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Directly transmitted unbalanced chromosome
abnormalities and euchromatic variants
J C K Barber
J. Med. Genet. 2005;42;609-629
doi:10.1136/jmg.2004.026955

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609

REVIEW

Directly transmitted unbalanced
chromosome abnormalities andeuchromatic variants

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J C K Barber...............................................................................................................................
J Med Genet 2005;42:609–629. doi: 10.1136/jmg.2004.026955

In total, 200 families were reviewed with directlytransmitted, cytogenetically visible unbalanced
chromosome abnormalities (UBCAs) or euchromatic
variants (EVs). Both the 130 UBCA and 70 EV families
were divided into three groups depending on the presenceor absence of an abnormal phenotype in parents andoffspring.
No detectable phenotypic effect was evident in 23/130(18%) UBCA families ascertained mostly through prenatal
diagnosis (group 1). In 30/130 (23%) families, the affected
proband had the same UBCA as other phenotypicallynormal family members (group 2). In the remaining 77/
130 (59%) families, UBCAs had consistently mild
consequences (group 3).
In the 70 families with established EVs of 8p23.1, 9p12,
9q12, 15q11.2, and 16p11.2, no phenotypic effect wasapparent in 38/70 (54%). The same EV was found in
affected probands and phenotypically normal family
members in 30/70 families (43%) (group 2), and an EV
co-segregated with mild phenotypic anomalies in only 2/
70 (3%) families (group 3). Recent evidence indicates thatEVs involve copy number variation of common paralogous
gene and pseudogene sequences that are polymorphic in
the normal population and only become visible at thecytogenetic level when copy number is high.
The average size of the deletions and duplications in all
three groups of UBCAs was close to 10 Mb, and these
UBCAs and EVs form the ‘‘Chromosome Anomaly
Collection’’ at http://www.ngrl.org.uk/Wessex/
collection. The continuum of severity associated withUBCAs and the variability of the genome at the subcytogenetic level make further close collaboration
between medical and laboratory staff essential todistinguish clinically silent variation from pathogenic
rearrangement.
...........................................................................
Correspondence to:
Dr J C K Barber, Wessex
Regional Genetics
Laboratory, Salisbury
District Hospital, Salisbury,
Wiltshire SP2 8BJ, UK;john.barber@salisbury.
nhs.ukReceived 8 September 2004
Revised 6 January 2005
Accepted 6 January 2005.................................................

T

he resolution of the light microscope meansthat conventional chromosome analysis islimited to the detection of imbalances
greater than 2–4 Mb of DNA. Consequently,
unbalanced
chromosomal
abnormalities(UBCAs) usually involve several megabases ofDNA, and the great majority are ascertained
because of phenotypic or reproductive effects
that bring patients to medical attention. The
more severely affected an individual, the more
likely they are to be investigated, creating anascertainment bias that does not reflect the fullrange of phenotypes that may be associated withimbalance of a particular chromosomal segment.
In examining subsequent cases, clinicians will
naturally tend to look for features alreadyreported and, at the same time, new and unusual
features are more likely to reach publication than
the absence of previously reported characteristics. Thus, a publication bias may compound apre-existing ascertainment bias.
Many structural UBCAs are unique in theliterature, and the phenotype associated with agiven imbalance may depend on a single
individual examined at a particular age. As aresult, it can take many years before thephenotype associated with a particular imbalance can be defined. However, directly transmitted chromosomal imbalances, where parents
and offspring have the same unbalanced cytogenetic abnormalities, provide the means of assessing the phenotype in one or more individuals at
different ages as well as the opportunity of
judging whether a chromosomal imbalance is apathogenic or coincidental finding.
These transmitted imbalances are of twocontrasting kinds. Firstly, there are the classic
UBCAs, in which the copy number of multiple
genes is either reduced or increased by one copy
as in a deletion or duplication. An increasing
number of exceptions to the rule that UBCAs
result in significant phenotypic consequences
have been reported in families ascertained for‘‘incidental’’ reasons such as prenatal diagnosis
because of maternal age. Secondly, there are the‘‘euchromatic variants’’ (EVs), which usuallyresemble duplications. In an increasing numberof instances, these reflect copy number variation
Abbreviations: CGH, comparative genomic
hybridisation; CNV, copy number variation; DCR, Down’s
syndrom critical region; EV, euchromatic variants; HAL,
haploid autosomal length; PWACR, Prader-Willi criticalregion; TNDM, transient neonatal diabetes mellitus;
UBCA, unbalanced chromosome abnormalities

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610

Barberof segments containing genes and pseudogenes, which arepolymorphic in the normal population and only reach thecytogenetically detectable level when multiple copies arepresent. These EVs segregate in most families without
apparent phenotypic consequences. Here, 130 families withtransmitted UBCAs are reviewed,1–106 together with a further
70 families107–143 segregating the five established euchromatic
variants of 8p23.1,108 9p12,130 9q12 (9qh),113 15q11.2,144 and16p11.2.128
The 200 families with UBCAs or EVs have been reviewed
with respect to the type of rearrangement, size of imbalance,
ascertainment, mode of transmission,and the presence orabsence of phenotypic effects. Many more cytogenetic andsubcytogenetic UBCAs and EVs are being identified now thathigher resolution techniques are being used for routine
constitutional analysis including high resolution molecular
cytogenetics145–147 and array comparative genomic hybridisation (CGH).148 149 Cytogenetically detectable anomalies withlittle or no phenotypic effect have previously been reviewed
only in book form,150 151 and the data from this review havebeen placed on a web site as the ‘‘Chromosome Anomaly
Collection’’ (http://www.ngrl.co.uk/Wessex/collection.html).

METHODS
The contents of this review have been accumulated over timeand are thought to contain the majority of documented
transmitted UBCAs and EVs. However, there is no systematicway of searching the literature for transmitted anomalies,
thus no claim can made that this review is comprehensive.
Criteria for inclusion
Families were selected on the basis of the direct verticaltransmission of euploid autosomal UBCAs, or EVs fromparent to child. As a result, aneuploid karyotypes were
excluded, with the exception of a number of unbalanced
tertiary monosomies resulting in transmitted karyotypes with45 chromosomes. Satellited autosomes have not been
included but are reviewed elsewhere.152 Supernumerarymarker and ring chromosomes were excluded because of
the confounding effects of a high degree of mosaicism on thephenotype.153–155 Transmitted imbalances of the sex chromosomes were also excluded because of the confounding effectsof X inactivation in females.
GroupsThe UBCA and EV families were divided into three majorgroups depending on the presence or absence of a detectablephenotypic effect in offspring, parents or both (table 1).
Group 1: families in which transmitted UBCAs or EVs had noapparent phenotypic consequences in probands, parents andother family members; group 2: families in which the same
UBCA or EV was found in affected probands as well as

Table 1

phenotypically normal parents and other family members;
and group 3: families in which the same UBCA or EV wasfound in affected probands as well as affected parents andother family members.
Phenotypic normality
Individuals were considered phenotypically affected when
any type of phenotypic anomaly was mentioned even if theaetiological role of the chromosome abnormality in the same
individual is questionable. It is acknowledged that individuals in a given family may not have necessarily been
examined by clinical genetic staff, but patients were
presumed normal unless otherwise stated.
Size of imbalances
Wherever stated, estimates of the size of the imbalances
derived by the authors of the relevant papers were used.
Elsewhere, the size of each imbalance was estimated bymeasuring the proportion of the normal chromosome
represented by the deleted or duplicated material on highresolution standardised idiograms and multiplying by the %haploid autosomal length (HAL) of the chromosome concerned.156 The % HAL was converted to Mb by multiplying by
the 2840 Mb estimated length of the human genome.157

RESULTSThe review covers 200 families in which 130 had transmitted
UBCAs and 70 had transmitted EVs.
Transmitted unbalanced chromosome abnormalities
The location and extent of the UBCAs is illustrated in fig 1,
and details of the 130 UBCA families in groups 1, 2, and 3 arelisted in Appendices 1, 2, and 3. Table 1 provides a summaryof the ascertainment and the sex of the transmitting parentsin each group and table 2 summarises the size of theimbalances.
The 130 families contained 374 UBCA carrying individuals
with 111 different transmitted autosomal rearrangements
involving 20 of the 22 autosomes, the exceptions being
chromosomes 12 and 17. Chromosomes 5, 8, and 18 were themost frequently involved. Independent confirmation by FISH
or molecular methods had been obtained in more than half
(87/130 or 67%) of the families.
Over half these families (77/130 or 59%) fell into group 3,
in which a degree of phenotypic expression is found in bothchildren and parents. Approximately a quarter fell into group2 (30/130 or 23%), in which an affected proband has thesame UBCA as an unaffected parent, and the remaining one
fifth made up group 1 (23/130 or 18%), in which neither
children nor parents are affected. Many of these imbalanceswere unique to the family concerned.

Summary of ascertainment and transmission of UBCAs and EVs
Ascertainment

Mode

Group

NoF

NCo

Con

PD

PA

MC

I

Other

M

P

B

1 (UBCAs)
2 (UBCAs)
3 (UBCAs)
Totals1 (EVs)2 (EVs)3 (EVs)Totals

23
30
77
130
38
30
2
70

66
78
230
374
94
84
6
184

17
17
53
87
15
15
1
31

19
1
4
24
29
0
0
29

0
25
71
96
0
31
2
33

2
0
1
3
4
0
0
4

1
1
0
2
0
0
0
0

1
3
1
5
4
0
0
4

15
19
58
92
18
13
1
32

5
9
12
26
17
9
1
27

3
2
7
12
3
8
–
11

NoF, number of families; NoC, number of carriers; Con, confirmed with an independent technique; PD, prenatal
diagnosis; PA, phenotypic abnormality; MC, miscarriages; I, Infertility; M, maternal transmission; P, Paternaltransmission; B, Both maternal and paternal transmission.

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Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

611

Figure 1 Idiograms with extent of duplications on the left hand side and deletions on the right hand side. Group 1 imbalances are in blue, group 2 inpurple, and group 3 in red. Filled coloured bars are UBCAs from peer reviewed papers; open coloured boxes are from abstracts only. Open blackboxes indicate alternative interpretations according to the authors concerned. Figures in black give the number of times independent families with thesame rearrangement have been reported (for example, four times). t, translocation; i, insertion; m, mosaicism in a parent; n, the four exceptional
UBCAs that were not directly transmitted.

Group 1: Phenotypically unaffected parents with thesame unbalanced chromosome abnormality as theirunaffected children
This group contained 23 families in which an unbalanced
rearrangement had been directly transmitted from parent tochild without phenotypic effect in 66 carriers. For completeness, four chromosomally unbalanced but phenotypicallynormal individuals were included from families in which
direct transmission from an unbalanced parent had not been
observed,158–161 making a total of 27 families. The majority (20/27; 74%) of these families was ascertained at prenatal
diagnosis because of maternal age (12/20). Of the remaining
seven (17%), three were ascertained for miscarriages,2 9 158

three because of the phenotype of a sibling20 160 161 ordaughter,159 and one for infertility.14
Of the 27 families, 14 had deletions, with an average size of
8.2 Mb (range 4.2–16.0 Mb) (table 2), and of these, 12
consisted mainly of G dark bands with or without some G
light flanking material. Seven families had transmitted
interstitial duplications with an average size of 13.6 Mb(range 3.4 Mb to 31.3 Mb), of which only the duplications of
8p2215 and 13q14-q2117 were largely G dark bands. There
were six families with unbalanced rearrangements, three of
which had been transmitted from a parent with the same
imbalance19–21 and three from a parent with a balanced formof the same rearrangement.159–161

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612

BarberTable 2 Estimated size of UBCA deletions andduplications
Group

Type

NumberRange (Mb)

Averagesize (Mb)

1

del
dup
del
dup
del
dup
del
dup
del+dup

14
7
7
19
38
26
59
52
111

4.2 to 16.0
3.4 to 31.3
3.6 to 10.0
2.0 to 11.4
2.7 to 30.8
4.0 to 26.1
2.7 to 30.8
2.0 to 31.3
2.0 to 31.3

8.2
13.6
7.5
6.1
10.9
11.0
9.9
9.6
9.8

2
3
Combined
Totaldel, deletion; dup, duplication.

