). Those authors studied 49 fetuses with vari-
ous malformations of unknown etiology.
The identical, familial subtelomeric 10q duplica-
tion (now considered being a common polymor-
phism) was found in 3 cases with various
anomalies. Similarly, Shaw-Smith et al. (2004)
used array-CGH at 1-Mb resolution to test 50 pa-
tients with clinical features (normal G-banded
karyotypes) for the presence of small chromosome
rearrangements. Copy-number alternations were
observed in 12 patients: 4 duplications
(at 3p26.2-26.3, 6q13, Xp22.3, Xq11.2) and 1 de-
letion (at 13q33.3-34). They seem to represent
genomic polymorphism, as they were inherited
from clinically normal parents. Recently a til-
ing-resolution BAC array-CGH (including 32447
clones) was applied by de Vries et al. (2005) to an-
alyze copy number alternations in a group of 100
patients with unexplained mental retardation. 258
heritable chromosomal micro-rearrangements,
probably not related to abnormal features, were
identified. As it was observed clinically relevant,
de novo imbalances were generally significantly
larger in size (0.54–12.37 Mb) than normal
genomic variants (0.05–2.16 Mb). These results
suggest that correctly employed molecular
karyotyping will always require investigation of
both the proband’s and parental samples analysis,
to avoid incorrect conclusions regarding the phe-
notype-genotype correlation and exclusion of
polymorphism. Currently many reports concern-
ing copy-number variation among phenotypically
normal individuals are also published. For in-
stance, Iafrate et al. (2004) and Sebat et al. (2004),
by the use of advanced molecular techniques (ar-
ray-CHG, oligonucleotide microarray analysis),
identified 255 and 221 (including 76 unique) poly-
morphic loci, respectively. A catalogue of
copy-number alteration in the human genome is
available in the Database of Genomic Variants, on
the website of the The Centre for Applied
Genomics in Toronto (http://projects.tcag.ca/vari-
ation/).
The publishing of cases of euchromatic chro-
mosome aberrations without phenotypic abnor-
163
malities remains to be important for future studies.
Molecular karyotyping will reveal a high number
of genome variations and their evaluation and
clinical significance will have to be investigated.
Polymorphism might be irrelevant for genetic syn-
dromes, but in future that information might be
used for pharmacogenetic studies or analysis of
susceptibility to particular diseases. Variant chro-
mosomes are harmless, but some of the examples
clearly show that they need deep investigations
and some cases might reveal cryptic unbalances
with clinical consequences. Cases of abnormali-
ties in patients carrying a familial euchromatic
chromosome abnormality are of special interest,
as they might reveal new pathogenic gene muta-
tions and help to describe new syndromes.
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