American Journal of Medical Genetics 75:367–381 (1998)

FISH and Molecular Studies of Autosomal

Supernumerary Marker Chromosomes Excluding
Those Derived From Chromosome 15: II. Review of
the Literature
John A. Crolla*
Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wiltshire, United Kingdom

of data using such approaches, the total number of re-

Using fluorescence in situ hybridization ported cases in many of the chromosomal subgroups
(FISH), supernumerary marker chromo- remains too small from which to decide whether karyo-
somes (SMC) from all the human autosomes type/phenotype correlations are emerging (with the ex-
except chromosome 5, have now been de- ception of chromosome 15, see [a] below).
scribed, most being derived from the acro- However, most autosomal SMC FISH studies have
centric autosomes. This review summarizes presented data from randomly and nonrandomly ascer-
the results of 168 cases of autosomal SMC tained patient groups, but some have attempted to
excluding those from chromosome 15 where overcome ascertainment bias in their karyotype/
FISH has been used to define the chromo- phenotype correlations by restricting their analyses to
somal origin of the SMC and from which randomly ascertained patients [Blennow et al., 1994;
phenotypic information is available. Al- Brøndum-Nielsen and Mikkelsen, 1995; Gravholt and
though the number of reported cases from Friedrich, 1995; Stetten et al., 1992; Verschraegen-
some of the chromosomal SMC groups re- Spae et al., 1993]. By pooling data from studies with
mains small, the pooled data suggest that very similar or identical design characteristics, it was
the risk of an abnormal phenotype associ- hoped that more meaningful patterns would emerge in
ated with a randomly ascertained de novo the smaller chromosomal categories. The results in-
SMC derived from the acrocentric auto- cluded in this review therefore include, as far as can be
somes (excluding 15s) is ∼7% compared with determined, most of the single and multiple case stud-
∼28% for SMCs derived from the nonacro- ies since 1991 when Callen and colleagues published
centric autosomes. Am. J. Med. Genet. the first in situ hybridization characterization of auto-
75:367–381, 1998. © 1998 Wiley-Liss, Inc. somal SMCs.
For reasons outlined below, SMCs from the following
KEY WORDS: supernumerary marker chro- chromosomal categories have been excluded:
mosomes; phenotype/karyo- (a) Those derived from chromosome 15, which are the
type correlations most commonly encountered SMC observed in man ac-
counting for approximately 30% of all autosomal mark-
ers [Buckton et al., 1985]. FISH and DNA studies have
INTRODUCTION demonstrated a correlation between the genetic con-
tent of inv dup(15)s and abnormal phenotypic effects
In the first paper by Crolla et al. [1998], the clinical [Cheng et al., 1994; Crolla et al., 1995; Flejter et al.,
and molecular results of 26 cases of autosomally de- 1996; Leana-Cox et al., 1994; Mignon et al., 1996; Rob-
rived supernumerary marker chromosomes (SMC) inson et al., 1993a].
were presented in which fluorescence in situ hybridiza- (b) SMCs derived from chromosome 22 associated
tion (FISH), together with other molecular methods, with patient’s presenting with the cat eye syndrome
were utilized to identify both the chromosomal origin, (CES). Recent studies using FISH and quantitative
and whenever possible, the chromosomal composition DNA techniques show that the SMC(22)s observed in
of the marker chromosomes. Despite the accumulation CES individuals contain two additional copies of a criti-
cal region of 22q11 euchromatin [McDermid et al.,
Contract grant sponsor: Action Research; Contract grant spon- 1986; Mears et al., 1994, 1995].
sor: Wellcome Foundation. (c) SMCs which can be identified using conventional
*Correspondence to: Dr John A. Crolla, Wessex Regional Ge- cytogenetic techniques including, for example, isochro-
netics Laboratory, Salisbury District Hospital, Salisbury, Wilts, mosomes of the short arms of chromosome 9, 12 and 18
SP2 8BJ, United Kingdom. E-mail: [email protected] all of which are associated with clearly defined clinical
Received 13 March 1997; Accepted 8 July 1997 phenotypes [Schinzel, 1984].
© 1998 Wiley-Liss, Inc.
368 Crolla

The following sections present tabulated summaries with one not known. Two cases were ascertained ante-
of the phenotypes published in association with auto- natally, one of which, a nonmosaic de novo SMC(3)
somal SMCs subdivided by chromosomal origin, ascer- [Müller-Navia, 1995, case 1] showed normal psychomo-
tainment and parental origin, together with the SMC’s tor development at 20 months; the second case (80% de
morphology and more detailed molecular composition if novo mosaic small ring) was described as a phenotypi-
known. The structural complexity, distribution of chro- cally normal fetus following termination of pregnancy
mosomal origins, and the relationship between chro- [Rauch et al., 1992, case 6]. One of the remaining cases,
mosomal origin and associated phenotypic risks are originally ascertained during a neonatal chromosome
discussed particularly with respect to those cases study [Callen et al., 1991, case 2] had two de novo
which have been randomly ascertained. SMCs, one small ring in 78% cells derived from chro-
mosome 3 and the other (22% cells) which did not hy-
RESULTS AND DISCUSSION bridize to any of the alphoid probes used. This patient
has microcephaly, mild developmental delay, and short
The cases included in this review are tabulated in stature. Case 2 of Crolla et al. [1998] was also referred
Tables I–XIV and the data are summarized below ac- because of short stature and shown to have a de novo
cording to the chromosomal origin of the SMCs. small ring-shaped SMC(3) in 8% cells. A similar de
novo SMC(3) seen in 56% of cells was described in a
SMCs Derived From Chromosome 1 (Table I)
patient with a dysplastic kidney who was otherwise
Of the seven cases reported, five are de novo and in phenotypically and intellectually normal [Rauch et al.,
two the parental origins could not be determined. Six of 1992, case 5]. The final SMC(3) was ascertained in a
the seven were mosaics with SMC(1) cell line frequen- neonate with hypotonia and feeding difficulties but
cies ranging from 15% to 90% and in most cases the with normal psychomotor development at 1 year. The
SMCs are described as small ring-shaped chromo- small ring-shaped SMC(3) was seen in 70% of periph-
somes. The two cases ascertained antenatally were eral blood cells and by reverse painting was shown to
both de novo, one nonmosaic [Crolla et al., 1998, case 1] comprise material from 3cen-q11 [Müller-Navia et al.,
and the other with the SMC(1) in 22–26% of cells [Mi- 1996, case 1].
chalski et al., 1993 case 1]. Postnatal follow-ups at 3
SMCs Derived From Chromosome 4 (Table III)
years and 9 months, respectively, showed normal chil-
dren. Four of the remaining five cases (all mosaics) Six cases with SMC(4) have been reported, all de
were ascertained because of abnormal phenotypes. One novo, two nonmosaics and four mosaics. Two were as-
case [Callen et al., 1990, case 1] with a de novo SMC(1) certained antenatally, one ring-shaped de novo nonmo-
in 25% of cells also had a deleted 18q and a phenotype saic in a fetus found at autopsy to have alobar holo-
consistent with this abnormality, and one case (15% prosencephaly [Blennow et al., 1993, case A], and the
mosaic) had severe mental retardation and multiple other a de novo SMC(4) in 27% cells from which no
congenital abnormalities [Chen et al., 1995]. A child phenotypic information was available following TOP
with developmental delay, general hypotonia, and [Crolla et al., 1992, case 2]. One case ascertained dur-
asymmetrical skull and facial appearance was found to ing a consecutive liveborn survey had a de novo SMC(4)
have a de novo SMC(1) in 20% of cells [Lanphear et al., in 75% of cells and was phenotypically normal at 7
1995]. A further case (70% de novo mosaic) was ascer- years of age [Gravholt and Friedrich, 1995, case
tained because of an abnormal facial appearance but 39997]. A case with a small ring-shaped nonmosaic de
normal intelligence [Callen et al., 1991, case 1]. Fi- novo SMC(4) was ascertained in a child with delayed
nally, a patient ascertained during a routine leukemia motor development, severe mental retardation, and in-
cytogenetic bone marrow investigation was found to sulin-dependent diabetes mellitus [Fang et al., 1995,
have a mosaic SMC(1) in both her marrow and periph- case B]. A further small ring-shaped de novo SMC(4) in
eral blood [Plattner et al., 1993a,b, case 17]. 30% of cells was ascertained because of mental retar-
SMCs Derived From Chromosome 2 (Table II) dation and minor anomalies, and shown molecularly to
have a complex structure comprising both pericentro-
Both SMC(2) reported are described as very small meric and 4q31.1→31.3 sequences [Callen et al., 1992,
ring chromosomes. The first case [Plattner et al., case 19 and reexamined by Fang et al., 1995, case A].
1993a,b, case 26] was ascertained in a child with in- The final case referred with possible fragile X syn-
fantile autistic behavior, had arisen de novo and was drome was confirmed when he was found to carry a
found in 30% of cells examined. The second, [Daniel large FRAXA expansion, with the de novo minute
1994, case 9], was probably a familial marker and was SMC(4) presumably a coincidental finding [Crolla et
present in brother and sister but their parents were not al., 1998, case 3].
examined. The sister had a poor reproductive history
and the marker was first identified in her brother fol- SMCs Derived From Chromosome 6 (Table III)
lowing an anencephalic stillbirth. All other carriers are Both SMC(6)s are described as small rings, are mo-
phenotypically and intellectually normal. saics and de novo in origin. One case was ascertained
SMCs Derived From Chromosome 3 (Table II) because of intrauterine growth retardation and severe
transient neonatal diabetes mellitus (TNDM). Molecu-
Five of the six SMC(3)s reported are mosaics (8–80% lar studies showed that the de novo marker (seen in
cells) with one nonmosaic. Five are de novo in origin, 78% of peripheral blood lymphocytes) was maternally
 Molecular Studies of Autosomal SMC: Review of Literature 369

