Open Access

Clinically abnormal case with paternally derived partial trisomy 8p23.3 to 8p12 including maternal isodisomy of 8p23.3: a case report

  • Dilek Aktas1Email author,
  • Anja Weise2,
  • Eda Utine1,
  • Dursun Alehan3,
  • Kristin Mrasek2,
  • Ferdinand von Eggeling2,
  • Heike Thieme2,
  • Ergul Tuncbilek1 and
  • Thomas Liehr2
Molecular Cytogenetics20092:14

DOI: 10.1186/1755-8166-2-14

Received: 06 May 2009

Accepted: 30 June 2009

Published: 30 June 2009

Abstract

Background

Because of low copy repeats (LCRs) and common inversion polymorphisms, the human chromosome 8p is prone to a number of recurrent rearrangements. Each of these rearrangements is associated with several phenotypic features. We report on a patient with various clinical malformations and developmental delay in connection with an inverted duplication event, involving chromosome 8p.

Methods

Chromosome analysis, multicolor banding analysis (MCB), extensive fluorescence in situ hybridization (FISH) analysis and microsatellite analysis were performed.

Results

The karyotype was characterized in detail by multicolor banding (MCB), subtelomeric and centromere-near probes as 46,XY,dup(8)(pter->p23.3::p12->p23.3::p23.3->qter). Additionally, microsatellite analysis revealed the paternal origin of the duplication and gave hints for a mitotic recombination involving about 6 MB in 8p23.3.

Conclusion

A comprehensive analysis of the derivative chromosome 8 suggested a previously unreported mechanism of formation, which included an early mitotic aberration leading to maternal isodisomy, followed by an inverted duplication of the 8p12p23.3 region.

Background

To date, a number of patients with inverted duplication of 8p have been identified through cytogenetic analysis [17] and different breakpoints related to 8p have been reported [4]. The distal breakpoint was predominantly in 8p23 and was found in combination with various proximal breakpoints (centromere, p11 and p12), but predominantly within 8p11.

An inverted duplication of 8p is associated with mental retardation, distinct facial anomalies, agenesis of corpus callosum and hypotonia. Although less common, congenital heart defects, coloboma, scoliosis and seizures are noted.

We report another patient with a complex rearrangement leading to an inverted duplication of 8p23.3 to 8p12. Phenotypic findings in our patient and previously reported chromosome 8p inverted duplications are reviewed and several important features are highlighted.

Case presentation

Clinical details

The male infant was the second child born to a non-consanguineous couple. Following a normal gestation and delivery, the boy was born at 40-weeks of gestation with a birth weight of 3.2 kg. There were no neonatal problems or feeding difficulty.

At 15 months of age, his weight was 11.3 kg (10th–25th centiles), length was 87 cm (90th–95th centiles), and head circumference was 48 cm (10th–25th centiles). He was evaluated for motor and language delay. Dysmorphic facial features including brachycephaly, prominent forehead, prominent nasal bridge, flared alae nasi, wide mouth with thin upper lip were present (Figure 1). Ears were large and posteriorly rotated. He had no eye or skeletal abnormalities. There was mild generalized hypotonia. He was still unable to sit and walk. He could roll on both sides, transfer objects hand-to-hand, but he could not use a spoon or fork for self-feeding.
https://static-content.springer.com/image/art%3A10.1186%2F1755-8166-2-14/MediaObjects/13039_2009_Article_42_Fig1_HTML.jpg
Figure 1

Frontal view of the reported case at 15 months of age.

An abdominal ultrasound was normal. Two-dimensional echocardiogram revealed small muscular ventricular septal defect. Brain MRI demonstrated agenesis of corpus callosum.

Methods

Karyotyping was performed on metaphase spreads prepared from peripheral blood lymphocytes by conventional methods. The aberrant karyotype was further studied applying multicolor banding (MCB) probe sets for chromosome 8 [8]; MCB-results were evaluated using the software of MetaSystems (Altlussheim, Germany) as previously described [9]. Moreover, a centromeric probe for chromosome 8 (Vysis), a subtelomeric probes for chromosome 8pter (Vysis),), a centromere-near probe in 8p11.21 (bA64C22 – BAC-PAC Chori resource) and the BAC-probes listed in Table 1 were used. The latter were kindly provided by Dr. W.W. Cai, Baylor College, Houston, Texas, USA.
Table 1

List of BAC probes used to confirm the presence of the duplication

FISH-probe

Chromosomal Location

Location in MB (NCBI 36.1)

FISH-result

   

#8

der(8)

Subtelomere probe (Vysis)

