European Journal of Medical Genetics 48 (2005) 175–181
www.elsevier.com/locate/ejmg
Case report
Prader–Willi syndrome with a karyotype
47,XY,+min(15)(pter->q11.1:) and maternal UPD
15—case report plus review of similar cases
Thomas Liehr a,*, Elke Brude b, Gabriele Gillessen-Kaesbach c,
Rainer König b, Kristin Mrasek a,
Ferdinand von Eggeling a, Heike Starke a
a
Institute of Human Genetics and Anthropology, Jena, Germany
b
Institute of Human Genetics, Frankfurt/Main, Germany
c
Institute of Human Genetics, Essen, Germany
Received 12 November 2004
Available online 17 February 2005
Abstract
Prader–Willi (PWS) and Angelman (AS) are syndromes of developmental impairment that can
result either from a 15q11-q13 deletion, paternal uniparental disomy (UPD), imprinting, or UBE3A
mutations. A small cytogenetic subset of PWS and AS patients are carriers of a so-called small supernumerary marker chromosome (sSMC). Here, we report on an previously unreported PWS case with
a karyotype 47,XY,+min(15)(pter->q11.1:) plus maternal heterodisomic UPD 15. A review of the
literature revealed, that for both, PWS and AS patients, cases with (1) a sSMC plus microdeletion of
the PWS/AS critical region, (2) inv dup(15) plus uniparental disomy (UPD) 15 and (3) cases without
exclusion of a microdeletion an UBE3A mutation or UPD are described. The present case as well as
the review of similar cases provides further evidence for the necessity to test UPD in prenatal cases
with a de novo sSMC and in postnatal cases with otherwise unexplainable clinical phenotype.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Small supernumerary marker chromosome (sSMC); Prader–Willi syndrome (PWS); Angelman syndrome (AS); Uniparental disomy (UPD) 15; Microdeletion
* Corresponding author. Institut für Humangenetik und Anthroplogie, Postfach, D-07740 Jena, Germany. Tel.:
+49 3641 935533; fax: +49 3641 935502.
E-mail address: [email protected] (T. Liehr).
1769-7212/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmg.2005.01.004
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T. Liehr et al. / European Journal of Medical Genetics 48 (2005) 175–181
1. Introduction
Prader–Willi syndrome (PWS) and Angelman syndrome (AS) are distinct human neurogenetic disorders involving several disease causing mechanisms. The principal genetic
defects in PWS are 15q11-13 deletions of paternal origin and maternal chromosome 15 uniparental disomy (UPD). In contrast, maternal deletions and paternal chromosome 15 UPD
are associated with AS. A small number of patients with PWS and AS were found to have
an imprinting defect. Mutations at the UBE3A gene account for approximately 5% of AS
and 10–15% of the AS patients have an unknown etiology. PWS is clinically characterized
by central hypotonia, hyperphagia, and obesity starting after the first year of life, delayed
motoneuronal developmental and mental deficiency, hypogenitalism and hypogonadism
later in life. AS is clinically characterized by a central congenital hypotonia, severe mental
delay, microcephaly with occipital flattening, profound speech delay, jerky voluntary movements, a happy disposition with paroxysms of laughter and a characteristic facial appearance which includes a prominent jaw wide mouth and midfacial hypoplasia ([30]; OMIM
#176270 and #105830).
Small supernumerary marker chromosomes (sSMC) are reported in 0.043% of newborn
infants, 0.077% of prenatal cases, 0.433% of mentally retarded patients and 0.171% of
subfertile people [14,15]. sSMC were recently defined as structurally abnormal chromosomes that cannot be identified or characterized unambiguously by conventional banding
cytogenetics alone, and are generally equal in size or smaller than a chromosome 20 of the
same metaphase spread [15]. sSMC carriers present in ~10% of the cases with an uniparental disomy (UPD) of the sSMC’s homologous chromosomes [15]. A special subgroup
of such sSMC cases is constituted by PWS or AS patients. Here, we report a new case with
the clinical phenotype of a PWS with an sSMC 15 plus an UPD 15.