TABLE I. SMC(1)
Parental origin
SMC Mosaic %
Ascertainment DN MAT PAT NK shape nonmosaic Phenotype/outcome Reference no/case no
PND 1 Min Nonmosaic Normal at 3 years 43/1
PND 1 Ring 22–26 Normal at 9 months 24/1
Developmental 1 Ring 20 Dev. delay; asymetrical skull and facial 22
delay appearance. General hypotonia
Minor 1 Ring 70 Abnormal facial appearance; normal IQ 10/1
anomalies
Deleted 18q 1 Ring 25 Has characteristic anomalies 9/1
phenotype associated with del(18q) syndrome
Failure to 1 Ring 15 Severe mental retardation; multiple 12
thrive congenital abnormalities
Leukemia 1 Ring 90 26 yr male with leukemia; SMC(1) 27 and 28/17
coincident constitutional finding
Abbreviations for Tables I–XIV: min 4 minute marker; bi-sat 4 bi-satellited; sat 4 satellited; ring 4 small ring shaped; sub-m 4 sub-metacentric; NK
4 marker’s shape or phenotype not given; Dev delay 4 developmental delay; MR 4 mental retardation; TNDM 4 transient neonatal diabetes mellitus;
DS 4 Down’s syndrome; TOP 4 termination of pregnancy; PND 4 prenatal diagnosis; IUGR 4 intra-uterine growth retardation. VSD 4 Ventral septal
defect. DMD 4 Duchenne muscular dystrophy; UPD 4 Uniparental disomy; NF1 4 Neurofibromatosis.
Reference list for Tables I–XIV: [1] Aalfs et al.[1996]; [2] Blennow et al. [1992]; [3] Blennow et al. [1993]; [4] Blennow et al. [1994]; [5] Blennow et al. [1995];
[6] Blennow and Tillberg [1996]; [7] Brøndum-Nielsen and Mikkelsen [1995]; [8] Butler et al. [1995]; [9] Callen et al. [1990]; [10] Callen et al. [1991]; [11]
Callen et al. [1992]; [12] Chen et al. [1995]; [13] Cooper et al. [1992]; [14] Crolla et al. [1992]; [15] Daniel et al. [1994]; [16] de Albuquerque Coelho et al.
[1996]; [17] Doneda et al. [1993]; [18] Fang et al. [1995]; [19] Gentile et al. [1993]; [20] Gravholt and Friedrich [1995]; [21] Johnson et al. [1992]; [22]
Lanphear et al. [1995]; [23] Melnyk and Dewald [1994]; [24] Michalski et al. [1993]; [25] Müller-Navia et al. [1995]; [26] Ohashi et al. [1994]; [27] Plattner
et al. [1993a]; [28] Plattner et al. [1993b]; [29] Raimondi et al. [1991]; [30] Rauch et al. [1992]; [31] Rosenberg et al. [1995]; [32] Stetten et al. [1992]; [33]
Sun et al. [1995]; [34] Thangavelu et al. [1994]; [35] van Langen et al. [1996]; [36] Verschraegen-Spae et al. [1993]; [37] Viersbach et al. [1994]; [38]
Voullaire et al. [1993]; [39] Wiktor et al. [1993]; [40] Crolla et al. [1997]; [41] Temple et al. [1995]; [42] Müller-Navia et al. [1996]; [43] Crolla et al. [1998];
[44] Chudoba (pers. com.); [45] Morrison et al. [1997].

derived comprising cen->p21.2 euchromatin but the normal development but who suffered severe meningi-
normal six homologues were paternally isodisomic. The tis as a child. The patient had minor anomalies. The
TNDM resolved spontaneously and at 3 years of age patient’s father who had the SMC(7) in 35% of cells was
the child is showing mild developmental delay. [Crolla said to be normal [Blennow et al., 1993, case B].
et al., 1998, case 5; Temple et al., 1995, case A]. The
second case was a smaller de novo SMC(6) seen in 58% SMCs Derived From Chromosome 8 (Table IV)
of cells and ascertained in a patient with severe mental
retardation. The normal six homologues in this patient Of the seven patients with SMC(8)s, all are de novo
were biparentally inherited [Crolla et al., 1998, case 4]. with five small ring-shaped chromosomes; two are non-
SMC(6)s have also been reported in two other cases mosaics and five mosaics. One case was antenatally
[Callen et al., 1991, case 3; Aalfs et al., 1996), in karyo- ascertained and was one of twins, the other twin being
types containing SMCs derived from other autosomes cytogenetically normal. At 5 years of age, the affected
and these cases are reviewed in the context of Tables twin showed autistic behavior, moderate mental retar-
XII—XIV. dation, and severe speech delay. This patient’s ring-
shaped marker was originally seen in 31% of amnio-
SMCs Derived From Chromosome 7 (Table III) cytes but in 95% of peripheral blood cells [Plattner et
One case of a paternally derived nonmosaic small al., 1993a,b, case 24]. One patient ascertained during a
ring-shaped SMC(7) was reported in a patient with neonatal cytogenetic survey with the marker in 50–

TABLE II. SMC(2) and SMC(3)

Parental origin
SMC Mosaic % Reference no/
Ascertainment DN MAT PAT NK shape nonmosaic Phenotype/outcome case no
SMC(2)
?Autistic 1 Ring 30 Infantile autism. Physically normal at 27 and 28/26
7.5yr + behavioral problems
Previous NTD 1 Ring Nonmosaic Normal male aged 30 15/9
SMC(3)
PND 1 Min Nonmosaic Normal at 20 months 25/1
PND 1 NK 80 TOP: Phenotypically normal fetus 30/6
Neonatal study 1 Ring 78 4 SMC(3) Microcephaly; mild dev delay, short 10/2
22 4 SMC(NK) stature
Short stature, 1 Ring 8 Short stature 43/2
?Turners
syndrome
Meningitis(?) 1 Ring 56 Dysplastic kidney 30/5
Hypotonia and 1 Ring 70 Normal psychomotor development at 42/1
feeding difficulties 12 months.
For abbreviation definitions and reference numbers see Table I.
370 Crolla

TABLE III. SMC(4), SMC(6), and SMC(7)

Parental origin
SMC Mosaic % Reference no/
Ascertainment DN MAT PAT NK shape nonmosaic Phenotype/outcome case no
SMC(4)
PND 1 Ring Nonmosaic TOP. Alobar holoprosencephaly 3/A
PND 1 Min 27 TOP. No phenotype given 14/2
Consecutive 1 NK 75 Normal at 7 years 20/39997
liveborn survey
Delayed motor 1 Ring Nonmosaic Severe MR; insulin-dependent 18/B
development diabetes mellitus
MR; minor 1 Ring 30 As in ascertainment 11/19 and 18/A
facial anomalies
Severe mental 1 Min 16 Has fragile X (FRAXA) 43/3
retardation and fits
SMC(6)a
IUGR, TNDM 1 Ring 74 TNDM. Otherwise normal 43/5;41/A
Severe mental 1 Ring 58 Severe mental retardation, fits 43/4
retardation scoliosis and facial anomalies
SMC(7)
Not given 1 father Ring Nonmosaic Normal development but ‘‘low 3B
35% performance.’’ Abnormal facial
appearance. Meningitis as a
child.
a
SMC(6) also seen in 6 + X Callen et al. [1991] case 3, see Table XIV. 6 + 9 Aalfs et al. [1996], see Table XII.
For abbreviation definitions and reference numbers see Table I.

67% of cells was normal at 7 years [Gravholt and Frie- delay was a de novo 36% mosaic, and on examination
drich, 1995, case 38587]. Four cases were reported to had pronounced psychomotor retardation but no other
have developmental delay in association with a num- dysmorphic features [Blennow et al., 1993, case D]. The
ber of other abnormalities. The first with hypotonia, remaining case had a SMC(9) in 70% of cells and was
psychomotor retardation, and minor facial anomalies ascertained because of developmental delay and minor
was nonmosaic [Melryk and Dewald, 1994]; the second, anomalies. However, this patient also had a low pro-
a 50% mosaic had skeletal abnormalities [Daniel et al., portion of cells with trisomy 9 [Raimondi et al., 1991].
1994, case 7]; the third with the marker in 40–72% of
SMCs Derived From Chromosome 10 (Table V)
cells examined from different tissues had an abnormal
facial appearance in addition to developmental delay One case with a SMC(10) in 66% of cells has been
[Blennow et al., 1993, case C], and the fourth, a non- reported. The patient presented with unilateral cleft
mosaic was seen in a patient with patent ductus arte- lip and palate and mild mental retardation. The paren-
riosus and minor facial anomalies [Ohashi et al., 1994]. tal origin of the marker was not determined [Blennow
Microdissection of this SMC(8) demonstrated a com- and Tillberg, 1996]. Additional molecular tests showed
plex composition including two copies of the 8p subtelo- that the small ring-shaped SMC comprised proximal
meric repeat and a functional centromere despite the short arm and centromeric sequences only.
lack of alphoid sequences at the primary constriction. A
small SMC(8) found in 40% of peripheral blood meta- SMCs Derived From Chromosome 11 (Table V)
phases was found in a child with minor facial anoma- One case with a de novo mosaic SMC(11) has been
lies, absence of the clitoris, and bilateral 5th finger described in a patient with mental retardation and ab-
clinodactyly. At 4 months, several anomalies consistent normal facial appearance [Rauch et al., 1992, case 7].
with trisomy 8 mosaicism were observed [Butler et al.,
1995]. SMCs Derived From Chromosome 12 (Table V)