In the 23 families in which the UBCA had been directlytransmitted from a parent to child, table 1 shows that thetransmission was maternal in 15 families (71%), paternal inin five, (22%), and from both parents in three (13%).

Group 2: Unaffected parents with the sameautosomal imbalance as their affected children
This group contains 30 families with 78 carriers (Appendix2). The majority (25/30; 83%) were ascertained because ofphenotypic abnormality (PA) in the proband. Of theremaining 5 (17%), two were ascertained because of thephenotype of a sibling proband,30 one because of infertility,42
one because of leukaemia27 and one as a result of prenatal
diagnosis following an abnormal ultrasound scan.31
Seven families had transmitted deletions with an average
size of 7.5 Mb (range 3.6–10.0 Mb) (table 2) of which threelargely involved the G dark bands 5p14 and 11q14.3.
Nineteen families had transmitted duplications with anaverage size of 6.1 Mb (range 2.0–16.3 Mb) of which the
duplications of 4q3230 and 8p23.232 were mainly G dark. Threefamilies had transmitted unbalanced translocations.
Table 1 shows that exclusively maternal transmission wasseen in 19/30 families (63%) of families, paternal in 9/30
(30%), and from both in 2/30 (7%).

Group 3: Affected parents with the same autosomal
imbalance as their affected children
This group contains 230 carriers from 77 families (Appendix
3). Of 77 families, 71 (92%) were referred for phenotypicabnormalities in the proband, which were, in most cases,
reflected to a lesser or greater extent in other carriers fromthe same family.
Four of the 77 families (5%) were ascertained throughprenatal diagnosis; two of these because of maternal age,58 91
one because of abnormal ultrasound,67 and one because of aprevious son with mental retardation.65 A single family wasinvestigated because of miscarriages106 and a single family
because of Prader-Willi syndrome in the proband.33
Thirty-eight families out of 77 (49%) had deletions with anaverage size of 10.9 Mb (range 2.0–30.8 Mb). Twenty-sevenfamilies (35%) had transmitted duplications with an average
size of 11.0 Mb (range 4.0–26.1). The remaining 12 (16%)
had transmitted unbalanced translocations of which 4 wereinsertional.
Table 1 shows that exclusively maternal transmission wasseen in 58/77 families (75%) of families, paternal in 9/30 (16%)
and transmission from carriers of both sexes in 7/77 (9%).

Group 1 and 2 UBCAs, especially those overlappingwith Group 3
Brief summaries are provided here of all group 1 and 2 UBCA
families. Group 3 families are included wherever group 3

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UBCAs overlapped with group 1 and/or group 2 UBCAs(fig 1).
der(1)(p32-pter)

One unconfirmed monosomy of 1p32 to pter was ascertainedat prenatal diagnosis and also apparently present in thefather.19 This UBCA, reported in abstract, is impossible toreconcile with a normal phenotype, as even small imbalancesof distal 1p are associated with a recognisable chromosomal
syndrome.162
dup(1)(p21-p31)

This large group 1 duplication was ascertained at prenatal
diagnosis for maternal age. The duplication was found in thephenotypically normal mother, and the outcome of pregnancy was normal at term.13
dup(1)(q11-q22)

This group 2 family was ascertained in a phenotypicallynormal boy of 9 with lymphadenopathy.27 A constitutional
duplication of proximal 1q was found in this boy, his
phenotypically normal mother and his elder sister, neitherof whom had lymphoma or leukaemia.
dup(1)(q42.11-q42.12)

This group 2 family was ascertained in a boy who fed poorly
and was in the 10th centile for growth.28 The duplication had
arisen de novo in the phenotypically normal mother and, by
the age of 3 years, the boy’s stature was in the 25th centile
when correlated with the height of his parents.
del(2)(p12-p12)

Two group 1 families with deletions of 6.1 Mb and 6.7 Mb
within G dark 2p12 were both ascertained at prenatal
diagnosis.1 At least 13 loci including a cluster of six pancreatic
islet regenerating genes were deleted. The pregnancies had
normal outcome at birth and there were no other apparent
phenotypic consequences in six other deletion carriers. It was
proposed that segmental haplosufficiency may be associatedwith low gene density, especially where genes within acluster on the normal homologue may compensate for eachother, or genes of related function are present on otherchromosomes.25 An overlapping 7.5 Mb group 3 deletion
extended into the gene rich part of 2p11.2 and was found in agirl with speech delay and in her mother, who has expressive
language difficulties (patients 25147 and 31). Both had mild
dysmorphic features.
del(2)(q13-q14.1)

A group 1 family was ascertained because a woman of
38 years had three early miscarriages. The deletion spanned
7 cM from YAC 791f4 to YAC 676d2. The consultand and herphenotypically normal mother had the same deletion, but themother had no history of miscarriage.2
del(3)(p25-pter)A terminal group 1 deletion with a 3p25.3 breakpoint was
ascertained at prenatal diagnosis in a fetus and phenotypically normal mother.3 In contrast, in a group 3 family, anaffected boy and his less severely affected mother had
features consistent with 3p-syndrome.46 It was suggested
that the 3p25.3 breakpoint was distal to the genes responsiblefor 3p-syndrome.3 However, this could also be an example ofnon-penetrance of a chromosomal deletion, as haploinsufficiency of the CALL gene is thought to give rise to mental
impairment and this gene should lie inside the deletion at
3p26.1.163
dup(3)(q25-q26)

A group 2 family contained two sisters with congenital heartdisease, mild developmental delay, dysmorphic, features andDownloaded from jmg.bmjjournals.com on 1 August 2005
Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

a dup(3)(q25q25).29 The same duplication was present in thenormal father, grandmother, and greatgrandmother. The
authors suggested a paternal imprinting effect, but this regionof chromosome 3 is not known to be imprinted. A group 3
family with a larger overlapping dup(3)(q25.3q26.2) was
independently ascertained once with congenital heart disease
and once with microcephaly.78 These families suggest that thephenotype associated with duplication of 3q25 can extend into
the normal range or that 3q25 contains a dosage sensitive locus
that gives rise to heart disease with variable penetrance.
dup(3)(q28q29)

A group 1 family was ascertained at prenatal diagnosis formaternal age and found in the phenotypically normal father
and an older sibling.12 A submicroscopic duplication of 3q29
was ascertained in siblings with moderate mental retardationand dysmorphic features164 but was also present in thephenotypically normal mother and sister.
dup(4)(q31-q32)

A group 3 family with a duplication of 4q31.1-q32.3 wasascertained in a mildly affected child and his mother, whowere both developmentally delayed.79 This prompted Maltby etal30 to report a smaller group 2 duplication of 4q32 ascertained
because of trisomy 21 in the proband. The duplication carrying
sister had sensorineural deafness and the mother had no
obvious clinical problems. The authors concluded that there
were insufficient consistent findings to suggest a clinicaleffect, but this family also suggests that overlapping duplications centred on G dark 4q32 have a variable phenotype thatcan extend into the normal range. Few clinical details of thegroup 3 family of Van Dyke77 were given.
del(5)(p15-pter) terminal

There were two group 2 deletions of 5p15.3 and 10 group 3monosomies of this region. The group 2 families had
microcephaly, a cat-like cry and developmental delay, but
not the severe delay and facial features of cri du chatsyndrome associated with deletions of 5p15.2.22 There werefour affected children in these group 2 families, but thecarrier parent was apparently normal in each case. ‘‘Atypical’’
cri du chat syndrome in parents and children has also been
described.51–55 These families suggest a variable phenotype
that can extend into the normal range but is more often
characterised by speech delay, occasional deafness, and low
to normal intelligence.
del(5) (p13-p15) interstitial

There were one group 1 and two group 2 deletions of 5p14
itself as well as four larger overlapping group 3 deletions. The
group 1 deletion of almost all 5p14 was ascertained at
prenatal diagnosis and found in a total of six normal
carriers.4 23 The G dark 5p14.1-5p14.3 group 2 deletion
ascertained in a patient with a peroxisomal disorder was
thought to be an incidental finding, as this condition had notpreviously been associated with any case of 5p deletion.10 In a
more recent family,23 a non-mosaic deletion contained within
5p14 was found in a proband with microcephaly, seizures,and global developmental delay; the phenotypically normal
father had the same deletion in blood, but only 1/500
fibroblasts. Nevertheless, given the eight carriers in the othertwo 5p14 deletion families and the normal phenotype of thefather, it seems likely the proband in this family represents
ascertainment bias rather than variable expression of aphenotype associated with this deletion. By contrast, all thefour overlapping group 3 deletions extended into adjacent G
light 5p13, 5p15 or both. The phenotype varied within andbetween families from mild21 to variable57 58 and severe in thefamily of Martinez et al,56 which showed that cri du chatsyndrome is compatible with fertility.

613

dup(5)(q15-q22.1)

A group 2 family with a dup(5)(q15q21) was ascertained at
prenatal diagnosis because a cystic hygroma was found in
one of two monzygotic twins using ultrasound.31 The authors
concluded that the dup(5) could be a coincidental finding inview of the discordant abnormalities in the twins after
delivery and the normal phenotype of the father. However,the father had suffered from epilepsy as a child and it is not
unknown for cytogenetic abnormalities to have different
consequences in monozygotic twins.165 A larger overlappinggroup 3 duplication also had a variable phenotype with mild
dysmorphic features in mother and son but no mental
retardation in the mother.80
dup(6)(q23.3-q24.3)

Both the group 2 families were ascertained with transientneonatal diabetes mellitus (TNDM) and have duplications
that include the paternally imprinted ZAC locus, which maps
to 6q24.2. Imprinting explains the presence of TNDM incarriers with paternal duplications and the absence of TNDM
in carriers with maternal duplications. While the proband
and father in the family of Temple et al41 were discordant for
TNDM, a degree of developmental delay in the father isprobably due to this inserted duplication extending beyond
band 6q24. An exceptionally mild phenotype was associatedwith an overlapping de novo 4–5 Mb deletion of 6q23.3-q24.2
that was of paternal origin.166
del(8)(p23.1/2-pter)A group 1 family with a del(8)(p23.1-pter) deletion was
ascertained at prenatal diagnosis in a fetus and phenotypically normal father.5 The deletion breakpoint was believed tobe more distal than the de novo deletions associated with
developmental delay and heart defects. However, a group 3
family with an 8p23.1-pter deletion was ascertained in a boyof 7 years with mental slowness, behavioural problems, andseizures.59 His sister and father had minimal phenotypicabnormalities with borderline to normal intelligence. A denovo terminal deletion of 8p23.1-pter was ascertained in agirl with initial motor and language delays but averagecognitive development and intellectual ability after closemonitoring over a period of 5 years.167 These examples
indicate that distal 8p deletions are associated with a mild
phenotype that can extend into the normal range.
del(8)(q24.13q24.22)