2. Case report
The 10 month male patient was born to a 26 year old woman in the 29th week of gestation by cesarean section indicated by a polyhydramnion (weight 1360 g = 50.-75. centile,
length 43 cm = 90.-97. centile, OFC 29.5 cm = 90.-97. centile). He had down slanting palpebrale fissures, strabismus, a severe muscular hypotonia, failure to thrive, breathingdifficulties combined with repeated infections of the respiratory tract and pneumonia, maldescensus testis and a hyperplasic scrotum.
Chromosomes from the peripheral blood of the child and the patients were prepared and
analyzed according to standard protocols [29]. Centromere specific multicolor fluorescence in situ hybridization (cenM-FISH) and subcentromere specific multicolor FISH
(subcenM-FISH) were done as previously described [20,26]. GTG-banding revealed the
presence of a de novo sSMC in 70% of the patient’s peripheral blood lymphocytes. The
origin and genetic content of the sSMC were described by cenM-FISH [20] and subcenMFISH [26]. The sSMC(15) of this case can be described as min(15)(pter->q11.1:) as no
signals were detectable with a probe specific for 15q11.2 [26] on the extra chromosome
(see Fig. 1A,B)—the applied BAC RP11-171C8 includes the STS marker SHGC36523 and is located ~60 kb proximal of UBE3A. FISH using a probe for the PWSCR
T. Liehr et al. / European Journal of Medical Genetics 48 (2005) 175–181
177
Fig. 1. Images were captured on a Zeiss Axioplan microscope (Zeiss, Jena, Germany) with the IKAROS and ISIS
digital FISH imaging system (MetaSystems, Altlussheim, Germany) using a XC77 CCD camera with on-chip
integration (Sony). (A) cenM-FISH results of the present case: the marker chromosome is identified as a min(15)
{arrowhead}. (B) subcenM-FISH probe set for chromosome 15 revealed the absence of centromere near euchromatic material. Thus, the sSMC was described as heterochromatic min(15)(pter->q11.1:). Abbreviations:
bA171C8 = BAC probe in 15q11.2; cep = centromeric probe; midi54 = probe for all p-arms of the human acrocentric chromosomes; wcp = whole chromosome paint. (C) Results of microsatellite analysis for D15S643 and
D15S642 in the mother (M), the father (F), and the child (C). Different alleles are labeled a, b, c, and d. Maternal
heterodisomy is apparent for D15S642, maternal UPD for both microsatellite markers.
(UBE3A probe, Abbott/Vysis) showed a normal signal constellation on both chromosomes
15. Even though the present sSMC is the best analyzed of all similar PWS/AS-cases with a
marker chromosome, the breakpoint could only be narrowed down by molecular cytogenetic approaches. The exact characterization of sSMC-breakpoints in general could only be
done by array-CGH studies followed by sequencing; however, this was not done yet for
either sSMC case.
UPD analysis was carried out as described in Ref. [26]. A maternal heterodisomic UPD
of the sSMC’s sister-chromosomes was determined by application of the microsatellite
probes D15S643 (15q14) and D15S642 (15q26), which were informative (see Fig. 1C).
The probes D15S17, D15S652, and D15S657 were non-informative (results not shown).
3. Discussion
As recently summarized derivatives of chromosome 15 constitute about one-third of all,
and ~60% of acrocentric chromosome derived sSMC [13–15]. As shown in Table 1 the
present case is the sixth reported PWS patient with an sSMC(15) and a confirmed maternal
UPD. A seventh PWS case has been reported with a sSMC(X) plus a maternal UPD 15
(case PM-7 in Table 1). Furthermore, one case, each, with a small supernumerary ring
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Table 1
Overview on the 24 cases with Prader–Willi and five cases with Angelman syndrome plus a sSMC available
throughout the literature. The corresponding references are given in the last column
Case
Banding cytogenetics
FISH-result
PWS-cases with deletion in PWS-critical region plus sSMC
PD-1 47,XY,+r(?)[70%]
r(15).ish(SNRPN-)
PD-2 47,XX,del(15)(q11.200-> q11.207),
n.a.