SMCs Derived From Chromosome 9 (Table IV) Three of the four reported SMC(12)s are de novo mo-
saics; two were ascertained antenatally and in one the
Six SMC(9)s have been reported, two de novo, three outcome was normal [Crolla et al., 1992, case 3] but not
maternal and, one where the parental origin was not described in the other [Callen et al., 1992, case 4]. The
determined. One case was a nonmosaic, with the re- third case was ascertained because of developmental
maining cases presenting with between 30% and 70% delay and had severe mental retardation and bilateral
of cells containing the marker. Four SMC(9)s were as- vesico-ureteric reflux [Callen et al., 1992, case 5]. The
certained antenatally, one of which was a de novo 40% fourth was a mosaic ascertained originally in a pheno-
mosaic which was normal at follow-up [Callen et al., typically normal neonatal death and found in 50% of
1990, case 2]. The remaining three were maternally the mother’s blood cells [Crolla et al., 1998, case 6].
transmitted (one nonmosaic and two mosaics) and in
SMCs Derived From Either Chromosomes 13 or
the two cases where follow-up information is available,
21 (Table VI)
the outcomes were normal [Callen et al., 1992, case 17;
Crolla et al., 1992, case 1]. One of the postnatally de- Of the 21 SMC(13/21) included in this review, 11
tected SMC(9)s ascertained because of developmental were de novo, three maternal, two paternal, and the
 Molecular Studies of Autosomal SMC: Review of Literature 371

TABLE IV. SMC(8) and SMC(9)

Parental origin
SMC Mosaic % Reference no/
Ascertainment DN MAT PAT NK shape nonmosaic Phenotype/outcome case no
SMC(8)a
PND 1 Ring 31–95 Autistic behavior, moderate MR, severe 27 and 28/24
speech delay at 5 yrs
Consecutive 1 NK 50–67 Normal at 7 yrs 20/38587
liveborn survey
Dev. delay 1 Ring Nonmosaic Hypotonia, minor facial abnormalities, 23
phychomotor retardation
Dev. delay 1 Ring 50 Mental retardation, abnormal facial 15/7
appearance, skeletal abnormalities,
clawing of toes
Dev. delay 1 Ring 40–72 Abnormal facial appearance, motor 3/C
retardation
Heart defect 1 Submeta Nonmosaic Developmental delay; mild dysmorphic 26
features; patent ductus arteriosus
Minor neonatal 1 Ring 40 ?Trisomy 8 mosaicism phenotype 8
abnormalities
SMC(9)b
PND 1 Min 40 Normal 9/2
PND 1 Ring Nonmosaic Normal 11/17
PND 1 Min 80 Normal 14/1
PND 1 Submeta 30 Not known 25/3
Dev. delay 1 Ring 36 Psychomotor retardation; no 3/D
dysmorphic facial features
Dev. delay and 1 NK 70 Micrograthia; one leg reduced in length; 29
facial anomalies additional ribs. NB has trisomy
9 mosaic cell line
a
One case of SMC(8) also seen in case with multiple markers [Plattner et al., 1993, case 22], see Table XII.
b
One further case with SMC(9) in karyotype with both SMC 9 + 6 Aalfs et al. [1996], see Table XII.
For abbreviation definitions and reference numbers see Table I.

origin of the remaining five was undetermined. Fifteen 1993a,b, case 10], and in one case the fetus, following
(71%) were nonmosaic. Twelve SMC(13/21) were ascer- TOP, had a VSD, spina bifida, and bilateral cataracts
tained antenatally and of the three nonmosaic familial [Brøndum-Nielsen and Mikkelsen, 1995, case 3]. A de
cases, the one maternal [Blennow et al., 1995, case 16] novo 40% mosaic mosaic SMC(13/21) ascertained dur-
and two paternal [Brøndum-Nielson and Mikkelsen, ing a consecutive liveborn survey was phenotypically
1995, cases 1 and 2] were transmitted without pheno- normal [Gravholt and Friedrich, 1995 case 42618].
typic effect. All five individuals with nonmosaic de novo Overall, therefore, 1 of the 13 (7.1%) randomly ascer-
SMC(13/21) were also normal at postnatal follow-up tained SMC(13/21) had a severely abnormal pheno-
[Crolla et al., 1992, case 6; 1998, case 9; Blennow et al., type. Of the nine remaining cases ascertained postna-
1995, case 16; Callen et al., 1992, case 9; 1991, case 6]. tally, five were phenotypically normal and were exam-
Of the four de novo mosaic antenatally ascertained ined initially for a variety of reasons including poor
SMC(13/21], two were normal [Crolla et al., 1998, cases reproductive history [Blennow et al., 1995, case 14]
8 and 12]; one showed marked facial anomalies but previous children with neural tube defects [Crolla et
normal development at follow-up [Plattner et al., al., 1998, case 7; Viersbach et al., 1994, case 1], a

TABLE V. SMC(10), SMC(11), and SMC(12)

Parental origin
SMC Mosaic % Reference no/
Ascertainment DN MAT PAT NK shape nonmosaic Phenotype/outcome case no
SMC(10)a
Abnormal 1 Ring 66 Unilateral cleft lip and palate. Mild MR 6
facies, mild MR
SMC(11)
Mental 1 NK 50 Mental retardation; dysmorphic facies 30/7
retardation
SMC(12)
PND 1 Min 38 Normal 14/3
PND 1 Ring 30 Not given 10/4
Dev. delay 1 Ring 20 Severe MR; bilateral vesico-ureteric 10/5
reflux
Poor reproductive 1 Min 50 Normal 43/6
history
a
A patient with a SMC(10) in a multiple marker karyotype has been reported [Voullaire et al., 1993], see Table XII.
For abbreviation definitions and reference numbers see Table I.
372 Crolla

family history of Down syndrome [Crolla et al., 1998, novo and the one nonmosaic bisatellited marker was
case 11], and a phenotypically normal stillbirth [Crolla reported in a patient with primary amenorrhoea
et al., 1998, case 10]. The three cases ascertained with [Callen et al., 1992, case 10]; two mosaic de novo
abnormal phenotypes were (1) a nonmosaic (parental SMC(14)s were ascertained in patients with develop-
origin not known) patient with polydipsia, small geni- mental delay [Crolla et al., 1992, case 7; 1998, case 13]
tals and a gynaecoid habitus [Daniel et al., 1994, case and the remaining de novo case was coincidentally ob-
2]; (2) a child with marked developmental delay with a served in a patient with trisomy 21 [Callen et al., 1991,
maternally inherited nonmosaic marker [Crolla et al., case 7]. The two maternally transmitted nonmosaic
1992, case 4], and (3) a de novo mosaic (10%) with mild markers were seen in patients with delayed puberty
facial anomalies and mild mental retardation [Crolla et and infertility, respectively [Blennow et al., 1995, case
al., 1992, case 5].
19; Gentile et al., 1993, case 1]. Two of the three pa-
SMCs Derived From Chromosome 14 (Table VII) ternally transmitted cases were in patients with DMD
and multiple malformations but normal intellectual
Out of 25 SMC(14)s included in this review, 12 were function, respectively, and in both cases the fathers
de novo, six maternal, four paternal, and in three the were normal [Callen et al., 1992, cases 12 and 14]. The
parental origin was not determined; 14 of the 25 (58%) third paternally transmitted SMC(14) was ascertained
were nonmosaic. Thirteen cases were randomly ascer- in a child with developmental delay and ? fragile X
tained, nine antenatally and four during a consecutive syndrome. His father, however, is normal [Crolla et al.,
newborn survey. Four de novo mosaic antenatal 1998, case 18]. The three remaining nonmosaic cases in
SMC(14)s were normal at postnatal follow-up [Callen which parental origin could not be determined were
et al., 1992, case 11; Crolla et al., 1992, case 7; 1997b, seen in patients with mental retardation [Crolla et al.,
case 14; Stetten et al., 1992, case 1] as were the two 1998, case 17], poor reproductive history [Crolla et al.,
maternally transmitted nonmosaics [Blennow et al., 1998, case 16] and in a preamniocentesis cytogenetic
1995, cases 17 and 18]. One fetus with a nonmosaic de
check [Crolla et al., 1998, case 15], respectively, the
novo SMC(14) was phenotypically normal following
latter two patients being intellectually and physically
TOP [Callen et al., 1992, case 13] and the outcomes in
a further two cases were not recorded [Callen et al., normal. Overall, therefore, SMC(14)s were associated
1992, case 15; Crolla et al., 1992, case 8]. All four con- with developmental delay/mental retardation in 4/25
secutive newborn cases were normal when followed-up cases (16.0%), and with the same frequency among pa-
at ages ranging from 6 to 21 years [Gravholt and Frie- tients ascertained with fertility or poor reproduction
drich, 1995, cases 40, 28239, 32830, 41934]. Of the 12 problems. Ascertainment in the four remaining cases
other postnatally identified SMC(14)s, four were de were most probably coincidental.

TABLE VI. SMC(13/21)

Parental origin
Mosaic % Reference no/
Ascertainment DN MAT PAT NK SMC shape nonmosaic Phenotype/outcome case no
PND 5 Bisat Nonmosaic All normal 43/9
NK Nonmosaic 5/16
Ring Nonmosaic 10/6
Bisat Nonmosaic 11/9
Sats Nonmosaic 14/6
PND 4 Bisat 46 Minor facial anomalies, normal 27 and 28/10
development
Ring 50 TOP, VSD, spina bifida, bilateral 7/3
cataracts
Min 60 Normal 43/8
Min 50 Normal 43/12
PND 1 NK Nonmosaic Normal 5/15
PND 2 Bisat Nonmosaic Both normal 7/1
Bisat Nonmosaic 7/2
Consecutive 1 NK 40 Normal 20/42618
liveborn survey
Mild MR 1 Bisat 10 Mild MR, minor facial anomalies 14/5
Family history of DS 1 Bisat Nonmosaic Normal 43/11
Dev. and speech delay 1 Bisat Nonmosaic Developmental & speech delay 14/4
Abnormal 1 Bisat Nonmosaic Polydipsia; small genitals and 15/2
phenotype gynaecoid habitus
History of NTD 1 Bisat Nonmosaic Normal 43/7
History of NTD 1 2 rings Nonmosaic Normal 37/1
Stillbirth 1 Bisat Nonmosaic Phenotypically normal stillbirth 43/10
Poor reproductive 1 NK Nonmosaic Normal 5/14
history
For abbreviation definitions and reference numbers see Table I.
 Molecular Studies of Autosomal SMC: Review of Literature 373

TABLE VII. SMC(14)