This group 1 family was ascertained because of a positive
triple screen test.6 The phenotypically normal mother had thesame deletion and a history of miscarriage and fetal loss. The
pregnancy with the deletion resulted in a 26 week phenotypically normal stillbirth with significant placental pathology.
dup(8)(p23.1p23.3)

A group 1 family was ascertained for oligoasthenospermia,
which was regarded as incidental in view of the normal
fertility of a male carrier relative.14
dup(8)(p23.1p23.2): the abnormalities in the probands
from three independent group 2 families with 2.5 Mb
duplications of G-dark 8p23.2 were inconsistent and notpresent in any of the carrier parents.32 The authors concluded
that duplication of G-dark 8p23.2 could probably bedescribed as a benign cytogenetic variant.
dup(8)(p23.1p23.1)

There were 3 group 2 families and 3 group 3 families withcytogenetic duplications of 8p23.1.33 84 The abnormalities in
the probands of the 3 group 2 families were inconsistent witheach other and the same duplication was present in one ofthe parents in each family with no reported phenotypicabnormalities. In the 3 group 3 families, the first was
ascertained with developmental delay while the carrier

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mother had short stature and abnormal feet.33 The second
had Prader-Willi syndrome as well as an 8p23.1 duplication
while the duplication carrier father had only atrial fibrillation.33 The third group 3 family was a developmentallynormal girl of 16 with a severe congenital heart defect.34 The
authors proposed that her duplication interrupted the GATABinding Protein gene (GATA4), which maps to 8p23.1 and is
known to give rise to heart defects when deleted. Her father
had an isolated right aortic arch and his milder heart defectwas attributed to mosaicism for the duplication. However,these cytogenetic duplications bear an uncanny resemblance
to the EVs of 8p23.1 (see below), which have been shown toresult from copy number expansion of a discrete domain withinband 8p23.1 that does not contain the GATA4 locus.108 109 Thus,
apparent duplications of 8p23.1 have been associated with awide variety of presentations but, as the content of many ofthese imbalances has not yet been determined, ascertainment
bias may account for some of these observations and further
analysis could distinguish genuine cytogenetic duplications
from euchromatic variants of 8p23.1.
dup(8)(p21.3-p23.1), (p22-p23.1) and (p21.3-p22 orp22-p23.1)

Developmental or speech delay has been associated with
duplications of 8p21.3-p23.1 in 2 group 3 families.86 Family 1
was ascertained with a complex heart defect but the motherand a sibling had the same duplication and no heart defects.
Family 2 was ascertained for speech delay in a girl who had
an IQ of 71 at age 6 and minor facial anomalies. Her carrier
sister also had speech delay as well as a heart defect and mild
facial dysmorphism. The normal phenotype in her father was
attributed to mosaicism for the duplication, which waspresent in 6/24 cells. The authors concluded that this duplication is associated with mild to moderate delay without
significant or consistent clinical features. A similar phenotype
was reported in the group 3 duplications of 8p22-p23.1.85 87
dup(8)(p22-p22)

A group 1 family with a small, ‘‘euchromatic expansion’’ ofdistal 8p22 was ascertained at prenatal diagnosis, confirmedwith CGH and found in the phenotypically normal motherand grandfather.15 Overlapping de novo duplications of 8p22p23.1 were recently reported using high resolution CGH in six
families and thought to have Kabuki make-up syndrome168
but these observations have not been replicated by others.169

Barberdup(10)(p13-p14)

This group 1 family was ascertained at prenatal diagnosis in a
family with a history of heart disease.16 The duplication was
found in the fetus with normal outcome at birth, thephenotypically normal mother and a further child who had
Tetralogy of Fallot (TOF). Other family members had TOF
without the duplication of 10p13 and the authors concluded
this is a duplication without phenotypic consequences.
del(11)(q25-qter)

The der(11)t(11;15) Group 2 family was ascertained for
infertility.42 No phenotypic anomalies were reported in either
the proband or his father but 61% of spermatocytes in theproband had XY multivalent contact at prophase suggesting a
causal connection between the unbalanced translocation in
the son despite the evident fertility of his father. Unpublishedobservations from this laboratory include another group 2deletion of most of 11q25 ascertained in a boy of 6 with
developmental delay (especially speech) but no heart defect.
His phenotypically normal father had the same deletion. The
larger overlapping group 3 deletion of 11q14.2-qter61 wasascertained in a child of nearly 3 with developmental delay.
She also had a VSD but a heart defect was not suspected in
the mother. Until more of these deletions have been mappedat the molecular level, it is impossible to say whether thephenotypically normal family members with 11q25 deletions
are examples of segmental haplosufficiency or a variablephenotype that extends into the normal range. A second
group 2 family in which an unbalanced der(11)t(11;22)translocation is dealt with under del(22q) below.43
del(13)(q14q14), dup(13)(q14.1q21.3) and dup(13)(q13q14.3)

A group 2 family with a deletion of 13q14 was ascertainedwith retinoblastoma.26 A larger overlapping group 3 deletion
was associated with both retinoblastoma and dysmorphic
features in a mother and child.62 As retinoblastoma isrecessive at the cellular level, the lack of a ‘second hit’ islikely to explain the absence of retinoblastoma in the motherof the first family.26 In a third family, unbalanced segregationof a balanced maternal ins(20;13)(p12;q13q14.3) insertion
resulted in deletion of 13q13-q14.3 and retinoblastoma in theproband.160 However, the proband’s older sister had aduplication of the same segment and was clinically normal
as was a younger sister at birth.

del(9)(p12.2p22.1)

A group 1 family was ascertained at prenatal diagnosis formaternal age when this deletion was found in the fetus aswell as the phenotypically normal father and grandmother.7
dup(9)(p12-p21.3)

A neonate ascertained with cri-du-chat syndrome had adeletion of chromosome 5 derived from her father who had
an unbalanced insertional duplication of 9p12-p21.3.159 The
estimated size of the duplication was 21 Mb including approximately 280 genes. The balanced ins(5;9)(p13.3;p12p21)
form of this insertion was present in the proband’s grandmother and uncle.

del(13)(q21q21) and dup(13)(q14-q21)

A group 1 del(13)(q21q21) was ascertained for recurrent
miscarriages in a phenotypically normal family.9 An overlapping group 1 dup(13)(q14-q21) was detected at prenatal
diagnosis when an extra 13q14 LIS1 signal was seen ininterphase cells and only a partial duplication of chromosome
13 in metaphases.17 The same duplication was present in themother who was clinically normal apart from hyposomia.
dup(13)(q14-q21) and dup(13)(q13-q14.3)

See del(13) entries above.

del(10)(q11.2-q21.2)

dup(14)(q24.3-q31)

This deletion was found in the clinically normal 29 year old
male partner of a couple referred for recurrent miscarriages.158
A patient with an overlapping de novo deletion had normal
physical and psychomotor development until the age of 6 but
subsequently developed symptoms of Cockayne syndrome.
As the excision repair gene (ERCC6) associated with theautosomal dominant type II Cockayne syndrome has been
mapped to band 10q21.1, it seems that deletion of proximal
10q is compatible with a normal phenotype but only if the
ERCC6 locus is excluded or non-penetrant.

In a group 2 family, imprinting might have explained thenormal phenotype in the father of a girl who had developmental delay, microcephaly and dysmorphic features at theage of 3K effects.34 However, grandmaternal transmission
could not be established as the father was adopted. In
addition, the girl had only a few of the features recorded inprevious cases of pure 14q duplication. It is therefore
impossible to be certain whether the dup(14) is the causeof the child’s phenotype or an incidental finding in thisfamily.

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Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

dup(15)(q11.2q13)

There are at least five group 235–39 and four group 3
families35 93 with transmitted interstitial duplications that
include the PWACR. The imprinted nature of this region
explains the fact that children with developmental delay and/or autism all had maternal duplications35–39 while the normalparents in three of these five families had duplications ofgrandpaternal origin.37–39 Both parents and children wereaffected in the four group 3 families35 93 but two out of three
unaffected grandparents again had duplications of grandpaternal origin.35 However, one mother with a paternallytransmitted duplication had mild developmental delay and itis therefore possible that the phenotype associated withpaternal duplications can extend into the mildly affected range.
Bolton et al35 compared the phenotype of 21 individuals from
6 families and found that maternally transmitteddup(15)(q11.2q13) was associated with a variable degree ofintellectual impairment and motor coordination problems but
only one individual met the criteria for classic autism.
del(16)(q21q21)

Two independent group 1 families were both ascertained at
prenatal diagnosis with deletions of G-dark 16q21.10–11 There
were two other phenotypically normal carriers in each family.
The family of Witt et al11 has previously been contrasted withan adult patient who had a cytogenetically identical deletionof 16q21170 but many of the features of 16q- syndrome.171
dup(16)(q12.1q12.1), (q11.2-q12.1) and (q11.2-q13.1)

Verma et al40 considered a duplication of 16q12.1 in an
autistic child of 4K and his clinically normal mother as an
unusual variant. The overlapping duplications of q11.2-q12.1
and q11.2-q13.1 were consistently associated with developmental delay, speech delay, learning difficulties and behavioural problems21 94 while de novo adult cases have been
associated with a more severe phenotype.172 In most of thesefamilies, the duplicated material is found within the major
16q11.2/16qh block of heterochromatin but these are clearly
not analogous to the EVs of 9q12/9qh (see below). It seems
that duplications of proximal 16q can be severe but are more
often associated with a variable cognitive phenotype that may
exceptionally extend into the normal range.
del(18)(cen-pter)

There were a total of 7 families with transmitted deletions of
18p including a single group 1 family with a deletion of
18p11.31-pter12 and 6 group 3 families with deletion breakpoints that ranged from p11.365 to the centromere.70 The
group 1 family was ascertained at prenatal diagnosis for araised serum AFP and had the smallest deletion. The group 3
family of Rigola et al65 was ascertained at prenatal diagnosis
because of a previous son with mental retardation. The
authors concluded that the phenotype in their 18p11.3-pter
deletion family was subtle as the mother had only mild
mental retardation and minor congenital malformations. In
another group 3 family,66 both the child and mother withdel(18)(p11.21-pter) had short stature, mental retardationand ocular anomalies. By contrast, the group 3 del(18)(p11.2pter) of Tonk and Krishna67 was ascertained because ofabnormal routine ultrasound findings. A very dysmorphic
fetus with features that included cyclopia was found after
spontaneous delivery at 24 weeks gestation while the motherhad mild mental retardation and some dysmorphic features
but. Concordant phenotypes with many of the features of
18p- syndrome were seen in the other three group 3 families
with larger 18p deletions.68–70
dup(18)(cen-pter)A group 1 family with a duplication of the whole of 18p was
ascertained at prenatal diagnosis following a raised serum