8p23

0.55

1x

1x

RP11-29A2

8p23

5.106 – 5.256

1x

2x

RP5-991O23

8p23

5.342 – 5.459

1x

2x

CTD-2629I16

8p23

6.689 – 6.785

1x

2x

RP11-540E4

8p23

8.029 – 8.179

1x

2x

RP11-211C9

8p23

8.504 – 8.677

1x

2x

RP11-241P12

8p23

9.788 – 9.958

1x

2x

RP11-177H2

8p23

10.696 – 10.796

1x

2x

RP11-589N15

8p23

11.740 – 11.803

1x

2x

RP11-433L7

8p22

14.316 – 14.461

1x

2x

RP11-60C8

8p22

15.290 – 15.445

1x

2x

RP11-44L18

8p22

15.557 – 15.699

1x

2x

RP11-255E13

8p22

16.333 – 16.472

1x

2x

RP11-19N21

8p22

16.444 – 16.618

1x

2x

RP11-525O22

8p22

17.846 – 17.950

1x

2x

bA64C22 – BAC-PAC Chori resource

8p11.21

n.a.

1x

1x

If not indicated differently the probes were derived from Dr. W.W. Cai, Baylor College, Houston, Texas, USA.

Microsatellite analysis was done as previously described [10] using the markers listed in Table 2.
Table 2

List of used microsatellite probes and results obtained for mother, father and child

Marker

Chromosomal location

Location in MB (NCBI build 36.1)

Mother

Father

Child

Result

D8S264

8p23

2.14

ac

bb

ccc

mat. UPD

D8S1099

8p23

6.04

bb

aa

bbb

mat. UPD

D8S1130

8p22

11.80

ab

bc

bb

n.i.

D8S1106

8p22

12.81

ab

ab

ab

n.i.

D8S1145

8p22

18.40

bc

ab

bbc

paternal

D8S1477

8p12

32.08

ab

cc

acc

paternal

D8S1110

8q11

53.29

bb

ab

bb

n.i.

D8S1113

8q12

59.85

ac

bd

ad

i/n

D8S1119

8q21

87.33

ab

ab

ab

n.i.

D8S1132

8q23

107.40

cc

ab

bc

i/n

D8S1128

8q24

128.65

ac

ab

bc

i/n

D8S373

8q24

143.91

bd

ac

ad

i/n

Abbreviations: a, b, c = type of alleles, mat. UPD = maternal uniparental disomy, n.i. = non informative; i.n. = informative normal.

Results

GTG-banded chromosome preparations were suggestive of duplication in 8p (Figure 2). The karyotype was characterized in detail using MCB (Figure 4), subtelomeric and centromere-near probes (Figure 3). The examinations indicated an inverted duplication involving segment 8p12→8p23.3, and the karyotype was re-interpreted as 46,XY,dup(8)(pter->p23.3::p12->p23.3::p23.3->qter). The subtelomeric region on 8p was not deleted and the karyotype represented partial trisomy 8p23.3 to 8p12. Chromosome analysis of both parents revealed normal results, with no indication of a rearrangement in 8p.
https://static-content.springer.com/image/art%3A10.1186%2F1755-8166-2-14/MediaObjects/13039_2009_Article_42_Fig2_HTML.jpg
Figure 2

GTG-banding result showing only the normal (#8) and the aberrant chromosome 8 of the present case, accompanied by an ideogram of a normal chromosome 8.

https://static-content.springer.com/image/art%3A10.1186%2F1755-8166-2-14/MediaObjects/13039_2009_Article_42_Fig3_HTML.jpg
Figure 3

Result of multicolor banding (MCB) shows the MCB-pseudo-coloring, the fluorochrome-profiles and the GTG-ideogram of the normal and the derivative chromosome 8.

https://static-content.springer.com/image/art%3A10.1186%2F1755-8166-2-14/MediaObjects/13039_2009_Article_42_Fig4_HTML.jpg
Figure 4

The normal and the aberrant chromosome 8 of the present case are depicted in inverted DAPI. A centromeric probe (blue), a centromere-near probe (green) and a subtelomeric probe (red) were hybridized together and revealed a more complex nature of the rearrangement.