Parental origin
Mosaic % Reference no/
Ascertainment DN MAT PAT NK SMC shape nonmosaic Phenotype/outcome case no
PND 1 Bisat Nonmosaic Normal fetus at autopsy 11/13
1 Bisat Nonmosaic Outcome not recorded 11/15
PND 2 Bisat Nonmosaic Both normal 5/17
Sats Nonmosaic 5/18
PND 4 Bisat; min 32–88 All normal 11/11; 43/14
Sats; min 32/1; 34/1
1 Min 60 Outcome not known 14/8
Newborn survey 1 NK Nonmosaic Normal 20/40
Newborn survey 1 NK Nonmosaic Normal 20/32830
Newborn survey 1 NK 60 Normal 20/28239
Newborn survey 1 NK 60 Normal 20/41934
Primary 1 Bisat Nonmosaic Normal 11/10
Amenorrhoea
Down syndrome 1 Ring 45 Down syndrome 10/7
Dev. delay 1 Min 13 Unusual facies; developmental delay 43/13
?Noonans 1 Min 90 Wide set eyes, bifid tongue, developmental 14/7
delay, hypermobile joints
Delayed puberty 1 Sats Nonmosaic Delayed puberty 5/19
Infertility 1 Bisat Nonmosaic Severe oligoasthenospermia 19/1
DMD 1 Bisat Nonmosaic DMD. Father and son intellectually normal 11/12
Heart and other 1 Sats % NK Multiple malformation in proband. Father 11/14
malformations and proband intellectually normal
Language delay 1 Bisat Nonmosaic Severe language problems; normal 43/18
?fragile X cognatively and mentally
Mental retardation 1 Bisat Nonmosaic Mental retardation 43/17
Poor reproductive 1 Bisat Nonmosaic Normal 43/16
history
Pre-amnio check 1 Min Nonmosaic Normal 43/15
For abbreviation definitions and reference numbers see Table I.

SMCs Derived From Either Chromosome 14 or of the 5 was nonmosaic. Three cases were ascertained
22 (Table VIII) antenatally, one de novo 90% mosaic which was normal
at 17 month postnatal follow-up [Crolla et al., 1992,
A total of 12 cases of SMC(14/22) are reviewed in
case 9] while the remaining two were terminated and
Table VIII, of which seven were de novo, two maternal,
in both cases no follow-up information was available
one paternal and in two the parental origin was not
determined. Seven of the 12 (58%) were nonmosaic, 10 [Crolla et al., 1998, case 20; Callen et al., 1991, case 8].
of which were ascertained antenatally. Of these, two de A postnatal maternally transmitted mosaic SMC(16)
novo nonmosaics [Plattner et al., 1993a,b, case 27; was ascertained in a child with microcephaly, severe
Daniel et al., 1994 case 1], 3 of the 4 de novo mosaics mental retardation, severe spacicity and minor facial
[Plattner et al., 1993a,b case 8; Brøndum-Nielsen and anomalies [Callen et al., 1990 case 3] while the mother
Mikkelsen, 1995, cases 4, 7] and a maternally trans- is normal. The remaining case, a de novo, nonmosaic
mitted nonmosaic [Brøndum-Nielsen and Mikkelsen, SMC(16) was ascertained because of mild mental
1995, case 5] were all normal at follow-up. Following handicap together with a teenage onset psychotic ill-
TOP, a fetus with a de novo nonmosaic marker was ness [Crolla et al., 1998, case 21].
reported at autopsy to have low-set ears, a short left
thumb but no major system congenital abnormalities SMCs Derived From Chromosome 17 (Table IX)
[Crolla et al., 1998, case 19]. Follow-up information for
the remaining two antenatally ascertained cases was Three cases have been reported, one an antenatally
not available. One mosaic case with the SMC(14/22) in ascertained de novo mosaic which at 2 years of age was
60% of cells also had trisomy 21 and the pregnancy was described as slightly mentally retarded [Brøndum-
terminated [Plattner et al., 1993a,b, case 23]. One of Nielsen and Mikkelsen, 1995, case 11]. The second
the two postnatally ascertained cases was a nonmosaic case, also a de novo mosaic, was ascertained in a pa-
(parental origin not known) in a man with oligospermia tient with obesity, short stature and mental retarda-
[Blennow et al., 1995, case 20] and the other case had tion [Rosenberg et al., 1995]. The third, a de novo mo-
Rett syndrome together with severe speech and devel- saic small ring(17), was shown to be positive with the
opmental delay [Plattner et al., 1993a,b, case 9]. 17 centromere probe as well as the D17S29 (Smith Ma-
SMCs Derived From Chromosome 16 (Table IX) genis) probe but negative with the D17S379 (Miller-
Dieker) cosmid. The patient was ascertained at 2 years
Five SMC(16)s have been reported, three de novo, with minor facial anomalies and mild social and motor
one maternal, and one paternal in origin, and only one delay [Morrison et al., 1997].
374 Crolla

TABLE VIII. SMC(14/22)

Parental origin
Mosaic % Reference no/
Ascertainment DN MAT PAT NK SMC shape nonmosaic Phenotype/outcome case no
PND 1 Bisat Nonmosaic Normal 27 and 28/27
PND 1 Bisat Nonmosaic Normal 15/1
PND 1 Bisat Nonmosaic TOP; low-set ears; short left thumb 43/19
PND 1 Bisat 45 Normal 27 and 28/8
PND 1 Min 85 Normal 7/4
PND 1 Min 50 Normal 7/7
PND 1 Min 50 TOP; no autopsy 7/6
PND 1 Bisat Nonmosaic NK 27 and 28/11
PND 1 Bisat Nonmosaic Normal 7/5
PND 1 Ring 60 TOP. NB Also with +21 27 and 28/23
Infertility 1 Bisat Nonmosaic Oligospermia 5/20
Postnatal 1 Bisat Nonmosaic Rett syndrome; speech and 27 and 28/9
developmental delay
For abbreviation definitions and reference numbers see Table I.

SMCs Derived From Chromosome 18 (Table IX) SMCs Derived From Chromosome 19 (Table X)

Two of the four cases were antenatally ascertained. Of the seven SMC(19) reported to date, four were de
One was a de novo mosaic which following TOP was novo, one maternal and in two the parental origin was
found to have an abnormal left kidney [Brøndum-
not known. Four of the seven were nonmosaic. Six
Nielsen and Mikkelsen, 1995, case 12] and the other,
cases were ascertained antenatally, three of which
also a de novo mosaic was phenotypically normal at
birth. The SMC(18) from this latter case was microdis- were de novo mosaics and normal at follow-up [Blen-
sected and reverse painting indicated that the marker now et al., 1995, case 5; Michalski et al., 1993, case 2;
comprised the whole of the short arm of chromosome 18 Crolla et al., 1998, case 22]. One de novo mosaic at
[Muller-Navia et al., 1995, case 2]. The two postnatally follow-up had a large head with frontal bossing, hypo-
ascertained cases were both de novo mosaics and ob- tonia and developmental delay [Crolla et al., 1992, case
served in (a) a case with what was thought to be famil- 11]. One maternally transmitted mosaic was normal at
ial short stature [Callen et al., 1991, case 9] and (b) in follow-up [Crolla et al., 1998, case 23] and the only
a case with multiple malformations including, VSD, nonmosaic SMC(19) had no phenotypic information [de
inperforate anus, and dysplastic kidney [Rauch et al., Albuquerque et al., 1996, case 4]. One mosaic (origin
1992, case 4]. Interestingly, this marker was positive not known) SMC[19] was ascertained as a severely
with a whole chromosome 18 painting probe but nega- floppy baby with failure to thrive [Crolla et al., 1992,
tive with the D18Z1 18 centromere-specific probe. case 10].

TABLE IX. SMC(16), SMC(17), and SMC(18)

Parental origin
Mosaic % Reference no/
Ascertainment DN MAT PAT NK SMC shape nonmosaic Phenotype/outcome case no
SMC(16)
PND 1 Min 90 Normal at 17 months 14/9
PND 1 Min 75 TOP phenotype not known 43/20
PND 1 Ring 50 TOP; fetus not examined 10/8
Dysmorphic 1 Min 75 Microcephaly, minor facial anomalies 9/3
severe MR, severe spasticity
Mild dev. delay 1 Min Nonmosaic Mild mental handicap and psychiatric 43/21
and retardation illness coming on in teens
SMC(17)
PND 1 Ring 75 Slightly retarded at 2 years 7/11
Abnormal 1 Min 94 MR, obesity, short stature 31
phenotype
Abnormal 1 Ring 13 Minor facial anomalies; mild motor 45
phenotype & social delay at 2 years
SMC(18)
PND 1 Ring 28 TOP; abnormal left kidney 7/12
PND 1 Min 66 Phenotypically normal at birth 25/2
Short stature 1 Ring 85 Intellectually normal ? familial short 10/9
(11 yrs.) stature
Multiple 1 Min 64 VSD, imperforate anus, dysplastic 30/4
malformations kidney. D18Z1 negative; wcp18
positive
For abbreviation definitions and reference numbers see Table I.
 Molecular Studies of Autosomal SMC: Review of Literature 375

TABLE X. SMC(19), SMC(20), and SMC(21)

Parental origin
SMC Mosaic % Reference no/
Ascertainment DN MAT PAT NK shape nonmosaic Phenotype/outcome case no
SMC(19)
PND 1 Ring 17 Normal 5/5
PND 1 Ring 42 Normal 24/2
PND 1 Min 82 Normal 43/22
PND 1 Ring 60 Large head, frontal bossing; hypotonia 14/11a
epicanthic folds; dev. delay
PND 1 Min 50 Normal 43/23
PND 1 Ring Nonmosaic Not known 16/4
Floppy baby 1 Min 50 Failure to thrive; severe floppiness 14/10
SMC(20)
Dev. delay 1 Min 48 Psychomotor retardation; no 3/E
minor anomalies
Dev. delay 1 Ring 60 Mild dysmorphic features; dev. delay; ring 20p 35
syndrome
Psychomotor 1 Min 57 Moderate psychomotor retardation and 43/24
retardation minor facial anomalies
Facial anomalies 1 Ring Nonmosaic Abnormal facies. Normal intellectually; 10/10
(2 yrs) clinodactly fingers 2,3,4. Transpalmar
crease
Growth 1 Min 44 Hyperactive; normal IQ; slight facial 44
retardation; facial abnormality; has UPD(20)mat
anomalies
Perinatal death 1 Min Nonmosaic 92,XXXX + 2mar(20). Features of 21
(x2mar) Tetraploidy.
SMC(21)
PND 1 Ring 64 TOP no follow up allowed 43/25
Abnormal facies 1 Ring 20 Anti-mongoloid slant 30/9
Dev. delay 1 Ring 44 Dev. delay, short stature, autism 33
DS features 1 NK 50 Signs of Down syndrome 30/8
a
Has additional SMC lacking alphoid repeats, see Table XIII.
For abbreviation definitions and reference numbers see Table I.