615

AFP.18 At 2 years of age, the child’s development was normal
and she shared bilateral short fifth fingers with her carriermother and pre-auricular pits with her father. After reviewing 14 other cases, the authors concluded that duplication of
18p produced little if any phenotypic effect. By contrast,
Moog et al95 ascertained a group 3 family with a duplicationof the whole of 18p in a child with psychomotor delay,slight craniofacial anomalies and moderate mental retardation. The mother had the same duplication in 80% of cells
and had been developmentally delayed. By the age of 26, she
had height and head circumference less than the 3rd centileand ‘‘borderline’’ mental impairment. The father was alsomentally retarded. The authors concluded that duplication of
18p is not a specific phenotypic entity but may be associatedwith non-specific anomalies and a variable degree of mental
impairment. Thus, duplication of 18p has mild phenotypicconsequences that can extend into the normal range.
dup(18)(q11.2q12.2)

This duplication was found in the fetus of a mother of 24
referred for prenatal diagnosis with a family history of
Down’s syndrome.161 The mother and her next child had abalanced ins(18)(p11.32;q11.2q12.2) insertion but a thirdchild had the corresponding duplication and was phenotypically normal at three months of age.
del(21)(q11.2-q21.3),(pter-21q21.2), (pter-q21)

A group 1, group 2 and group 3 family were each ascertained
as a result of Down’s syndrome in the proband. In eachfamily, tertiary monsomic forms of unbalanced translocations were found in two or more other family members. In
the group 1 family,20 there were no reported phenotypicanomalies in four family members. However, it is possiblethat this fusion of 6p and 21q involved no actual loss ofcoding material especially as de novo loss of subtelomeric 6p
has been associated with mental retardation, dysmorphic
features and a heart defect.163 In the group 2 family, an
unbalanced 19;21 translocation with deletion of pter-q21.1
and a possible deletion of 19p was ascertained in a childbecause of Down’s syndrome in a sibling proband.44 The child
had only behavioural difficulties and the carrier mother wasof average intelligence. In the group 3 family, four family
members had a complex unbalanced 21;22 translocation andeffective monosomy for 21q21.2-pter.104 This family had aconsistently mild phenotype with developmental delay,learning disabilities and poor social adjustment. The only
group 3 deletion of the 21q11.2-q21.3 region75 was ascertained in a child with dislocation of the hips at 11 months ofage. By the age of 5 he had motor and language delay and themother had mild mental retardation. The authors concluded
that psychomotor retardation is the only consistent feature ofproximal 21q deletion with a variable degree of expression ofother minor anomalies. Roland et al75 also pointed out that
more severe de novo cases have been reported as well as a denovo case with normal intelligence but poor motor skills.173 A
duplication of proximal 21q with normal phenotype has also
been reported.174
del(22)(q11.21-pter)In the group 1 family, an unbalanced tertiary monosomic(9;22) translocation was ascertained during prenatal diagnosis and found in three other family members.21 The 9q
subtelomere was intact, but a diminished signal from BAC
609C6 indicated a 22q11.21 breakpoint and the loss of somecoding material from proximal 22q. In the group 2 family, an
unbalanced der(11)t(11;22) tertiary monosomy was ascertained in a dysmorphic boy with a heart defect, his two
siblings, and his mother.43 The phenotype could have resulted
from the deletions of either 11q25 and proximal 22 or both.
As only one of the two siblings had a heart defect and the

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mother was clinically normal, the authors suggested that theunbalanced karyotype might be a coincidental finding inview of the variability of the phenotype. However, variable
expression of heart defects is now well known in transmitted
submicroscopic deletions of 22q11.2101 175 and suspected in
11q25 deletions (see del(11)(q25-qter) above). In the group 3
family, an unbalanced der(4)t(4;22) translocation and monosomies of both 4q35.2-qter and proximal 22q were ascertained in a dysmorphic boy with a heart defect.101 The
complete and partial Di George syndrome seen in the son andmother was attributed to the proximal 22q deletion, althoughheart defects have subsequently been described in otherunbalanced submicroscopic translocation involving 4q.163

Euchromatic variants
The cytogenetic locations of the five major EVs are illustrated
in fig 2, and the details of 70 EV families in Appendices 4, 5,
and 6. By contrast with the UBCA families, each of these EVs
has been independently ascertained on multiple occasions. Of
the 70 families, 38 were group 1 (54%), 30 were group 2(43%), and only two were group 3 (3%). Table 1 provides asummary of the ascertainment and sex of the transmitting
parents in each group. The EVs of 8p23.1, 15q11.2, and16p11.2 have been described as constitutional cytogenetic
amplifications because they involve variable domains that are
only detectable at the cytogenetic level when present in
multiple copies.109 120 133 177

Group 1 EVs: Phenotypically unaffected parents withthe same EV as their unaffected children
This group contains 38 families with 94 carriers involving all
five of the most common EVs established to date (Appendix
4). Of the 38 families, 30 were ascertained at prenatal
diagnosis (79%),12 of whom had undergone the procedure
because of maternal age. Four families were referred forrecurrent miscarriages and one for loss of a pregnancy, but it
is difficult to reconcile this with phenotypically silent EV
unless such variation predisposes to larger imbalances or
non-disjunction of the same chromosome; this has not been

Barbershown in any of the families listed here to date. Two families
were investigated because of trisomy 21 in a relative and thefinal family was ascertained incidentally during a survey ofnewborns.113
Table 1 shows that exclusively maternal transmission wasseen in 18 of the 38 families (47%) of families, paternal in 17(45%), and transmission from both in three families (8%).

Group 2 EVs: Unaffected parents with the same EV
as their affected children
Appendix 5 contains 84 carriers from 30 families. All 30 wereascertained for dissimilar phenotypic abnormalities in theprobands. One family was independently ascertained once ina male of 62 years with myelodysplasia139 and once in a childof 3 years with developmental delay and mild dysmorphic
features.128 Six other family members were phenotypicallynormal and this child was later diagnosed with fragile X
syndrome (Thompson, personal communication).
Table 1 shows that exclusively maternal transmission wasseen in 13 of the 30 families (43%), paternal in nine (30%)
and transmission from both in eight (27%).

Group 3 EVs: affected parents with the same EV as
their affected child
There were only two families in this group (Appendix 6). In
the first family, an 8p23.1 EV was associated with very mild
dysmorphism in a mother and her two daughters; further
family members were not available and the association of EV
and phenotype remains questionable.142 In the second
family,143 short stature cosegregated with a proximal 15q
amplification variant that was later shown to involve
multiple copies of the proximal 15q pseudogene cassette.176
Apart from short stature, the proband had slight hypotonia
and a tendency to hyperphagia but no functional modification of the PWACR could be found. The authors concluded
that this EV was probably not related to the child’s phenotype. Transmission was maternal in both families.

Group 1, 2, and 3 EVs especially where theseoverlap with UBCAs
Brief summaries are provided of the group 1 and 2 EV
families with particular attention to those instances wheregroup 1 and 2 EVs overlap with each other or with group 3
EVs (fig 2).
8p23.1v

Figure 2 Idiograms with the position at which EVs occur marked byarrows. Group 1 EV imbalances are in blue; group 2 EV in purple, andgroup 3 EV in red. Figures give the number of times independent families
with the same rearrangement have been reported (for example, eighttimes).

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At least 11 families have been reported with this apparent
duplication of 8p23.1 (8 in group 1 EV, 2 in group 2 EV and 1
in group 3 EV). Twenty-five out of the 27 carriers in the first
three reports were phenotypically normal.108 110 111 Similarfindings were reported in two further families107 129 while only
minimal features were found in the single group 3 family.142
Williams et al110 found variation of 8p23.1 in a developmentally delayed boy of 18 months but his delay was said to be‘‘spontaneously resolving’’ by the age of 2 years (Williams L,
personal communication). Hollox et al109 used quantitative
multiplex amplifiable probe hybridisation to show that theunderlying basis of the duplication in three of these EV
families was the increased copy number of a domain of atleast 260 kb containing three defensin genes (DEFB4,
DEFB103, and DEFB104) and a sperm maturation gene
(SPAG11). Semi-quantitative FISH indicated that an olfactory
receptor repeat is also involved and a recent contig suggeststhat this domain is normally within the distal 8p23.1 OR
repeat itself (REPD).177 Total copy number of this domain innormal controls varied between 2 and 7, whereas EV carriers
had between 9 and 12 copies. Expression of DEFB4 wasincreased with copy number and, as the defensins encode
cationic antimicrobial peptides, it has been suggested that
increased copy number could enhance resistance to infection

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Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

or modify the effects of Pseudomonas aeruginosa in cystic
fibrosis.109 Copy number variation of a 1 Mb domain that lies
7 Mb from the telomere (CNP 45) has been detected innormal controls,178 but it is not certain that this coincides
with the defensin EV, which is thought to lie at or adjacent to
REPD at 7.5 Mb from the telomere. Tsai et al33 and Kennedy etal84 claim that duplications of 8p23.1 are associated with
developmental delay and heart disease but have not mapped
the extent of their duplications (see UBCA dup(8)(p23.1p23.1) above). Recent evidence submitted for publication179 indicates that duplications and EVs of 8p23.1 resemble
each other at the cytogenetic level but can be separated into
two distinct groups: (a) genuine 8p23.1 duplications of theinterval between the olfactory receptor repeats including the
GATA4 gene and associated with developmental delay andheart defects; and (b) EVs that involve increased copy
number of the variable defensin domain only and do nothave phenotypic conseqences.
9p12v

There are at least eight families with this EV (six group 1 EVs
and two group 2 EVs), which resembles a duplication of G
dark 9p12 and is negative when C banded. Webb et al112
described the extra material as being of ‘‘intermediate
density’’ when G banded, noted how the extent of the extra
material can vary when transmitted, and suggested that thisEV is a homogeneous staining region. As 9q12 EVs derivefrom a unit present in multiple copies in both 9p and 9q115 180(see below), it is likely that the cytogenetic 9p EVs also reflectincreased copy number of a variable domain by analogy withthe 16p11.2 EVs (see below). It is possible that these coincidewith the 9p11 and 9q12 polymorphisms identified by Sebat etal (CNPs 51 and 52).178
9q12v/9qhv

There are at least seven families with this EV, which reflects
extra C band negative, G dark material that is found within
the major 9q12/qh block of heterochromatin (six group 1 EVs
and one group 2 EV). The group 2 EVs had 9q13-q21
breakpoints,132 but resembles the other 9q12/qh EVs at thecytogenetic level. YAC 878e3 hybridises to the extra material
in the 9q12/qh EVs, and subclones of this YAC indicate thatthese EVs derive from a large unit present in multiple copies
in both proximal 9p and juxtaheterochromatic 9q13.115 180 A
shared identity between subclones and expressed sequencetags suggests that this variation includes coding sequences.180
Sequences of this type may also underlie the unconfirmed
claim that a separate type of 9q12v chromosome exists withmaterial derived from 9q13-q21.151
The established 9q12 EVs are clearly not analogous to theextra euchromatic material found within the major 16p11.2/
qh block of heterochromatin, which has so far always been agenuine duplication of proximal 16q (see UBCA dup(16)above).
15q11.2v

At least 32 families have been reported with extra material
within proximal 15q (10 group 1 EVs, 21 group 2 EVs, and asingle group 3 EV family). These EVs resemble duplications
or triplications and can be misinterpreted as a duplication of
15q11.2-q13 or even a deletion of the homologous 15. The
underlying basis of this EV is variation in the copy number ofa cassette of neurofibromatosis (NF1), immunoglobulin
heavy chain (IgH D/V), gamma-aminobutyric acid type A5
subunit (GABRA5), and B cell lymphoma 8 (BCL8A)
paralogous pseudogenes,120 133 176 which map between the
PWACR and the centromere. The NF1 pseudogene has 1–4
copies in controls and expands to 5–10 copies in EV carriers,
while the IgH D region has 1–3 copies in controls and expands
to 4–9 signals in the majority of EV carriers.120 This expansion