Microsatellite analysis (Figure 6) gave hints for an inverted duplication of the paternally derived chromosome 8 (markers D8S11145 and D8S1477 in Table 2). However, only maternal alleles could be observed for the markers D8S264 and D8S1099, both located in position 2.14 and 6.04 Mb according to NCBI build 36.1. A deletion of the corresponding region could have been an explanation for this finding, however, FISH using the three probes RP11-29A2, RP5-991O23 and CTD-2629I16 located in 5.2, 5.4 and 6.6 Mb, respectively, could not confirm this possibility (see Figure 5). Thus, a mitotic recombination of maternally and paternally derived chromosomes 8, involving a loss of the paternally derived region 8p23.3 must have appeared prior to the building of the inverted duplication (Figure 7).
https://static-content.springer.com/image/art%3A10.1186%2F1755-8166-2-14/MediaObjects/13039_2009_Article_42_Fig5_HTML.jpg
Figure 5

Three examples of the microsatellite anlysis result are shown. For the markers D8S264, D8S1145 and D8S1477 the different alleles are shown for the mother (M), the father (F) and the child (C). For result interpretation see Tab. 2.

https://static-content.springer.com/image/art%3A10.1186%2F1755-8166-2-14/MediaObjects/13039_2009_Article_42_Fig6_HTML.jpg
Figure 6

The normal and the aberrant chromosome 8 of the present case are depicted in inverted DAPI. In summary, the presence of three copies of the probes RP11-29A2 (green) and RP5-991O23 (red) could be proven by FISH.

https://static-content.springer.com/image/art%3A10.1186%2F1755-8166-2-14/MediaObjects/13039_2009_Article_42_Fig7_HTML.jpg
Figure 7

Suggested mode of formation of the derivative chromosome 8 of the present case.

Discussion

Several studies have shown that particular subset of segmental duplications such as the olfactory receptor (OR) gene clusters are the substrate for the formation of intrachromosomal rearrangements involving the short arm of chromosome 8. At the OR gene cluster, an intersister chromatid recombination [11] and an interhomologous chromatid ectopic recombination [12] event have been proposed for chromosome rearrangements of 8p. The inv dup (8) consistently originate in maternal meiosis [12] and all the mothers of subjects with inv dup (8p) are heterozygous for an inversion polymorphism, present in 26% of normal controls, between the OR gene clusters [11, 12]. Furthermore, polymorphic marker analysis also indicated that inv dup (8p) was partially heterodisomic indicating that two copies of maternal allele were present [13]. In our report, microsatellite analyses revealed the paternal origin of the duplication and gave hints for a mitotic recombination involving about 6 Mb in 8p23.3. The mode of formation of the derivative chromosome 8 in the present patient was suggested as loss of paternally derived region 8p23.3 and recombination of maternally and paternally derived chromosome 8 (Figure 7)

We report on an inverted duplication of region 8p12→23.3 presenting with significant motor development delay, hypotonia, facial dysmorphisms, ventricular septal defects and corpus callosum agenesis, most of which were reported in previous studies [47, 11]. The regions 8p21 and 8p22 were commonly duplicated in all patients with inv dup (8p). Though different breakpoint regions for inv dup (8p) are reported, the clinical findings are quite homogeneous. In our report, however, the subtelomeric region was not deleted. We propose that the phenotypic findings of these patients are mainly due to trisomy 8p12→23.3 with an inverted duplication of 8p. Recently, a duplication of 8p23.1 and triplication of 8p23.2 in patients affected by mental retardation and minor facial dysmorphisms have been presented [14].

A limited number of patients with inv dup 8p have so far been reported in the literature should not lead us to the conclusion that this duplication occurs extremely rare; it is more likely that it is rarely reported because of relatively non-specificity of the abnormalities in these patients and the cytogenetic band assignment by conventional cytogenetic analysis is difficult. The application of MCB demonstrates the occurrence of different inverted duplications within the short arm of chromosome 8.

Conclusion

Inverted duplications on chromosome 8p are observed more frequently by the aim of technical improvement in routine cytogenetics. More complex karyotypes are being delineated by widely available use of newly developed tools. In conclusion, the present patient suggests that there might be a certain predisposition to chromosome 8p for more complex aberrations other than inverted duplications, which should be considered during the cytogenetic evaluation.

Consent Section

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.

Declarations

Acknowledgements

We would like to thank to the family who participated in this study. This work was supported parts by the Ernst-Abbe-Stiftung and the Evangelische Studienwerk e.V. Villigst. The BAC probes listed in Table 1 were a generous gift of Dr. W.W. Cai, Baylor College, Houston, Texas, USA.

Authors’ Affiliations

(1)
Department of Genetics, Hacettepe University Faculty of Medicine
(2)
Institut für Humangenetik und Anthropologie
(3)
Department of Peditarics Cardiology, Hacettepe University Faculty of Medicine

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Copyright

© Aktas et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.