+inv dup(15)(q11.1)[100%]
PWS-cases with maternal UPD 15 plus sSMC
PM-1 47,XY,+inv dup(15)(q11)[70%]
n.a.
PM-2 47,XX,+inv dup(15)(q11)[100]
inv dup (15)(q11)
PM-3 47,XY,+inv dup(15)(q11)[45%]
inv dup (15)(q11)
UPD result
Reference
no UPD 15
n.a.
[3]: case 1
[19]: case 2
mat UPD 15
mat UPD 15
mat UPD 15
min(15)(pter-> q11.1:)
min(15)(pter-> q11.2)
inv dup(15)(pter->
q11: :q13->pter)
PM-7 47,XX,+r(?)[50%]
mar(X)
PWS-cases with suspected maternal UPD 15 or microdeletion plus sSMC
P-1
47,XX,+min(15)(q1?)[60%]
n.a.
P-2
47,XY,+min(15)(pter-> q12:)[100%]
n.a.
P-3
47,XY,+min(15)(pter-> q12~3:)[100%]
n.a.
P-4
47,XY,+min(15)(pter-> q21:)[100%]
n.a.
mat UPD 15
mat UPD 15
mat UPD 15
[23]: case 2
[2]
[6]: case
WJK303
Present case
[4]
[18]: case 13
mat UPD 15
[3]: case 2
n.a.
n.a.
n.a.
n.a.
P-5
47,XX,+inv dup(15)(q11)[80%]/
n.a.
PWS-cases with suspected maternal UPD 15 or microdeletion plus sSMC
P-6 to 47,XX,+inv dup(15)(q11)[100%]
n.a.
P-7
P-8
47,XY,+inv dup(15)(q11)[100%]
n.a.
P-9
47,XY,+inv dup(15)(q11~q12)[100%]
n.a.
P-10
47,XX,+inv dup(15)(q11~q12)[41%]
n.a.
P-11
47,XY,+inv dup(15)(q11)[75%]
n.a.
P-12
47,XY,+inv dup(15)(q11)[53%]
n.a.
P-13
47,XY,+mar[100%]
mar(15)
P-14
45,XX,trob(15;15)[44%]/
mar1 = r(15)(::p11.1->
46,XX,trob(15;15),+mar1[53%]/
q11.2::) mar2 = r(15;15)
46,XX,trob(15;15),+mar2[3%]/
(::p11.1->
46,XX,trob(15;15),+mar1x2[0%]
q11.2::p11.1-> q11.2::)
(in fibroblasts: 30%/75%/4%/1%)
P-15
48,X,t(Y;15)(q21;q12), +inv
n.a.
dup(15)x2[2.5%]/
47,X,t(Y;15)(q21;q12), +inv
dup(15)[47%]/
46,X,t(Y;15)(q21;q12)[50.5%]
AS-cases with microdeletion in AS-critical region plus sSMC
AD-1 47,XY,del(15)(q11->q13),
inv dup(15)(q11~12)
+mar[100%]
n.a.
[8]
[24]
[9]
[10] case
personally
communicated
by Lubunski
[11] 1 case
n.a.
[7,21]
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
[16]: case 9
[31]
[27]
[17]: case 1
[17]: case 2
[12]: case 3
[19]: case 1
n.a.
[10]: case 1
n.a.
[25]
PM-4
PM-5
PM-6
47,XY,+mar[70%]
47,XX,+mar[100%]
47,XY,+mar [85%]
(continued on next page)
T. Liehr et al. / European Journal of Medical Genetics 48 (2005) 175–181
179
Table 1
(continued)
Case
Banding cytogenetics
FISH-result
AS-cases with paternal UPD 15
AP-1 47,XY,+inv dup(15)(q11)[60%]/
n.a.