617

has been described as constitutional cytogenetic amplification.123 Similar variation may be expected at the other sites towhich NF-1 pseudogenes map including 2q21, 2q23-q24,
14q11.2, 18p11.2, 21q11.2, and 22q11.2.181 It is likely that the
1.6 Mb copy number polymorphism detected by Sebat et al178
in 15q11 (CNP 69) coincides with the 15q11.2 EV cassette.
The claim that a separate 15q12.2-q13.1 EV exists has not yet
been confirmed with locus specific probes.151
16p11.2v

There are at least 12 families in the literature (seven group 1
EVs and five group 2 EVs) with extra material withinproximal 16p, which can resemble a duplication of G dark
16p12.1. This EV also reflects increased copy number ofanother cassette of immunoglobulin heavy chain (IgH) andcreatine transporter and cDNA related to myosin heavy chain(SLC6A8) paralogous pseudogenes, which map to proximal
16p.21 123 Normal chromosomes are thought to have twocopies, and it is estimated that EV chromosomes have 12.123
Other components of this cassette have either been excluded(the 6p minisatellite123) or not yet tested for copy number
variation at this locus (the adrenoleukodystrophy pseudogene182 183).
Variation in normal controls has also been found by Iafrate
et al,184 who believe that the TP53TG3 (TP53 target gene 3) is
included, and the 2.5 Mb polymorphism (CNP 75) found by
Sebat et al178 in 16p11 is likely to coincide with the 16p11.2
EV.

EVs and somatic variation
One exceptional family, omitted from the Tables above, blurs
the distinction between UBCAs and EVs. Savelyeva et al185
described three families with somatic inversions, duplications, and amplifications of a ,2 Mb segment of 9p23-p24 inassociation with BRCA2 insA mutations. In their family 3, theinstability of 9p was found in a mutation carrying father aswell as his phenotypically normal mutation negative son. In
this case, it is as if the somatic instability associated with agene mutation has been transmitted as an independent trait
in the germ line. Limited unpublished observations in thislaboratory suggest that copy number of the domain involvedin the 8p23.1 EVs can also be amplified in somatic cells.

DISCUSSION
In this review, 200 families with microscopically visible
cytogenetic anomalies have been separated into two groupsof 130 families with UBCAs and 70 with EVs. These have thenbeen subdivided into three groups depending on the presenceor absence of phenotypic consequences in parents andchildren (table 3).
Among the UBCA families, most have a degree ofphenotypic effect and thus, at the cytogenetic level, a lackof phenotypic consequences is the exception rather than therule. However, discussion with colleagues suggests that
UBCAs without phenotypic effect are frequently not published and therefore more common than is apparent from theliterature. The data in this review are consistent with the ideathat microscopic and submicroscopic imbalances of multiple
evolutionarily conserved loci can be compatible with anormal phenotype.186
Alternative explanations for the phenotypicvariability in transmitted UBCAs

Group 11.

Ascertainment bias: the majority of Group 1 imbalanceswere ascertained at prenatal diagnosis for maternal age
and may therefore be skewed towards the mildly or
unaffected end of the phenotypic spectrum.187 In
addition, few of the children who were reportedlywww.jmedgenet.com

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618

BarberTable 3 Summary of the three groups
Type of transmitted chromosome anomalyGroupsTransmitted UBCAs (n = 130)

Euchromatic variants (EVs) (n = 70)

Groups 1 to 3

Copy number not variable in the normal population.
Chromosomal segments of several megabases in size;
copy number change usually plus or minus one.
Most have phenotypic consequences.
n = 23 (18%). Most group 1 families ascertained at
prenatal diagnosis. Unknown whether post-natally
ascertained cases would also be free of phenotypic
effect. Homozygous imbalances of the same typeunlikely to be equally free of phenotypic consequences.
n = 30 (23%). Most group 2 families ascertained v
ia phenotype of offspring. Some likely to becoincidental to phenotype, some causal and someof uncertain significance.
n = 77 (59%). Common co-segregation of group 3
imbalance and mild phenotype common and likely to
be causal in the great majority of families.

Copy number variable in the normal population. Pseudogene or genecasettes of limited extent; relatively high copy number changes needed
for cytogenetic visibility. None has established phenotypicconsequences.
n = 38 (54%). Most group 1 families ascertained at prenatal diagnosis.
Assumed that postnatally ascertained cases also free of phenotypic
effect. Homozygous copy number variants unlikely to have significant
phenotypic consequences.

Group 1: normal offspringwith normal parents

Group 2: affected offspringwith normal parents

Group 3: affected offspringwith affected parents

2.

3.

4.

5.

normal at term have been followed up over a period ofyears by a medical geneticist.
Low gene content especially in G dark, late replicating
euchromatin: many of the group 1 deletions involve G
dark bands to which few genes map.1 However,deletions and duplications that include G light bands
are also compatible with a normal phenotype (fig 1),
and deletions restricted to a single G dark band may also
have phenotypic consequences, for example, the 14q31
deletion associated with developmental delay and minor
dysmorphism in at least three members of the Group 3
family reported by Byth et al.63
Absence of dosage sensitive loci: it is well known thatmany genes are not dosage sensitive, and imbalances
involving a limited number of genes may not include
genes that are dosage sensitive.
Functional redundancy: deletions or duplications ofgenes that have additional or related copies outside an
imbalanced segment may have no detectable effect on
the phenotype. Gu188 has reviewed whole genome
analyses in yeast that suggest that alternative metabolic
pathways can substitute for a pathway affected bymutation or that functional complementation can arise
from duplicate genes. It has also been suggested that
deletions involving gene clusters may be better bufferedbecause of the remaining cluster of related genes on thenormal homologue.1 A similar argument can be madefor the deletion of genes that have related copies onother chromosomes.25
Allelic exclusion: Knight189 has reviewed the growing
evidence that specific alleles have allele-specific levels of
expression. It is conceivable that a high expressing allele
could compensate for a deleted locus and a low
expressing allele for a duplicated gene in a given
individual but unlikely that these would be coinheritedover several generations of the same family.

2.

3.

4.

5.

6.

7.

8.

Group 2
1.

Ascertainment bias: fertility may itself be a selector of
more mildly affected individuals. In addition, phenotypically affected children or young adults are more likely
to come to medical attention than their mildly affectedor unaffected parents; in five families with transmitted
microscopic and submicroscopic deletions of 22q11.2,
congenital heart disease was more common in affectedchildren than in affected parents, and some mildly
affected siblings would have been unlikely to have beenwww.jmedgenet.com

9.

n = 30 (43%). Most group 2 families ascertained via phenotype ofoffspring. Phenotype of probands assumed to reflect ascertainment
bias in all cases.
n = 2 (3%). Rare co-segregation of group 3 variant and mild
phenotype regarded as coincidental in both families.

ascertained in the absence of their more severely
affected brothers or sisters.175
Imprinting: this is an established mechanism for the
discordant phenotypes associated with transmitted
duplications of the TNDM locus (6q24.2) or the
PWACR (15q11.2-q13) but an unlikely reason in regionsthat are not known to be imprinted.
Phenotypic variation extending into the normal range:
in a number of UBCA families, a mildly affected proband
has an unaffected parent with the same imbalance.
Chromosomal non-penetrance: if deletions and duplications involve only one or few dosage critical loci, then the
non-penetrance associated with single locus Mendelianconditions may apply. In addition, the action of a modifiergene on a key dosage sensitive locus might result in thepresence or absence of a phenotypic effect depending on
the presence or absence of a modifying allele.
Unmasking of a recessive allele in a proband: this could
result in effective nullisomy of a gene within a deletion.
Alternatively, the lack of a second somatic mutation is
likely to explain the lack of retinoblastoma in themother of an affected child in the group 2 family with adeletion of 13q14.26
Mosaicism in a parent: most parental karyotypes were
established from peripheral blood samples in two generation pedigrees and mosaicism has been established insome (see imbalances with an ‘‘m’’ in fig 1). Mosaicism
is, however, an unlikely explanation in pedigrees where
only the probands are affected and there are three ormore generations with the same imbalance.
Undetected differences at the molecular level: most ofthese abnormalities are characterised at the cytogenetic
level, and possible molecular differences have not been
excluded.
Unreported abnormal phenotype: it is frequently
assumed that parents are phenotypically normal
although closer inspection by a clinical geneticist mightreveal subtle anomalies that might otherwise escapedetection, for example, deletions of distal 5p were
initially reported in developmentally delayed children
and normal parents in the abstract by Bengtsson et al,190
but mild effects in parents were later described.54
Coincidence: any other unidentified genetic, epigenetic,or environmental factor that could coincide with akaryotypic abnormality that would otherwise be phenotypically neutral.

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Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

Group 3
1. Consistently mild phenotype: survival into adulthood,fertility, and relatively independent lives are the hallmarks of families in group 3, among whom the majority
have imbalances that consistently give rise to relatively
mild phenotypic abnormalities.
2. Chance co-segregation: it may be necessary to examine
the wider family to establish whether genotype andphenotype co-segregate by chance.
Microscopic and submicroscopic UBCAs and EVs
The fact that group 1 cytogenetic UBCAs ranging in size from,4 to ,30 Mb can be free of phenotypic effect implies that amuch higher proportion of subcytogenetic imbalances will
also be compatible with fertility and a phenotype in thenormal range. Using high resolution CGH with a resolution of,2 Mb, Kirchhoff et al145 147 have already found that ,10% of
the identified imbalances are transmitted, although not all
are associated with a normal phenotype. Testing for
subtelomeric imbalances has identified transmitted imbalances with and without phenotypic effects, and ‘‘polymorphic’’ deletions and duplications that occur in morethan one independent family.146 163 164 191 192 Using 1 Mb
resolution array CGH on two different sets of patients,,50% of identified imbalances in a total of 70 patients weretransmitted.148 149
Deletions, duplications, and copy number variation at themolecular level have been reviewed by Buckland,193 and 1 Mb
arrays are also providing evidence of large scale copy number
variation.184 An idea of the level of polymorphism that will befound using tiling path arrays has been provided by Sebat etal,178 who found 76 copy number differences of segments withan average size of ,500 kb in 20 normal individuals using
representational oligonucleotide microarray analysis. Some of
the band assignments of these copy number variations(CNVs) coincide with some of the UBCAs in this review
but, in general, it is unlikely that variation of a 500 kb CNV
within a large confirmed UBCA has a significant impact on
the presence or absence of any associated phenotype. The factthat the established EVs map to paralogous repeat regions
hampers direct comparisons, although areas of likely overlap
are indicated under the individual EV entries above and arebeing collected in the Database of Genomic Variants (http://
projects.tcag.ca/variation/). As the size of UBCAs and CNVs
approaches each other, the distinction between a large single
copy CNV and a short UBCA may become a matter ofsemantics.
The EVs identified to date clearly do not have thephenotypic consequences associated with UBCAs. However,their gene content and copy number variation in normal
individuals does not exclude a possible role in traits thatshow continuous variation. It is also interesting that some ofthe human EVs involve genes that have testis specificexpression (for example SPAG11 in the 8p23.1 EVs); additional copies of a variable domain might be under strong
selection if they conferred a significant effect on fertility. A
possible role for the 20 000 pseudogenes in the humangenome has also been raised by Hirotsune et al,194 who foundthat interruption of the makorin-1 pseudogene in transfection experiments had a detrimental affect on expression of
the wild type makorin-1 gene. Copy number variation is also
associated with the low copy repeats and duplicons thatpredispose to genomic disorders,195 196 chromosome abnormalities,197 198 and evolutionary breakpoints.199 It therefore
remains possible that the frequency and consequences ofaberrant recombination between these repeats is influenced
by copy number variation at homologous and paralogous
sites.