SMCs Derived From Chromosome 20 (Table X) case 9] developmental delay, short stature and autism
[Sun et al., 1995] and some signs of Down syndrome
All five SMC(20)s included were ascertained postna- [Rauch et al., 1992, case 8].
tally, four de novo and one maternal in origin and two
of the five were nonmosaic. All five cases were pheno- SMCs Derived From Chromosome 22 (Table XI)
typically abnormal. Three de novo mosaic cases were
ascertained because of developmental delay and/or psy- The studies quoted in Table XI exclude those which
chomotor retardation [Blennow et al., 1993, case E; van have focused specifically on patients with SMC(22) in
Langen et al., 1996; Crolla et al., 1998, case 24] and a association with the cat eye syndrome (CES). Those
de novo nonmosaic SMC(20) was found in a child with included have been identified during systematic stud-
abnormal facial appearance and clinodactyly of the 2nd, ies designed primarily to determine the chromosomal
3rd and 4th fingers but with a normal intellect [Callen origins of all autosomal SMCs. Using these criteria a
et al., 1991, case 10]. A small de novo mosaic (44%) total of 18 SMC(22)s are reviewed, 10 de novo, four
heterochromatic SMC(20) was found in a child ascer- maternal, two paternal and in two the parental origin
tained with growth retardation and minor facial was not determined. One of the 18 cases was reported
anomalies. At 4 years the child’s IQ and motor neuro- to be a mosaic; 12 cases were randomly ascertained,
logical development were normal. Molecular studies eight during antenatal diagnosis and four in the course
showed maternal uniparental heterodisomy of the nor- of a consecutive newborn survey. Six of the eight pre-
mal chromosome 20 homologues (Chudoba, personal natally ascertained cases (three de novo and three fa-
communication). The one maternally transmitted milial) were normal at postnatal follow-up, [Blennow et
SMC(20) was ascertained as a multiply malformed al., 1995, cases 22 and 23; Stetten et al., 1992, case 2;
perinatal death with a tetraploid karyotype in addition Doneda et al., 1993; Crolla et al., 1997, cases 5 and 6];
to the SMC(20) mat [Johnson et al., 1992]. one de novo case was a phenotypically normal fetus
following TOP [Crolla et al., 1997, case 3] and one de
SMCs Derived From Chromosome 21 (Table X) novo SMC(22) was seen in a terminated fetus which at
autopsy had an inperforate anus, preauricular tags,
The one antenatally ascertained mosaic SMC(21) re- and right cystic kidney [Verschraegen-Spae et al.,
sulted in TOP without follow-up information [Crolla et 1993, case 2]. Three of the four randomly ascertained
al., 1998, case 25]. Three de novo mosaics were ascer- liveborns with SMC(22), one de novo and two familial,
tained in patients with abnormal phenotypes including were normal at follow-up [Gravholt and Friedrich,
antimongoloid palpebral fissures [Rauch et al., 1992, 1995, cases 36319, 39906 and 45539] while one patient
376 Crolla

with a de novo SMC(22) was described as having minor tient was ascertained because of delayed speech but
anomalies but normal intellect [Gravholt and Fried- normal motor development at 4 years [Voullaire et al.,
rich, 1995, case 531]. Three of the six SMC(22)s ob- 1993]. A further case with two morphologically distinct
served in patients ascertained with abnormal pheno- de novo SMCs derived from chromosome 13 was ascer-
types had diagnoses consistent with CES. All three tained in a child with minor anomalies, mental retar-
SMC(22)s were nonmosaics, two were de novo [Callen dation and conductive hearing loss on the left side
et al., 1992, case 16; Crolla et al., 1997, case 1] and the [Cooper et al., 1992]. Two de novo mosaic markers,
origin of the third was not determined [Daniel et al., from chromosomes 6 and 9, respectively, were seen in a
1994, case 13]. One paternally transmitted case was patient with mild developmental delay and abnormal
ascertained because of severe hypotonia and develop- facial features [Aalfs et al., 1996]. A further patient
mental delay in the index case while the carrier father with a de novo mosaic SMC(3) together with a SMC
was normal [Crolla et al., 1997, case 2], one was coin- without detectable alphoid sequences was seen in a
cidentally ascertained in a family segregating a bal- child presenting with microcephaly and mild develop-
anced constitutional translocation (11;22) [Crolla et al., mental delay [Callen et al., 1991, case 2]. One case
1997, case 4] and one de novo nonmosaic case was as- ascertained postnatally with two SMC from 18 and 13/
certained with thymic and adrenal hypoplasia, and en- 21 has also been reported and was ascertained at 20
larged liver [Blennow et al., 1995, case 21]. months because of multiple congenital abnormalities
SMCs Derived From Two or More Chromosomes including cardiac, skeletal, and genital-urinary malfor-
in the Same Karyotype (Table XII) mations. However, at 11 months, he was developmen-
tally normal [Plattner et al., 1993a,b, case 20]. Two
Seven cases are reviewed in which either two or more ring-shaped SMCs, one an SMC(12) and the other an
SMCs of autosomal origin have been detected in the SMC(13/21), were originally ascertained in a child with
same karyotype or by FISH were found to have mul- multiple anomalies. The parental karyotypes were nor-
tiple chromosomal origins. In one case a paternally mal and the proband transmitted both ring-like mark-
transmitted SMC(13/21) was found in a patient with ers to a daughter also born with multiple congenital
two morphologically distinct de novo SMC(10) chromo- abnormalities who died of an intraventricular hemor-
somes, one a deleted 10q and the second a r(10) com- rhage at 13 days of age [Plattner et al., 1993a,b, case
posed of the remaining portion of distal 10q. This pa- 21a+b]. An apparent centric fusion SMC involving cen-

TABLE XI. SMC(22)

Parental origin
Mosaic % Reference no/
Ascertainment DN MAT PAT NK nonmosaic Phenotype/outcome case no
PND 1b Nonmosaic Normal 5/22
PND 1b Nonmosaic Normal 5/23
PND 1b 76 Normal 32/2
PND 1a Nonmosaic Normal. Slight hearing loss right side, mosaic 40/5
postnatally
PND 1b Nonmosaic TOP. Normal phenotype at autopsy 40/3
PND 1b Nonmosaic TOP. Preauricular tags, right cystic kidney 36/2
inperforate anus
PND 1b Nonmosaic Normal 17
PND 1b Nonmosaic Normal 40/6
Consecutive 1b Nonmosaic Minor facial anomalies 20/531
liveborn survey
Consecutive 1a Nonmosaic Normal 20/36319
liveborn survey
Consecutive 1a Nonmosaic Normal 20/39906
liveborn survey
Consecutive 1a Nonmosaic Normal 20/45539
liveborn survey
Abnormal 1b Nonmosaic Enlarged liver fibrosis and cirrhosis; thymic and 5/21
phenotype adrenal hypoplasia
Multiple 1b Nonmosaic Cat eye syndrome 11/16
malformations
Parent of t(11;22) 1a Nonmosaic Normal 40/4
carrier
Multiple 1b Nonmosaic Signs of cat eye syndrome except colobomata 15/13
malformations
Multiple 1b Nonmosaic Signs of cat eye syndrome except colobomata 40/1
malformations
Severe hypotonia/ 1b Nonmosaic Severe hypotonia, dev. delay and generalised 40/2
dev. delay siezures
a
Monocentric.
b
Dicentric.
For abbreviation definitions and reference numbers see Table I.
 Molecular Studies of Autosomal SMC: Review of Literature 377

tromeres 13/21 and 14 was transmitted without phe- by Rauch et al. [1994] was reported to be a small r(18)
notypic effect from mother to a daughter who was as- which was identified using a whole chromosome 18
certained because of a poor reproductive history [Crolla paint but was negative with the D18Z1 alphoid repeat
et al., 1997b, case 26]. probe (see Table IX).
SMCs in Which the Chromosomal Origin Could Autosomal SMCs Seen in Association With
Not Be Determined Using Alphoid Repeats Markers Derived From the X Chromosome
(Table XII) (Table XIV)
The chromosomal origins of eight reported SMCs One of the four cases is a complex de novo nonmosaic
could not be determined using a panel of alphoid cen- SMC composed of sequences from chromosomes X, 5,
tromere-specific probes, presumably because they and 7 characterized by reverse painting and ascer-
lacked detectable arrays of pericentromeric alpha sat- tained in a patient with severe mental and growth re-
ellite DNA, or were composed of other classes of repeti- tardation and beaked nose, shrill cry, and microgna-
tive DNA not detectable with the probes used in the thia [Blennow et al., 1992]. The remaining three cases
majority of investigations. Three of these SMCs were were de novo mosaics containing supernumerary r(X)
detected antenatally, one being a maternally transmit- chromosomes (i.e., in addition to apparently normal sex
ted mosaic marker in which both the mother and child chromosome complements) together with SMCs of au-
were normal [Daniel et al., 1994, case 6] and two de tosomal origin. Two cases ascertained with develop-
novo markers, one nonmosaic in which the fetus was mental delay had markers derived from chromosomes
phenotypically normal at autopsy [Crolla et al., 1992, X+6 [Callen et al., 1991, case 3) and X+17 [Wiktor et
case 15] and the other a mosaic with two SMCs, one of al., 1993], respectively. The remaining case had SMCs
which was derived from chromosome 19 (see Table X), derived from 4 different chromosomes (X,8,14/22 and
and at post natal follow up was found to have a large 15) and this patient had presented with multiple con-
head, hypotonia, and developmental delay [Crolla et genital abnormalities [Plattner et al., 1993a,b, case 22].
al., 1992, case 11]. Four cases were ascertained during
the course of population cytogenetic surveys, two in Distribution of SMC by Chromosomal Origin
normal individuals [Gravholt and Friedrich, 1995, case and Morphology
27883; Callen et al., 1992, case 20], one in a patient
with a maternally transmitted mosaic marker who had The chromosomal origins of the 168 SMC cases pre-
psychomotor retardation and abnormal facial appear- sented in Tables I–XIV show an expected excess from
ance [Gravholt and Friedrich, 1995, case 27621] and acrocentric autosomes despite the exclusion of
the fourth in a patient with microcephaly and mild de- SMC(15)s. Overall, 81/168 (∼48%) were derived from
velopmental delay, although in this case the karyotype either chromosomes 13 or 21 (centromeres indistin-
also contained a SMC(3) [Callen et al., 1991, case 2 (see guishable using alphoid repeat probes) 14 or 22. Of
Table II). The final case was seen in a patient with these 53/81 (65%) had satellites at one or both ends,
normal intellectual capacity but abnormal facial ap- eight were small rings (∼10%) and 13 (16%) were de-
pearance [Daniel et al., 1994, case 8]. Case 4 reported scribed as minutes. The morphology of the remainder