AP-2 47,XY,+mar[100%]
inv dup(15)(q11)
AS-cases with suspected paternal UPD 15 or microdeletion plus sSMC
A-1 to 47,XY,+mar[100%]
inv dup(15)(q13)
A-2
UPD result
Reference
pat UPD 15
pat UPD 15
[23]: case 1
[22,28]
n.a.
[5]: cases 1 and
2
Abbreviations: AS = Angelman syndrome; FISH = fluorescence in situ hybridization; mat = maternal; n.a. = not
available; pat = paternal; PWS = Prader–Willi syndrome; UPD = uniparental disomy.
chromosome 15 or an inv dup(15)(q11.1) are described, which have no UPD or UPD not
tested, plus a deletion of the PWS-critical region (cases PD-1 and PD-2 in Table 1). Additionally, 15 PWS cases with minute- (cases P-1 to P-4, P15), inv dup- (cases P-5 to P-12),
ring- (case P-14) or marker-chromosomes not specified (case P-13) were reported, in which
it was not tested if a PWS-deletion, -mutation or UPD were present.
Interestingly, only five cases with AS plus an sSMC(15) are described. All three for
PWS-patients mentioned groups are available in complete analogy in AS-patients, as well.
One case with sSMC(15) plus microdeletion (case AD-1), two cases with inv dup(15) plus
paternal UPD 15 and two cases without exclusion of a microdeletion, mutation or UPD.
In all 29 cases summarized in Table 1 the sSMC was de novo. The development of such
a minute sSMC(15) can be explained by partial trisomic rescue; the existence of such a
mechanism for the development of a sSMC was recently proven by the observation of a
min(22) in the born child and a trisomy 22 mosaicism in the placenta [1]. Thus, in the
present case with a minute sSMC(15) trisomic rescue could have happened, however, such
a simple mechanism cannot be taken into consideration for the explanation of UPD in case
of an inv dup or a ring chromosome 15. Inv dup chromosomes are thought to evolve by a
U-type exchange during meisois I [15]. Thus, for the development of UPD in connection
with an inv dup(15) it must be speculated, that one germ cell provides no normal chromosome 15 besides the inv dup(15) and fertilization happens with a germ cell which has two
uniparentally derived chromosomes 15. Another possibility is, that the germ cell with the
inv dup(15) meets a normal haploid partner and the single chromosome 15 is duplicated as
a postzygotic event. Similar mechanisms may happen for small ring chromosomes 15.
Nonetheless, small ring chromosomes can also evolve from minute chromosomes and vice
versa or even to inv dup chromosomes within one patient (see e.g., [13] case 8 W-p21/11 or 8 W-p11.1/1-1).
Three of the 29 cases have a proven microdeletion in the PWS/AS-critical region but no
UPD. One of those sSMC had a ring chromosome shape (case PD-1), the other two were
inv dup chromosomes (cases PD-2 and AD-1). An UPD was excluded for case PD-1. The
evolution of the observed karyotypic changes could only be reconstructed by postulating
several independent rearrangement-events.
In summary, 23 cases with sSMC(15) plus PWS, one case with sSMC(X) plus PWS and
five cases with sSMC(15) plus AS are described in the literature including the present case.
Both, UPD as well as microdeletions can be associated with an sSMC and causative for
PWS or AS. However, the implementation of different sSMC-shapes as well as the simultaneous occurrence of microdeletions or UPD in PWS or AS remains still far from being
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T. Liehr et al. / European Journal of Medical Genetics 48 (2005) 175–181
understood. Nonetheless, further evidence for the necessity to exclude the presence of an
UPD especially in prenatal cases with a de novo sSMC is given by this review. Additionally, even though very rare, microdeletion in the PWS/AS-critical region should be tested
in cases with a de novo sSMC(15).
Acknowledgements
Supported by the Dr. Robert Pfleger-Stiftung.
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