619

Transmission
Table 1 indicates that there are more female than maletransmitting carriers in the UBCA groups 1 and 2 incomparison with EV groups 1 and 2. This trend was more
pronounced in the affected carriers of group 3. This suggeststhat unbalanced chromosome complements may have a moredeleterious affect on male than female meiosis, as has
previously been suggested for balanced translocation andring chromosome carriers.155 200 Alternatively, the figures may
reflect social differences, whereby a phenotypically affected
man is less likely to be able to find a partner while aphenotypically affected woman might be more susceptible toexploitation by normal men. However, further detailed
pedigree analysis will be necessary to distinguish between
these possibilities with adjustment for ascertainment bias
and inclusion of only those families in which both parents
have been karyotyped.
Reproductive implications
Relatively little is known about the behaviour of UBCAs at
meiosis. The great majority of the simple deletions andduplications in the UBCA families has apparently beentransmitted without giving rise to any additional imbalanceat the cytogenetic level. The same cannot be said of
imbalances derived from translocations or insertions; inthese families, the phenotypically normal family members
have frequently been ascertained via siblings with more
extensive unbalanced segregants of the same rearrangements(see many of the PA* families in Appendices 1 and 2). In
addition, a clinically normal father with an insertional
duplication of 9p transmitted a deletion of chromosome 5
to a proband with cri du chat syndrome; this deletion would
not have been predicted unless the insertion is more complex
than it appears at the cytogenetic level.159
Miscarriages were recorded in two group 1 UBCA
families,2 9 and seem likely to be incidental for two reasons:(a) imbalances small enough to be compatible with a normal
phenotype would be unlikely to give rise to fetal demise, and(b) the duplication or deletion loop formed at meiosis isunlikely to provide an opportunity for recombination that
could conceivably result in the generation of larger imbalances.
Similarly, four group 1 EV families were ascertained for
miscarriages but it is difficult to reconcile phenotypicallysilent euchromatic variation with miscarriage unless suchvariation predisposes to other larger imbalances of the same
chromosome or to non-disjunction of the whole chromosome. This has not been established in any of the families
reviewed here to date.
Nosology
Polymorphism is strictly used for variation that has afrequency of 1% or more in the population. It is therefore asuitable term for the common copy number variationthat underlies cytogenetic EVs, but not for rare transmitted
deletions or duplications; these might be considereddimorphic or heteromorphic but cannot accurately bedescribed as polymorphic.
It is common practice to call a deletion or duplication avariant once other phenotypically normal family memberswith the same imbalance have been identified, and Jalal andKetterling151 have proposed that all UBCAs and EVs without
phenotypic effect should be described as euchromatic
variants. However, describing euchromatic deletions andduplications as variants is to modify a genotypic description
with a phenotypic one and to confuse single copy number
changes with more extensive copy number variation. Because
most UBCAs without phenotype have only been described insingle families, the term ‘‘deletion or duplication without
phenotypic effect’’ has been preferred,150 and ‘‘phenotypicwww.jmedgenet.com

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620

deletion variant’’ or phenotypic duplication variant’’ might bepreferable once a number of families and/or individuals withsimilar imbalances have been assembled. Given the extensive
copy number variation associated with EVs, it is proposedthat the term euchromatic variant is restricted to the
expanded range of copy number variation that is visible atthe cytogenetic level.
The term ‘‘transmitted’’ is preferred to ‘‘familial’’ as thelatter is also used in families where balanced rearrangements
have given rise to more than one chromosomally unbalanced
individual but no direct transmission from an unbalanced
individual has taken place.
The abbreviation ‘‘var’’ for variant was replaced with ‘‘v’’ in
ISCN 1995.201 The band description followed by ‘‘v’’ (forexample, 8p23.1v) has therefore been used for euchromatic
variation within cytogenetic bands that has no apparent
phenotypic effect.

Aetiology of chromosomal phenotypes
When deletions and duplications of most of the autosomal
complement of Drosophila were produced by Lindsley et al,202
the authors found few regions that were haplolethal or
triplolethal, and concluded that most of the deleterious
effects of segmental aneuploidy are caused by the ‘‘additiveeffects of genes that slightly reduce viability and not by theindividual effects of a few aneuploid lethal genes among alarge array of dosage insensitive loci’’. Consistent with theresults of Lindsley et al,202 Epstein203 204 proposed an ‘‘additive’’model in which the phenotype is the consequence of theadditive effects of altered copy number of each gene within
an unbalanced chromosome segment. As a result, imbalancesof restricted size would include fewer genetic loci and be lesslikely to have detectable phenotypic consequences. By
contrast, Shapiro and others have proposed an ‘‘interactive’’model,205 206 in which the phenotype is the result of thedestabilisation of developmental processes resulting from thecumulative and synergistic effects of all the unbalanced lociwithin a segmental imbalance. Under this model, it could beargued that small imbalances are insufficient to destabilise
developmental processes to the point at which a phenotypic
effect is detectable. The difference may not be academic; if
the phenotype results from a few dosage sensitive loci, thenthe prognostic implications of a given imbalance could be
inferred from the dosage of these key loci. If, however, thephenotype depends on the synergistic interactions of many
genes of small effect, the diagnostic implications may bemuch harder to predict.207 In practice, chromosomal syndromes are likely to reflect a combination of both (a) the
effects of a relatively small number of dosage sensitive loci oflarge effect, for example, those within the critical regions forsyndromes such as cri du chat, in which small interstitialdeletions, large terminal deletions, and unbalanced translocations all result in a recognisable facial gestalt; and (b) the
cumulative effect of relatively large numbers of loci ofindividually small effect, for example, those imbalances ofthe short arm of chromosome 5 that do not include the cri duchat critical region and are generally associated with amilder, more non-specific phenotype. A Down’s syndrome
critical region (DCR) has also been identified, but extensive
phenotypic analysis of partial duplications of chromosome 21
indicates that genes both inside and outside the putative DCR
contribute to the phenotype of full trisomy 21 Down’s
syndrome.208 In addition, expression analysis shows that
Down’s syndrome alters the dosage of genes on chromosome
21 as well as genes on other chromosomes.209

CONCLUSIONS
Evidence summarised in this review indicates that mosttransmitted UBCAs have phenotypic effects but there are a

www.jmedgenet.com

Barbergrowing number of exceptions. These show that autosomal
deletions and duplications with an average size of almost
10 Mb are compatible with fertility and a normal phenotype,especially in families selected on the basis of the directtransmission of an imbalance between two or more family
members. However, it has yet to be established that a given
imbalance will be consistently free of phenotypic consequences in multiple independent families or as de novo
events. Consequently, (a) not all transmitted imbalanceswith an affected proband and a normal parent will becoincidental, and careful analysis of the extended family
may be necessary; and (b) some de novo imbalances may
not be causal, and knowledge of the gene content will
not always discriminate between causal and non-causal
rearrangements.
The established EVs represent an extreme of variation thatis already reflected in the multiple copy number variants
being identified at the subcytogenetic level178 and may beparticularly associated with regions of recent paralogous genetransposition.123 Consequently, (a) phenotypically neutralsubcytogenetic EVs will be a common finding that will need
to be distinguished from pathogenic alterations, and (b)although EVs are not associated with the detrimental effects
of most UBCAs, copy number variation may yet be found tohave a bearing on quantitative traits such as response todrugs or infection.
Diagnostic genetic services still encounter families who
have lived for many years under the mistaken impressionthat heterochromatic variation, identified in the early years ofconventional cytogenetics, was responsible for the congenitalabnormalities, malignancy, or reproductive loss in a proband
or family.198 This review provides classic cytogenetic precedents for areas of the genome that may be free ofpathogenic consequences. However, the continuum of severity associated with UBCAs and subcytogenetic imbalances
will require clinical genetic precision to exclude subtle
phenotypic manifestations in otherwise phenotypically normal individuals, and laboratory resources to distinguishclinically silent variation from pathogenic rearrangement.210
To this end, data from this review are available at (http://
www.ngrl.org.uk/Wessex/collection.html). New resources
such as the European Chromosome Abnormality Registerof Unbalanced Chromosome Abnormalities (ECARUCA)(http://www.ecaruca.net/), the DatabasE of Chromosomal
Imbalance and Phenotype in Humans using Ensembl
Resources (DECIPHER)(http://www.sanger.ac.uk/PostGenomics/decipher/) and the Database of Genomic Variants(http://projects.tcag.ca/variation/) will provide the means ofaccelerating the process of distinguishing pathogenic alterations from phenotypically neutral variation in the immediate
future.

ACKNOWLEDGEMENTS
P Jacobs, A Sharp, and N Cross are thanked for their helpfulcomments on this review. VMaloney is thanked for constructing theidiograms and J Gladding for her help with the preparation of themanuscript.
.....................

Author’s affiliations

J C K Barber, Wessex Regional Genetics Laboratory, Salisbury HealthCare NHS Trust, Salisbury District Hospital, Salisbury, Wiltshire SP2 8BJ,
UK; Human Genetics Division, Duthie Building, Southampton University
Hospitals Trust, Tremona Road, Southampton, UK; National Genetics
Reference Laboratory (Wessex), Salisbury Health Care NHS Trust,Salisbury District Hospital, Salisbury, Wiltshire SP2 8BJ, UK
Competing interests: none declared

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Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

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Carpenter N, Daumer C, Dignan P, Disteche C, Graham JM Jr, Hugdfins L,
McGillivray B, Miyazaki K, Ogasawara N, Park JP, Pagon R, Pueschel S,
Sack G, Say B, Schuffenhauer S, Soukup S, Yamanaka T. Down syndrome
phenotypes: the consequences of chromosomal imbalance. Proc Natl Acad
Sci USA 1994;91:4997–5001.
209 FitzPatrick DR, Ramsay J, McGill NI, Shade M, Carothers AD, Hastie ND.
Transcriptome analysis of human autosomal trisomy. Hum Molec Genet
2002;113:249–56.
210 Cody JD, Hale DE. Precision in phenotyping and genotyping. Am J Med
Genet 2004;131A:313.