TABLE XII. SMC (Multiple)

Parental origin
Mosaic % Reference no./
Ascertainment Chromosome(s) DN MAT PAT NK SMC shape nonmosaic Phenotype/outcome case no
Dysmorphic 13 + 13 1 Rings Nonmosaic Dysmorphic facial features. 13
features MR. Conductive hearing
loss on left side
Neonatal 3 + NK 1 Rings 78 + 22 Microcephaly, mild dev. 10/2a
chromosome delay
survey
Dev. delay 6+9 1 Rings 44 + 39 Mild dev. delay and 1
dysmorphic features
Postnatal 13/21 + 18 1 Rings 40 + 40 Congenital heart defects, 27 and 28/20
malformed T-12 vertebrae,
microphallus,
undescended testes.
Normal development at 11
months
Dev. delay 4 yrs 10 + 10 + 13/21 1 (10) 1 (13/21) Ring + Bi-sat Nonmosaic Delayed speech development 38
(× 2 mar) but normal motor activity
Dev. delay and 12 + 13/21 1 Rings 53 + 4 Mild cerebral palsy and 27 and 28/21
multiple learning difficulties, low a+b
congenital intelligence. Transmitted
abnormalities both markers to daughter
who died 12 days after
birth. Also dysmorphic
Poor reproductive 13/21 + 14 1 Min 87 Normal 43/26
history (centric fusion)
a
Also quoted in Table II.
For abbreviation definitions and reference numbers see Table I.
378 Crolla

TABLE XIII. SMC (NK) i.e., Negative With All Alphoid Repeats
Parental origin
SMC Mosaic % Reference no/
Ascertainment DN MAT PAT NK shape Nonmosaic Phenotype/outcome case no
PND 1 Min 60 Normal 15/6
PND 1 Min Nonmosaic TOP, Normal phenotype at autopsy 14/15
PND 1 Min 20a Large head, hypotonia, dev. delay 14/11
Consecutive liveborn 1 NK 20 Normal 20/27883
survey
Consecutive liveborn 1 NK 50 Psychomotor retardation; 20/27621
survey facial abnormalities
Population survey 1 Ring % not given Normal 11/20
Neonatal chromosome study 1 Ring 78 + 22 Microcephaly + mild dev delay NB 10/2
also with SMC(3)c
Facial abnormalites 1 Min 20% 1 copyb Abnormal facial appearance, 15/8
75% 2 copies normal intellectually
a
i.e., 20% of cells with mar negative for alphoid probes; 80% cells overall contained mar(19) with 1 or 2 copies of the centromere, see also Table VIII.
b
Weak signals at low stringency.
c
See Table II.
For abbreviation definitions and reference numbers see Table I.

was not given. By contrast 61% of SMCs from the other alphoid centromeric sequences revealed the presence of
autosomes were described as small rings, 27% as min- two copies of the 8p subtelomeric repeat flanking what
utes and 3.5% as submetacentric shaped with the mor- the authors postulated may be an ancient (repressed)
phology of the remaining marker not described. Overall intercalary centromere reactivated during the forma-
therefore, 61 SMCs were described as a small ring; 36 tion of the marker. [Ohashi et al., 1994]. Further mo-
as minutes, 53 satellited, three metacentrics, and in 15 lecular studies of a SMC(4) originally identified with
the morphology was not described. From the cases re- alphoid repeats [Callen at al., 1992], was subsequently
viewed, SMCs derived from all the autosomes except shown to have a complex composition including peri-
chromosome 5 have been reported but with only one centromeric and 4q31.1->31.3 sequences and from the
case from chromosomes 7, 10, and 11, respectively. results was postulated to have arisen as a breakdown
Furthermore, in most cases reviewed, a single SMC product of a larger r(4) [Fang et al., 1995]. A new class
derived from a single autosome was described, but in of repetitive DNA was identified in a further case of an
7/168 (∼4%) two or more SMCs were described from alphoid negative SMC which was shown to contain a
different autosomes and in 4/168 (∼2%) an autosomal hitherto unknown class of repetitive DNA which the
SMC was observed together with a marker derived authors termed sn5, the marker itself being derived
from the X chromosomes. In all cases with two or more from chromosome 20 [Johnson et al., 1992]. In this con-
SMCs detected in the same individual, the patient was text, further investigations of the SMCs reviewed in
phenotypically abnormal (Tables XII and XIV). Table XIII found to lack alpha satellite DNA detectable
with the alphoid centromere repeat probes may reveal
Structural Heterogeneity of SMCs Revealed by other examples of structural heterogeneity. Alterna-
FISH Studies tively, these SMCs may genuinely be devoid, or se-
verely depleted, of alpha satellite sequences, suggest-
While most autosomal SMCs are derived from a
ing that alphoid DNA may not be an essential compo-
single autosome, there are a number of reports of more
nent of normal centromere function.
complex SMC structures exemplified by an exceptional
metacentric SMC which by forward and reverse chro- Risk Assessments of SMCs With Reference to
mosome painting was shown to contain sequences de- Their Chromosomal Origins
rived from chromosomes X, 5 and 7 [Blennow et al., Can it be concluded from the data reviewed above
1992]. Investigations of an SMC apparently devoid of that determining the chromosomal origin of an autoso-

TABLE XIV. SMC (X + A) i.e., X and Autosomal

Parental origin
SMC Reference no/
Autosome(s) Ascertainment DN MAT PAT NK shape Nonmosaic mosaic Phenotype/outcome case no
X+ %(X) %(A)
6 Developmental 1 Rings 44 56 Abnormal appearance; 10/3
delay at 4/12 telecanthus; wide spaced
eyes; syndactyl toes 3 + 4
17 Developmental 1 Rings ∼50 ∼50 Educationally subnormal; 39
delay and NF1 NF1
8, 14/22, 15 Postnatal 1 Rings 100 8 4 79 Multiple congenital 27 and 28/22
14/22 4 58 abnormalities
15 4 10
5+7 Abnormal 1 Submeta Nonmosaic Severe mental and growth 2
at birth retardation, shrill cry,
beaked nose, micrognathra.

For abbreviation definitions and reference numbers see Table I.

 Molecular Studies of Autosomal SMC: Review of Literature 379

mal SMC with FISH and/or other molecular techniques between acrocentric (satellited) and nonacrocentric
contributes useful additional information on pheno- (nonsatellited) derived SMCs are compared. The FISH
type/karyotype correlations? In an attempt to answer figures suggest that the risk associated with a ran-
this question, an analysis was carried out of the 70 domly ascertained nonacrocentric de novo SMC is
cases in Tables I–XIV which had been randomly ascer- double that obtained using conventional methods
tained and for which follow-up clinical information was (28.6% versus 14.7%; [X2 4 1.25 P<0.2). By comparison,
available. the difference between the acrocentric (satellited)
The results are shown in Table XV, from which it can groups are not significantly different (7.1% versus
be seen that 9/70 (12.8%) of all the randomly ascer- 10.9%). This discrepancy may be partly accounted for
tained SMC patients (i.e., whether de novo or familial) by the inclusion in Warburton’s data of six inv dup(15)
were either physically and/or intellectually abnormal markers at least one of which was suspected to have
at follow-up. However, only 2/28 (7.1%) SMCs derived Prader-Willi syndrome at follow-up (see below). Further-
from the acrocentric chromosomes (excluding chromo- more, as discussed above, FISH studies have shown that
some 15) i.e., a small r(13) [Brøndum-Neilsen and Mik- approximately 25% of SMCs derived from the acrocen-
kelsen, 1995, case 3] and a dic(22) [Verschraegen-Spae trics lack satellites so that a proportion of the nonsatel-
et al., 1993, case 2] were associated with an abnormal lited markers included in Warburton’s figures may have
phenotype compared with 6/21 (28.6%) when the SMC been derived from acrocentric autosomes.
was derived from a nonacrocentric autosome. Further- Overall, these FISH-derived risk estimates associ-
more, eight of the nine SMCs associated with an ab- ated with the antenatal ascertainment of SMCs should
normal phenotype were de novo in origin, while one be considered as minimum figures as it is very difficult
was maternally transmitted and associated with ab- to know, without detailed clinical follow-up informa-
normalities in both the mother and her daughter tion over a number of years, what proportion of the
[Gravholt and Friedrich, 1995]. All six de novo nona- phenotypically normal individuals go on to exhibit de-
crocentric SMCs were small ring like chromosomes, velopmental or intellectual problems which might be
five were mosaics and in addition, in two of the six related to the presence of the SMC. However, the pau-
cases the patients had karyotypes containing SMCs de- city of detailed follow up data was an acknowledged
rived from two different autosomes. Four of the six in- limitation of the Warburton [1991] study, but it is
dividuals were mentally retarded and/or developmen- hoped that these figures will become better defined as
tally delayed and the remaining two had an abnormal the literature on the subject grows.
left kidney and alobar holoprosencephaly, respectively
[Brøndum-Neilsen and Mikkelsen, 1995, cases 11 and General Conclusions From Molecular Studies of
12; Callen et al., 1991, case 2; Crolla et al., 1992, case Autosomal SMCs
11; Blennow et al., 1993, case A; Plattner et al., 1993a,b, From the data reviewed above, it is clear that, with
case 24]. the exception of markers derived from chromosome 15
Prior to FISH studies, the most frequently quoted and 22 (the latter in association with CES), no clearly
risk of an abnormal phenotypic outcome associated defined correlations have yet emerged between the
with a randomly ascertained de novo SMC was 13%, chromosomal origins of SMCs derived from other auto-
with slight but not significant differences ascribed to somes and abnormal phenotypes. However, although
satellited (10.9%) versus nonsatellited SMCs (14.7%), a still based on a relatively small number of randomly
figure derived from follow-up data of 377, 357 cytoge- ascertained cases, the data reviewed here suggest that
netic prenatal diagnoses [Warburton, 1991]. In Table small ring-shaped SMCs derived from nonacrocentric
XVI the FISH-derived risk estimates have been com- autosomes are associated with an approximately 30%
pared to Warburton’s data by which it can be seen that risk of impaired intellectual developmental and/or
the overall risk associated with autosomal de novo physical abnormality (Tables XV and XVI).
SMCs derived from both these data sets are similar Although these data remain inconclusive in some
(13% versus 16.3%). However, there are statistically ways, a number of indicators have emerged which are of
significant differences when the rate of abnormalities immediate diagnostic significance and provide pointers

TABLE XV. Risk Estimate Associated With FISH Identified and Randomly Ascertained Autosomal SMCs
Normal Phenotypic Abnormal phenotypic
outcome outcome
Chromosomal Parental No. %
origin origin Mosaics Nonmosaics Mosaics Nonmosaics Total abnormal abnormal
Acrocentrics DN 12 14 1 1 28 2/28 7.1%
(Excluding 15) MAT 1 9 — — 10 — —
n 4 42 (60%) PAT — 4 — — 4 — —
NK — — — — — — —
Subtotal 13 27 1 1 42 2/42 4.7%
Autosomal DN 13 2 5 1 21 6/21 28.6%
nonacrocentrics MAT 3 1 1 — 5 1/5 20%
n 4 28 (40%) PAT — — — — — — —
NK 1 1 — — 2 — —
Subtotal 17 4 6 1 28 7/28 25%
Totals 30 31 7 2 70 9/70 12.8%
380 Crolla

TABLE XVI. Summary of Risk Estimates Associated With Randomly Ascertained De Novo SMCs
Normal phenotypic Abnormal phenotypic
outcome outcome
No. %
Marker phenotype Study Mosaic Nonmosaic Mosaic Nonmosaic Total abnormal abnormal
Satellited or Ag-NOR-positive Warburtona 17 32 2 4 55 6/55 10.9
(Acrocentrics) This studyb 12 14 1 1 28 2/28 7.1
Satellited or Ag-NOR-negative Warbuton 39 19 7 3 68 10/68 14.7
(non-acrocentrics) This study 13 2 5 1 21 6/21 28.6
Totals Warburtona 56 51 9 7 123 16/123 13.0
This studyb 25 16 6 2 49 8/49 16.3
a
Six identified as inv dup(15) on the basis of DAPI staining, one of which is ?PWS, see text.
b
Excluding inv dup(15), see text.