Downloaded from jmg.bmjjournals.com on 1 August 2005
Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

625

Appendix 1 Group 1: phenotypically unaffected parents with the same unbalanced chromosome abnormality as theirunaffected children
RegionSizeCon

Ascertainment

Mode

C

Ref

del
2
2
2
3
5
8
8
9
10
11
13
16
16
18

p12-p12p12-p12q13-q14.1
p25.3-pter
p14-p14
p23.1/2-pter
q24.13q24.22
p21.2-p22.1
q11.2q21.2
p12
q21-q21
q13q22
q21-q21
p11.31-pter

6.1
6.9
6.0
10.1
13.8
6.1
4.2
7.6
13.3
6.1
16.0
7.0
7.0
4.4
Av 8.2

F,M
F,M
F
F
M
F
P,F
–
P
–
–
F
M
–

PD Previous +18
PD Maternal age
MC Miscarriages
PD Maternal age
PD Maternal age
PD Maternal age
PD Triple screen
PD Maternal age
MC Miscarriages
PD Maternal age
MC Miscarriages
PD Maternal age
PD Maternal age
PD Serum AFP

Mat
Both
Mat
Mat
Mat
Pat
Mat
Both
N
Mat
Mat
Mat
Pat
Pat

5
3
2
2
6
2
2
3
1
3
2
3
3
2

Family 1
Family 21
2
3
4
5
6
7
158
8
9
10
11
12

dup
1
3
8
8
10
13
18

p21-p31q28-q29
p23.1-p23.3
p22
p13-p14q14-q21
p11.2-pter

31.3
8.6
6.1
3.4
5.3
18.3
22.0
Av 13.6

F
P
F
F
F
F
M

PD Maternal age
PD Maternal age
I Oligoasthenospermia
PD Triple screen
PD Low serum screen
PD Maternal hyposomia
PD Raised seurm AFP

Mat
Pat
Mat
Both
Mat
Mat
Mat

2
3
3
3
3
2
2

13
12
14
15
16
17
18

dup(9)(p12-p21.3)

21.0

P,F

PA*Phenotype of daughter

N

1

159

dup(13)(q13-q14.3)

11.6

B

PA* Phenotype of sibling

N

1

160

dup(18)(q11.2q12.2)

10.0

F

PD FH Down’s syndrome

N

1

161

del 1p32-pter dup?

48.5

–

PD Maternal age

Pat

2

19

del ?6p25-pter &?21q11-pterdel 22q11.21-pter(9q subtel intact)
27 families––

PA* Phenotype of sibling

Mat

4

20

4.1
0.0

F

PD Maternal age

Mat

4

21

21/27

PD 20/27; MC 3/27;
PA* 3/27; I 1/23

Mat 15/23;
pat 5/23;
both 3/23

70

8 Abstract onlyder
der(5)
ins(5;9)der(20)ins(20;13)
der(18)ins(18;18)
der(1)
t(1;?)
der(6)
t(6;21)der(9)t(9;22)
Totals1

Entries in italics are abstracts only. Con, confirmed with FISH and/or CGH (F); chromosome paint (P); molecular (M) or biochemical analysis (B); C, number ofcarriers in family; PD, prenatal diagnosis; PA, phenotypic abnormality; PA*, phenotypic abnormality due to another identified cause; MC, miscarriage; I, infertility;
Mat, maternal; Pat, paternal; Both, maternal and paternal transmission; N, Not transmitted from an unbalanced parent; m, mosaic.

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626

BarberAppendix 2 Group 2: unaffected parents with the same unbalanced chromosome abnormality as their affected children
RegionSizeCon

Ascertainment

Mode

C

Ref

del
5
5
5
5
7
11
13

p15.2-pter
p15.3-pter
p14.1-p14.3
p14-p14p22-pter
q14.3-q14.3
q14-q14

9.6
8.1
9.4
6.4
5.5
3.6
10.0
Av 7.5

F,M
F,M
P
F
–
–
M

PA Cat cry, microcephaly
PA Low birth weight, microcephaly
PA Peroxisomal disorder
PA Dev delay, microcephaly, seizures
PA Patient on Intensive Care Unit
PA Dev delay
PA Retinoblastoma

Mat
Pat
Mat
Patm
Mat
Pat
Mat

2
4
2
2
3
5
2

Family 322
22
Family 4
10
23
24
25
26

dup
1
1
3
4
5
6
8
8
8
8
8
8
14
15
15
15
15
15
16

q11-q22q42.11-q42.12
q25-q25
q31.3-q33
q15-q21q24.2-q24.2
p23.2-p23.2
p23.2-p23.2
p23.2-p23.2
p23.1-p23.1
p23.1-p23.1
p23.1-p23.1
q24.3-q31
q11-q13q11-q12q11-q13q11-q13q11-q13q12.1-q12.1

11.4
4.1
10.4
10.6
16.3
2.0
2.5
2.5
2.5
6.5
6.5
6.5
9.8
4.0
4.0
4.0
4.0
4.0
5.1
Av 6.1

F
–
–
P
F
F
F
F
F
–
–
–
F
M
F
M
M
–
F

L Leukaemia
PA Short stature
PA Dysmorphic, CHD
PA* Trisomy 21 in proband
PD Cystic hygroma on ultrasound
PA Transient Neonatal Diabetes
PA Short stature
PA Dysmorphic features
PA Dev delay, inguinal testis
PA Dysmorphic
PA MCA
PA Autistic behaviour
PA Dev delay
PA Dev delay, ?fragile X
PA Dev delay
PA Autism
PA Dev delay
PA Autism
PA Autism

Mat
Mat
Both
Mat
Pat
Pat
Mat
Pat
Mat
Pat
Mat
Mat
Pat
Mat
Mat
Mat*
Mat*
Mat*
Mat

3
2
5
3
3
2
2
2
2
2
2
2
2
3
2
3
2
2
2

27
28
29
30
31
21
32
Family 2
Family 332
Family 432
33
Family 1
Family 733
33
Family 834
Family 135
36
37
38
39
40

dup 6q23.3-q24.2

8.1

F,M

PA TNDM

Both

3

41

del 11q25-qter
del 15q11-pterdel 11q25-qter
del 22q11-pterdel 19p13-pterdel 21q21.1-pter
30

–
–
–
–
–
–

I Infertility

Pat

2

42

PA Unusual facies, physical & mental
retardation
PA* Down’s syndrome in one of twins

Mat

4

43

Mat

3

44

PA 25/30; PA* 2/30; PD 1/30;
I 1/30; L 1/30

Mat 16/30;
mat* 3/30;
pat 9/30;
both 2/30

78

2 Abstract onlyder
der(2)
ins(2;6)
der(11)t(11;15)der(11)t(11;22)der(21)t(19;21)
Totals

–
–
–
19/30

Entries in italics are abstracts only. Con, confirmed with FISH and/or CGH (F); chromosome paint only (P) or molecular analysis (M); C, number of carriers infamily; PD, prenatal diagnosis; PA, phenotypic abnormality; PA*, phenotypic abnormality due to another identified cause; MC, miscarriage; I, infertility; Mat,
maternal; Pat, paternal; Mat* paternal origin in normal parent; Both, maternal and paternal transmission; m, mosaic.

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Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

627

Appendix 3 Group 3: affected parents with the same unbalanced chromosome abnormality as their affected children
RegionSizeCon

Ascertainment

Mode

C

Ref

del
1
2
3
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
5
5
8
9
11
13
14
15
18
18
18
18
18
18
18
18
18
20
21
22
Subtotal

q42.1-q42.3
p11.2-p12
p25-pter
p15.2-p16.1
q33-qterq33-q35.1
q33-q33
q32-q33
p15.32-pter
p15.31-pter
p15.3-pter
p15.3-pter
p15.3-pter
p15.3-pter
p15.3-pter
p15.1-pter
p14-p15.3
p13.3-p14.3
p13.1-p14.2
p13-p15.1
p23.1-pter
q31.2-q32
q24.2-qter
q14.1-q21.3
q31-q31q11-q12
p11.3-pter
p11.21-pter
p11.2-pter
p11.23-pter
p11.2-pterp (pre-banding)
q23-qter?q21-qter
q22.3-qter
p11.2-p12.2
q11-q21.3
q11.2-q11.2
38 families

7.1
7.5
9.1
15.9
18.6
13.3
2.7
8.0
9.5
9.5
8.2
9.5
9.5
8.7
8.7
13.6
20.4
13.6
8.2
17.0
6.2
3.2
9.6
19.9
8.2
2.0
5.7
12.9
14.3
7.2
14.3
20.1
5.7
30.8
8.6
5.8
17.3
2.0
Av 10.9

P
F,M
–
–
F
–
–
–
–
F
F
M
M
M
M
–
–
M
–
F
–
–
B
M
M
F, P
–
P
P
F
–
M
–
–
–
M
M
21/38

PA Dev delay, ADD
PA Wilm,s tumour, dev delay
PA Speech delayPA
PA MCA inc macrocephaly and language delay
PA Dev delay
PA Dev delay and dysmorphic features
PA Dev delay and dysmorphic features
PA Dev motor, speech delay
PA Speech delay, dysmorphic
PA Cat cry at birth, low birth weight
PA Speech delay, hearing loss, mild MR
PA Speech delay, mild dev delay
PA Speech delay, raspy voice
PA Speech and dev delay
PA MCAPA Cri-du-chat
PA Microcephaly, small
PA Speech delay
PD Maternal age
PA Mental slowness, behaviour, seizures
PA Dev dela, FTT, unusual appearance
PA Dev delay
PA Leukocoria
PA Dev delay
PA MR
PD Previous son with MR
PA MR; short stature
PD Abnormal ultrasound
PA MCAPA MR, short stature
PA Failure to thrive, ptosis
PA Dysmorphic
PA MCAPA
PA Dysmorphic
PA Dislocated hips
PA Cardiac failure
PA 35/38; PD 3/38

Mat
Mat
Mat
Mat
Mat
Mat
Mat
Mat
Mat
Pat
Pat
Both
Mat
Mat
Both
Mat
Mat
Mat
Both
Mat
Pat
Matm
Mat
Mat
Both
Mat
Mat
Mat
Mat
Mat
Mat
Matm
Mat
Mat
Mat
Mat
Mat
Mat
Mat 32/38;
pat 3/38;
both 4/38

2
2
2
2
2
3
2
2
4
4
4
3
2
3
6
2
2
4
6
4
3
2
2
2
4
2
2
2
2
3
2
3
2
5
2
2
2
4
107

45
1
Family 3
46
47
48
49
Family 150
50
Family 2
51
52
53
Family I54
54
Family II
54
Family III
Family IV54
55
56
57
21
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
6/38 Abstracts
only

dup
1
3
4
4
5
7
7
7
8
8
8
8
8
8
8
8
9
10
11
14
15
15
15
15
16
18
21
Subtotal

q23-q25
q25.3-q26.2
q31.22-q33
q31.1-q32.3
q15-q22.1
p12.2-p13
p12.1-p13
q32-q36.1
p23.1-p23.1
p23.1-p23.1
p23.1-p23.1
p22-p23.1
p21.3-p23.1
p21.3-p23.1
p21.3-p22 or p22-p23.1
p12-p21.1
p22-p24
p13-p15
q13.5-q21 or q21-q23.1
q13-q22
q11.2-q13
q11.2-q13
q11.2-q13
q11-q13
q11.2-q12.1
cen-pterq22-qter
27 families

15.7
17.0
19.5
18.6
13.6
5.5
6.9
17.8
6.5
6.5
6.5
9.6
9.6
9.6
9.6
6.9
11.4
4.0
13.8
26.1
4.0
4.0
4.0
4.0
5.1
21.5
18.3
Av 10.9