on how best to develop our understanding of the REFERENCES

mechanisms underlying the role of an SMC in produc- Aalfs CM, Jacobs ME, NiesteOtter MA, Hennekam RCM, Hoovers JMN
ing abnormal phenotypic effects. As stated above, au- (1996): Two supernumerary marker chromosomes, derived from chro-
tosomal SMCs containing detectable euchromatin are mosome 6 and 9, in a boy with mild developmental delay. Clin Genet
apparently more frequently associated with abnormal 49:42–46.
phenotypes, and further detailed molecular character- Blennow E, Anneren G, Bui TH, Berggren E, Asadi E, Nordenskjöld M
(1993): Characterization of supernumerary ring marker chromosomes
ization of markers ascertained in normal and abnormal by fluorescence in situ hybridization (FISH). Am J Hum Genet 53:433–
individuals together with detailed long-term clinical 442.
follow-up information may help to identify areas of the Blennow E, Bui TH, Kristoffersson U, Vujic M, Anneren G, Holmberg E,
genome which are more sensitive to dosage imbalance. Nordenskjöld M (1994): Swedish survey on extra structurally abnormal
chromosomes in 39 105 consecutive prenatal diagnoses: Prevalence and
However, even if the SMC is characterized molecularly, characterization by fluorescence in situ hybridization. Prenat Diagn
the data presented here would suggest that a cautious 14:1019–1028.
approach to antenatal risk assessment is indicated. Blennow E, Nielsen KB, Telenius H, Carter NP, Kristoffersson U, Holm-
While it appears very likely that a least a proportion berg E, Gillberg C, Nordenskjöld M (1995): Fifty probands with extra
of SMCs directly exert a detrimental phenotypic effect structurally abnormal chromosomes characterized by fluorescence in
situ hybridization. Am J Med Genet 55:85–94.
via dosage imbalance(s), a number of studies have re-
Blennow E, Telenius H, Larsson C, Devos D, Bajalica S, Ponder BAJ,
ported the coexistence of SMCs with UPD in chromo- Nordenskjöld M (1992): Complete characterization of a large marker
somes 6 [James et al., 1995], 15 [Cheng et al., 1994; chromosome by reverse and forward chromosome painting. Hum Genet
Mignon et al., 1996; Robinson et al., 1993b] and 20 90:371–374.
(Chudoba et al., personal communication). However, Blennow E, Tillberg E (1996): Small extra ring chromosome derived from
chromosome 10p: Clinical report and characterisation by FISH. J Med
very few systematic studies designed to ascertain the Genet 33:399–403.
frequency of UPD in association with SMCs have been Brøndum-Nielsen K, Mikkelsen M (1995): A 10-year survey, 1980–1990, of
reported, and until more data are accumulated it would prenatally diagnosed small supernumerary marker chromosomes,
appear prudent to identify the parental origins of the identified by FISH analysis. Outcome and follow-up of 14 cases diag-
normal homologues in those cases where the chromo- nosed in a series of 12 699 prenatal samples. Prenat Diag 15:615–621.
somal origin of the SMC corresponds to an autosome Buckton KE, Spowart G, Newton MS, Evans HJ (1985): Forty-four pro-
bands with an additional ‘‘marker’’ chromosome. Hum Genet 69:353–
with a known imprinting effect [Ledbetter and Engel, 370.
1995; Robinson et al., 1996]. Butler MG, Roback EW, Allen GA, Dev VG (1995): Identification of a ring
In conclusion, molecular studies of SMCs can be used chromosome as a ring 8 using fluorescent in situ hybridization (FISH)
to provide information on the chromosomal origin and in a child with multiple congenital anomalies. Am J Med Genet 57:
494–495.
composition of autosomal SMCs, and in the case of
SMC(15) and (22), correlations can be made with some Callen DF, Ringenbergs ML, Fowler JCS, Freementle J, Haan EA (1990):
Small marker chromosomes in man: Origin from pericentric hetero-
confidence between the genetic content of these mark- chromatin of chromosomes 1, 9 and 16. J Med Genet 27:155–159.
ers and their associated phenotypic risks. It may well Callen DF, Eyre HJ, Ringenbergs ML, Freemantle CJ, Woodroffe P, Haan
be that similar correlations between SMCs from other EA (1991): Chromosomal origin of small ring marker chromosomes in
autosomes and clinical phenotypes may not emerge, man. Characterization by molecular genetics. Am J Hum Genet 48:
769–782
but the data so far published suggests that at least a
Callen DF, Eyre H, Yip MY, Freemantle J, Haan EA (1992): Molecular
proportion of these chromosomes may have a complex cytogenetic and clinical studies of 42 patients with marker chromo-
etiology and may provide valuable insights into the ef- somes. Am J Med Genet 43:709–715.
fects of dosage imbalances for many regions of the ge- Chen H, Tuckmuller CM, Batista DAS, Wertelecki W (1995): Identification
nome. of supernumerary ring chromosome 1 mosaicism using fluorescence in
situ hybridization—Brief clinical report. Am J Med Genet 56:219–223.
ACKNOWLEDGMENTS Cheng SD, Spinner NB, Zackai EH, Knoll JHM (1994): Cytogenetic and
molecular characterization of inverted duplicated chromosomes 15
The work carried out in this laboratory on supernu- from 11 patients. Am J Hum Genet 55:753–759.
merary marker chromosomes was funded with grants Cooper LF, Coss CA, Jabs EW (1992): Re-evaluation of the origin of a
marker chromosome in a patient with 47,XX,r(13)(p11q34),+mar by
from Action Research and the Wellcome Foundation. molecular cytogenetics. Clin Genet 42:323–325.
The author is particularly indebted to Professor Pat
Crolla JA, Dennis NR, Jacobs PA (1992): A non-isotopic in situ hybridisa-
Jacobs for her constructive criticisms of this manu- tion study of the chromosomal origin of 15 supernumerary marker
script. chromosomes in man. J Med Genet 29:699–703.
 Molecular Studies of Autosomal SMC: Review of Literature 381
Crolla JA, Harvey JF, Sitch FL, Dennis NR (1995): Supernumerary marker Morrison PJ, Smith NM, Martin KE, Young ID (1997): Mosaic partial
15 chromosomes: A clinical, molecular and FISH approach to diagnosis trisomy 17 due to a ring chromosome identified by fluorescence in situ
and prognosis. Hum Genet 95:161–170. hybridisation. Am J Med Genet 68:50–53.
Crolla JA, Howard P, Mitchell C, Long FL, Dennis NR (1997): A molecular Müller-Navia J, Nebel A, Schleiermacher E (1995): Complete and precise
and FISH approach to determining karyotype and phenotype correla- characterization of marker chromosomes by application of microdissec-
tions in six patients with supernumerary marker(22) chromosomes. tion in prenatal diagnosis. Hum Genet 96:661–668.
Am J Med Genet 72:440–447. Müller-Navia J, Nebel A, Oehler D, Theile U, Zabel B, Schleiermacher E
Crolla JA, Long FL, Rivera H, Dennis NR (1998): FISH and molecular (1996): Microdissection and DOP-PCR based reverse chromosome
study of autosomal supernumerary marker chromosomes excluding painting as a fast and reliable strategy in the analysis of various struc-
those derived from chromosome 15: I Results of 26 new cases. Am J tural chromosome abnormalities. Prenat Diagn 16:915–922.
Med Genet 75:355–366. Ohashi H, Wakui K, Ogawa K, Okano T, Niikawa N, Fukushima Y (1994):
Daniel A, Malafiej P, Preece K, Chia N, Nelson J, Smith M (1994): Iden- A stable acentric marker chromosome: Possible existence of an intercalary
tification of marker chromosomes in thirteen patients using FISH prob- ancient centromere at distal 8p. Am J Hum Genet 55:1202–1208.
ing. Am J Med Genet 53:8–18. Plattner R, Heerema NA, Yurov YB, Palmer CG (1993a): Efficient identi-
de Albuquerque Coelho K-EF, Egashira M, Kato R, Fujimoto M, Matsu- fication of marker chromosomes in 27 patients by stepwise hybridiza-
moto N, Rerkamnuaychoke B, Abe K, Harada N, Ohashi H, Fukushima tion with alpha-satellite DNA probes. Hum Genet 91:131–140.
Y, Niikawa N (1996): Diagnosis of four chromosome abnormalities of Plattner R, Heerema NA, Howard-Peebles PN, Miles JH, Soukup S,
unknown origin by chromosome microdissection and subsequent re- Palmer CG (1993b): Clinical findings in patients with marker chromo-
verse and forward painting. Am J Med Genet 63:468–471. somes identified by fluorescence in situ hybridization. Hum Genet 91:
Doneda L, Dalpra L, Tibiletti MG, Larizza L (1993): Prenatal diagnosis of 589–598.
an extranumerary i(22p) with normal phenotype. Ann Genet Paris 36: Raimondi E, Ferretti L, Young BD, Sgaramella V, Decarli L (1991): The
154–158. origin of a morphologically unidentifiable human supernumerary mini-
Fang YY, Eyre HJ, Bohlander SK, Estop A, Mcpherson E, Trager T, Riess chromosome traced through sorting, molecular cloning, and in situ hy-
O, Callen DF (1995): Mechanisms of small ring formation suggested by bridisation. J Med Genet 28:92–97.
the molecular characterization of two small accessory ring chromo- Rauch A, Pfeiffer RA, Trautmann U, Liehr T, Rott HD, Ulmer R (1992): A
somes derived from chromosome 4. Am J Hum Genet 57:1137–1143. study of ten small supernumerary (marker) chromosomes identified by
Flejter WL, Bennett-Baker PE, Ghaziuddin M, McDonald M, Sheldon S, fluorescence in situ hybridization (FISH). Clin Genet 42:84–90.
Gorski JL (1996): Cytogenetic and molecular analysis of inv dup(15) Robinson WP, Binkert F, Gine R, Vazques C, Miller W, Rosenkranz W,
chromosomes observed in two patients with autistic disorder and men- Schinzel A (1993a): Clinical and molecular analysis of five inv dup(15)
tal retardation. Am J Med Genet 61:182–187. patients. Eur J Hum Genet 1:37–50.
Gentile M, Susca F, Resta N, Stella A, Cascone A, Guanti G (1993): Infer- Robinson WP, Wagstaff J, Bernasconi F, Baccichetti C, Artifoni L, Fran-
tility in carriers of two bisatellited marker chromosomes. Clin Genet zoni E, Suslak L, Shih LY, Aviv H, Schinzel AA (1993b): Uniparental
44:71–75. disomy explains the occurrence of the Angelman or Prader-Willi syn-
Gravholt CH, Friedrich U (1995): Molecular cytogenetic study of supernu- drome in patients with an additional small inv dup(15) chromosome. J
merary marker chromosomes in an unselected group of children. Am J Med Genet 30:756–760.
Med Genet 56:106–111. Rosenberg C, Borovik CL, Canonaco RS, Sichero LC, Queiroz APS, Vianna-
Morgante AM (1995): Identification of a supernumerary marker de-
James RS, Temple IK, Dennis NR, Crolla JA (1995): A search for unipa-
rived from chromosome 17 using FISH. Am J Med Genet 59:33–36.
rental disomy in carriers of supernumerary marker chromosomes. Eur
J Hum Genet 3:21–26. Schinzel A. (1984): ‘‘Catalogue of Unbalanced Chromosome Aberrations in
Man.’’ Berlin: Walter de Gruyter.
Johnson DH, Kroisel PM, Klapper HJ, Rosenkranz W (1992): Microdissec-
tion of a human marker chromosome reveals its origin and a new fam- Stetten G, Blakemore KJ, Courter AM, Coss CA, Jabs EW (1992): Prenatal
ily of centromeric repetitive DNA. Hum Mol Genet 1:741–747. identification of small mosaic markers of different chromosomal ori-
gins. Prenat Diagn 12:83–93.
Lanphear N, Lamb A, Oppenheimer S, Soukup S (1995): Supernumerary
chromosome marker (1) in a developmentally delayed child—Brief Sun YM, Rubinstein J, Soukup S, Palmer CG (1995): Marker chromosome
Clinical Report. Am J Med Genet 57:400–403. 21 identified by microdissection and FISH. Am J Med Genet 56:151–
154.
Leana-Cox J, Jenkins L, Palmer CG, Plattner R, Sheppard L, Flejter WL,
Zackowski J, Tsien F, Schwartz S (1994): Molecular cytogenetic analy- Temple IK, James RS, Shield JPH, Crolla JA, Sitch FL, Betts P, Howell
sis of inv dup(15) chromosomes using probes specific for the Prader- WM, Baum JD, Jacobs PA (1995): An imprinted gene for diabetes? Nat
Willi/Angelman syndrome region: Clinical implications. Am J Hum Genet 9:110–112.
Genet 54:748–756. Thangavelu M, Pergament E, Espinosa R, Bohlander SK (1994): Charac-
Ledbetter DH, Engel E (1995): Uniparental disomy in humans: Develop- terization of marker chromosomes by microdissection and fluorescence
ment of an imprinting map and its implications for prenatal diagnosis. in situ hybridization. Prenat Diagn 14:583–588.
Hum Mol Genet 4:1757–1764. van Langen IM, Otter MA, Aronson DC, Overweg-Plandsoen WCG, Hen-
McDermid HE, Duncan AMV, Brasch KR, Holden JJA, Magenis E, Sheehy nekam RCM, Leschot NJ, Hoovers JMN (1996): Supernumerary ring
R, Burn J, Kardon N, Nöel B, Schinzel A, Teshima I, White BN (1986): chromosome 20 characterized by fluorescence in situ hybridization.
Characterization of the supernumerary chromosome in Cat Eye syn- Clin Genet 49:49–54.
drome. Science 232:646–648. Verschraegen-Spae MR, Van Roy N, de Perdigo A, De Paepe A, Speleman
F (1993): Molecular cytogenetic characterization of marker chromo-
Mears AJ, Duncan AMV, Budarf ML, Emanuel BS, Sellinger B, Siegelbar-
somes found at prenatal diagnosis. Prenat Diagn 13:385–394.
telt J, Greenberg CR, McDermid HE (1994): Molecular characterization
of the marker chromosome associated with cat eye syndrome. Am J Viersbach R, Schwanitz G, Nothen MM (1994): Delineation of marker chro-
Hum Genet 55:134–142. mosomes by reverse chromosome painting using only a small number of
DOP-PCR amplified microdissected chromosomes. Hum Genet 93:663–
Mears AJ, ElShanti H, Murray JC, McDermid HE, Patil SR (1995): Minute
667.
supernumerary ring chromosome 22 associated with cat eye syndrome:
Further delineation of the critical region. Am J Hum Genet 57:667–674. Voullaire LE, Slater HR, Petrovic V, Choo KHA (1993): A functional
marker centromere with no detectable alpha- satellite, satellite-III, or
Melnyk AR, Dewald G (1994): Identification of a small supernumerary ring CENP-B protein—Activation of a latent centromere. Am J Hum Genet
chromosome 8 by fluorescent in situ hybridization in a child with de- 52:1153–1163.
velopmental delay and minor anomalies. Am J Med Genet 50:12–14.
Warburton D (1991): De novo balanced chromosome rearrangements and
Michalski K, Rauer M, Williamson N, Perszyk A, Hoo JJ (1993): Identifi- extra marker chromosomes identified at prenatal diagnosis: Clinical
cation, counselling, and outcome of two cases of prenatally diagnosed significance and distribution of breakpoints. Am J Hum Genet 49:995–
supernumerary small ring chromosomes. Am J Med Genet 46:88–94. 1013.
Mignon C, Malzac P, Moncla A, Depetris D, Roeckel N, Croquette M-F, Wiktor A, Van Dyke DL, Weiss L (1993): Brief Clinical Report—
Mattei M-G (1996): Clinical heterogeneity in 16 patients with inv dup Characterization of a de novo 48, XX, +r(X), +r(17) by in situ hybrid-
15 chromosome: Cytogenetic and molecular studies, search for an im- ization in a patient with neurofibromatosis (NF1). Am J Med Genet
printing effect. Eur J Hum Genet 4:88–100. 45:22–24.