–
F
–
F
–
F
F,M
–
P
–
–
F
P
P
P
F,B
F
F
F
P
M
M
M
F+M
F
F
F
21/27

PA Mild MR and dysmorphism
PA Microcephaly; CHD and deafness
PA Mild MR and dysmorphism
PA Dev delay, nasal speech
PA Hyperactive, mild MR
PA Failure to thrive
PA Short stature, ?Silver-Russell
PA Dev delay, behavioural problems
PA CHDPA Dev delay
PA* Dev delay, hypotonia, (PWS)
PA Mild MR only
PA CHD
PA Speech delay
PA MR, short stature, hypertelorism
PA Dev delay
PA Short, low IQ, dysmorphic
PA Dev delay especially speech
PD Maternal age
PA Dev delay
PA Dev delay, hypogonadism
PA Severe MR
PA Dev delay
PA Dev delay
PA Speech delay
PA Dysmorphic, moderate MR
PA Unusual appearance
PA 25/27; PA* 1/26; PD 1/26

Mat
Both
Mat
Mat
Mat
Mat
Mat
Mat
Patm
Mat
Pat
Mat
Mat
Pat
Mat
Mat
Pat
Both
Mat
Mat
Mat*
Mat*
Mat*
Mat
Pat
Matm
Mat
Mat 20/27;
pat 5/27;
both 2/27

2
9
2
3
2
4
2
2
2
3
2
3
3
3
3
4
2
6
2
3
6
3
5
6
4
2
3
191

Family A
78
Family B77
79
80
81
82
83
84
Family 333
Family 433
85
Family 186
86
Family 2
87
88
89
90
91
92
Family 235
Family 335
35
Family 4
Family A93
94
Family 2
95
21
3/27 Abstracts
only

dup 2q11.2-q21.1

28.1

P

PA Unusual facies, language delay

Mat

2

96

del 22q13.3
dup 10p14-p15

–
15.0

F
F,M

PA Mitral valve prolapse
PA MCA

Mat
Pat

2
3

97
98

dup q11.2-q13.1

11.9

F

PA Dev delay

Matm

3

Family 194

derder(8)
ins(8;2)
ins(7;22)
der(9)
ins(9;10)der(16)ins(16;16)

77

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628

BarberAppendix 3 Continued
der(4)
t(4;5)
t(4;14)der(4)
t(4;22)der(5)
t(5;?)
der(10)t(5;10)der(22)t(21;22)der(20)t(6;20)der(Y)t(Y;8)
Subtotal

TotalsRegionSizeCon

Ascertainment

Mode

C

Ref

del 4q34-qter; dup
5p15.1-pterdel 4 or 14
del 4q35.2-qter; del22q11.2-pterdel 5p15.32-pter;dup?
dup 5q35-qter; del10q26.13-qter
del 21q21.2-pter

13.3
15.0
10.0
1.3
12.4
6.8
–
3.4
6.6
21.6

F

PA MR, dysmorphic

Mat

2

99

M
–

PA Genital and retinal abnormalities
PA CHD, dysmorphism

Pat
Mat

2
2

100
101

F

PA ?Cri-du-chat

Both

4

102

F

PA Dysmorphic

Mat

2

Family 1103

F

PA* Sibling with Down’s syndrome

Mat

5

104

dup 6p23-pter; del20p13-pter
dup 8p22-pter

17.4
4.4
17.8

F

PA Dev delay, dysmorphic features

Pat

2

105

P

MC Miscarriages 63

Pat

3

106

12 families

11/12

PA 10/12; MC 1/12; PA* 1/12

77 families

53/77

PA 71/77; PA* 1/77; PD 4/77; MC 1/77

Mat 6/12;
pat 5/12;
both 1/12
Mat 58/77;
pat 12/77;
both 7/77

132

1/12 Abstracts
only

230

10/77 Abstracts
only

Entries in italics are abstracts only. Abbreviations: Con, confirmed with FISH and/or CGH (F); chromosome paint only (P) molecular analysis (M) or biochemistry(B); C, number of carriers in family; PD, prenatal diagnosis; PA, phenotypic abnormality; PA*, phenotypic abnormality due to another identified cause; MC,miscarriage; I, infertility; Mat, maternal; Pat, paternal; Both, maternal and paternal transmission; m, mosaic.

Appendix 4Group 1 EV: phenotypically unaffected parents with the same euchromatic variant as their unaffected children

RegionCon

Ascertainment

Mode

C

Reference

8
8

p23.1
p23.1

P
F

PD Maternal age
MC Miscarriages

Pat
Mat

2
6

8
8
8
8
8
8
9
9
9
9
9
9
9
9
9
9
9
9
15
15
15
15
15
15
15
15
15
15
16
16
16
16
16
16
16
16
Total

p23.1
p23.1
p23.1
p23.1
p23.1
p23.1
p12
p12
p12
p11.2-p12
p11.2-p12
p11.2-p12
q12/qhq12/qhq12/qhq12/qhq12/qhq12/qhq11.2v
q11.2v
q11.2v
q11.2v
q11.2-q13
q11.2-q13
q11.2-q13
q11.2-q13
q11.2-q13
q11.2Rq13
p11.2v
p11
p11
p11
p11
p11
p11
p11
38

F
–
–
–
–
–
–
–
–
–
–
–
F
–
–
–
–
–
F
F
F
F
M
M
M
M
M
P
F
–
–
–
–
–
–
–
15/38

PD Maternal age
PD Maternal age
PD SIRPD
PD
PD
PD Previous NTD
PD Previous NTD
PD Previous NTD
NS Newborn survey
PD Previous +21
PD Maternal age
PD Maternal age
PA* Down’s syndrome
PD Maternal age
MC Miscarriages
PD Maternal age
PA* Trisomy 21 in sibling
SB Pregnancy loss
PD
PD
PD
PD Serum increased risk
PD Serum increased risk
PD Maternal age
PD Raised AFP
PD Serum increased risk
PD Maternal age
MC Miscarriages
MC Miscarriages and stillbirth
PD Not recorded
PD Maternal age
PD Maternal age
PD Parental anxiety
PD FH NTDPD Maternal age
PD 30/38; MC 4/38; PA* 2/38;
SB 1/38; NS 1/38

Pat
Both
Pat
Pat
Pat
Mat
Both
Mat
Mat
Mat
Pat
Mat
Pat
Pat
Mat
Pat
Pat
Mat
Mat
Mat
Pat
Mat
Mat
Mat
Pat
Both
Pat
Pat
Mat
Mat
Pat
Mat
Mat
Mat
Pat
Pat
18/38 Mat;
17/38 Pat;
3/38 Both

3
4
2
2
2
2
4
2
3
2
2
5
2
2
2
2
2
3
3
2
2
2
2
2
3
3
3
2
2
2
2
4
2
2
2
2
94

107
108
Family 1
Family 1109
108
Family 2108
Family 4
Case 1110
111
Family 1
Family 2111
Family 3111
112
Family 1
Family 2112
112
Family 3
113
Family 1114
114
Family 2
115
116
117
Family 1118
Family 2118
119
Family A120
120
Family C
120
Family D
Family E120
121
Family 16
Family 17121
Family 18121
121
Family 19
Family 20121
122
123
Case 1
Family 1124
124
Family 2
125
126
127
Case 1128
128
Case 2
4/38 Abstracts only

Entries in italics are abstracts only. Con, confirmed with FISH and/or CGH (F); chromosome paint only (P) or molecular analysis (M); C, number of carriers infamily; PD, prenatal diagnosis; PA, phenotypic abnormality; PA*, phenotypic abnormality due to another identified cause; MC, miscarriage; SB, stillbirth;I, infertility; Mat, maternal; Pat, paternal; Both, maternal and paternal transmission; m, mosaic.

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Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

629

Appendix 5 Group 2 EV: unaffected parents with the same euchromatic variant as their affected children
Chr

RegionCon

Ascertainment

Mode

C

Reference

8
8

p23.1
p23.1

P
–

PA Dev delay: ADHD, mild dysmorphism
PA Short stature

Both
Both

4
3

9
9
9
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
16
16
16
16
16
Total

p+
p+
q13-q21 (q12/qh)
q11.2v
q11.2v
q11.2v
q11.2v
q11.2v
q11.2-q13
q11.2-q13
q11.2-q13
q11.2-q13
q11.2-q13
q11.2-q13
q11.2-q13
q11.2-q13
q11.2-q13
q12-q13q12-q13
q11.2
q11.2-q12
q11-q13
q11.2-q13.3
p11.2
p11.2
p11.2
p11.2
p12+
30

–
–
–
F
F
F
F
F
M
M
M
M
M
M
M
M
M
–
–
–
–
–
–
–
–
–
–
–
15/30

PA MCAPA Protruding tongue
PA Hypoplastic lungs and hydrops
PA Autism
PA Dev delay, mod MR
PA Autism and mild dysmorphism
PA Dev delay, mild dysmorphic features, inguinal hernia, talipes
PA Dev delay, gynaecomastia
PA ?FX Dev delay, learning difficulties
PA DD Communication difficulties
PA ?FX Language disorder, macrocephaly
PA ?FX Communication problems
PA SS; Mild dev delay
PA CHD; VSD, pulmonary stenosis, hypoplastic toes
PA ?Beckwith-Wiedemann
PA IUGR, antimongoloid slant, epicanthic folds ?+21
PA FTT Sickly child, poor growth
PA Skeletal abnormalities
PA Hydrops (non-immune)
PA Hypotonia; ?PWSPA Obesity
PA Congenital abnormalities
PA Prader-Willi syndrome in child
PA Dev delay, dysmorphism; MD Myelodysplasia
PA Macrocephaly and hypospadias
PA MCA
PA Cleft palate
PA ?Fragile X syndrome
PA 29/30; PA + MD 1/30

Mat
Mat
Mat
Pat
Mat
Mat
Both
Mat
Both
Both
Pat
Pat
Mat
Mat
Pat
Pat
Mat
Mat
Mat
Pat
Mat
Pat
Pat
Both
Both
Mat
Both
Pat
13/30 Mat;
9/30 pat;8/30 both

6
2
2
2
2
2
5
2
3
3
2
2
3
2
2
2
2
4
3
2
2
2
2
8
3
2
3
2
84

129
Family 5108
109
Family 2
Family 2130
131
132
Family F120
120
Family G
120
Family H
Family 1133
133
Family 2
Family 5121
Family 6121
121
Family 7
Family 8121
121
Family 9
121
Family 10
Family 11121
121
Family 12
Family 13121
Patient E134
134
Patient A
135
136
137
138
128 139
Case 3
Case 1140
Case 2140141
123/30 Abstract only

Entries in italics are abstracts only. Abbreviations: Con, confirmed with FISH and/or CGH (F); chromosome paint only (P) or molecular analysis (M); C, number ofcarriers in family; PD, prenatal diagnosis; PA, phenotypic abnormality; PA*, phenotypic abnormality due to another identified cause; MD, Myelodysplasia; IUGR,
intra-uterine growth retardation; Mat, maternal; Pat, paternal; Both, maternal and paternal transmission; m, mosaic.

Appendix 6 Group 3 EV: Affected parents with the same euchromatic variants as theiraffected children
Chr

RegionCon

Ascertainment

Mode

C

Ref

8
15
Total

p23.1
q11-q122

F,P–
1

PA Mild dysmorphism
PA Short stature
PA 2/2MatPat
Mat 1; pat 1

3
3
6

142
143

Chr, chromosome; Con, confirmed with FISH (F); chromosome paint (P) or molecular analysis (M); C, number ofcarriers in family; PD, prenatal diagnosis; PA, phenotypic abnormality; MC, miscarriage; I, infertility; Mat,
maternal; Pat, paternal.

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