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Keywords:

  • chromosome 21;
  • mental retardation;
  • array-CGH;
  • 21q interstitial deletion;
  • thrombocytopenia

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. CLINICAL REPORTS
  6. RESULTS
  7. DISCUSSION
  8. URLS
  9. Acknowledgements
  10. REFERENCES

During the last few years, an increasing number of microdeletion/microduplication syndromes have been delineated. This rapid evolution is mainly due to the availability of microarray technology as a routine diagnostic tool. Microdeletions of the 21q22.11q22.12 region encompassing the RUNX1 gene have been reported in nine patients presenting with syndromic thrombocytopenia and mental retardation. RUNX1 gene is responsible for an autosomal dominant platelet disorder with predisposition to acute myelogenous leukemia. We report on three novel patients with an overlapping “de novo” interstitial deletion involving the band 21q22 characterized by array-CGH. All our patients presented with severe developmental delay, dysmorphic features, behavioral problems, and thrombocytopenia. Comparing the clinical features of our patients with the overlapping ones already reported two potential phenotypes related to 21q22 microdeletion including RUNX1 were highlighted: thrombocytopenia with ± mild dysmorphic features and syndromic thrombocytopenia with growth and developmental delay. © 2010 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. CLINICAL REPORTS
  6. RESULTS
  7. DISCUSSION
  8. URLS
  9. Acknowledgements
  10. REFERENCES

Several cases with a deletion of the long arm of chromosome 21 have been described, identified through standard cytogenetic analysis or array-CGH [Rethore and Dutrillaux, 1973; Yamamoto et al., 1979; Nielsen and Tranebjaerg, 1984; Huret et al., 1991; Bartsch et al., 1994; Chettouh et al., 1995; Theodoropoulos et al., 1995; Barnicoat et al., 1996; Orti et al., 1997; Valero et al., 1999; Ehling et al., 2004; Shaw-Smith et al., 2004; Yao et al., 2006; Hoyer et al., 2007; Beri-Dexheimer et al., 2008; Shinawi et al., 2008; Lyle et al., 2009; Lindstrand et al., 2010; van der Crabben et al., 2010]. To date 12 deletions involving bands 21q22.11q22.12 have been reported in literature and recurrent features include prenatal growth retardation with microcephaly, developmental delay and thrombocytopenia. Here, we report on the clinical description and molecular data of three new patients with de novo 21q22.11q22.12 interstitial deletions, identified by array-CGH and compare their features with those of other patients with overlapping deletions. Furthermore, we investigated the deleted region for the presence of both coding and miRNAs genes.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. CLINICAL REPORTS
  6. RESULTS
  7. DISCUSSION
  8. URLS
  9. Acknowledgements
  10. REFERENCES

Oligonucleotide Array CGH

Array based-CGH analysis was performed using commercially available oligonucleotide microarrays Human Genome CGH Microarray 44B Kit and Human Genome CGH Microarray 244A Kit (Agilent Technologies, Santa Clara, CA) as previously reported using patients' genomic DNA extracted from peripheral blood samples [Pescucci et al., 2007; Bonaglia et al., 2008]. Labeling and hybridization were performed following the protocols provided by Agilent Technologies. The median spatial resolution is nearly 35 kb for 44B and 8.9 kb for 244A while the functional resolution is nearby 100 kb for 44B and 24 kb for 244A.

CLINICAL REPORTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. CLINICAL REPORTS
  6. RESULTS
  7. DISCUSSION
  8. URLS
  9. Acknowledgements
  10. REFERENCES

Patient 1

The patient is a 17-year-5-month old girl, the first child of healthy nonconsanguineous parents. At the time of delivery the mother and father were 33 and 39 years old respectively. She was born after a prolonged labor at the end of a pregnancy where reduced fetal movements and placenta aging were detected. At birth, she showed the following parameters: weight 2,400 g (<3th centile), length 47 cm (10–25th centile), head circumference (OFC) 33 cm (25–50th centile). Soon after birth she showed difficulty to thrive, inconsolable crying and sleep-wake rhythm alterations. Frequent colds and otitis during infancy were noted. At the age of 3 months lack of eye contact, hypotonia and failure to thrive were detected. She had severe developmental delays while she began to sit unassisted at 1 year of age, she never acquired verbal abilities and has never acquired sphincter control. X-rays of her hands showed short second phalanx of II and V finger bilaterally, cone-shaped epiphyses of phalanges and delayed bone age (7 months vs. 2 months and 10 years vs. 7.5 years). X-rays of her feet showed acro-osteolysis of the third phalanges of the I and II finger bilaterally. Different blood tests showed persistent thrombocytopenia and erythrocytopenia, and normal levels of thyroid hormones. Standard ophthalmologic and audiometric examinations, a resting ECG, EEG, echocardiography, brain MRI and karyotype with 400 bands resolution were also normal. She was first seen at our medical unit at the age of 17.5 years (Fig. 1). Her weight was 38 kg (<5th centile), height 131 cm (<5th centile), and OFC 52 cm (<3th centile). She also presented with a round and coarse face, pigmented peri-orbital skin, downslanting palpebral fissures, almond-shaped eyes, downturned corners of the mouth, prominent lower lip, crowded teeth, small and low-set ears, small hands and feet, dystrophic nails, and dry skin (Fig. 1). She showed self-aggressiveness, trunk rocking, tongue stereotypic movements, bruxism, and hypersialorrhea. Presently, she is able to walk alone but she does not eat solid food and speech is absent.

thumbnail image

Figure 1. A: Photographs of the three patients described in this paper at the age of 17 years and 5 months (#1), 23 years (#2), and 10 years (#3). Frontal view showing hypertelorism, broad nose, down turned corner of the mouth and thin upper lip. B: Pictures of hand and feet of Patients 1 and 2 showing dysplastic nails and edema of the feet. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Patient 2

This boy was the first child of healthy unrelated young parents. The mother had a previous spontaneous miscarriage. Pregnancy was normal. Delivery took place at 38 weeks of gestation. The newborn had growth retardation (weight: 2,400 g, length: 45 cm). He was referred for the first time at the age of 1.5 years. Clinical examination showed facial dysmorphisms with scaphocephaly, hypertelorism, smooth philtrum, anteverted nares, camptodactyly, hypoplastic nails and edema of the feet. CT scan demonstrated corpus callosum agenesis. Thrombocytopenia was diagnosed at 13 months of age. Psychomotor milestones were delayed: walking was achieved at age 6.5 years and he never developed speech. He developed epilepsy. At 24 years of age the patient had a very short stature (142 cm), microcephaly and facial dysmorphisms with midface hypoplasia, short palpebral fissures, bulbous nasal tip, and thick lips (Fig. 1). Brachydactyly, clino-camptodactyly, proximal implantation of the thumbs, hypoplasia of the toe nails, sacral dimple and hypoplastic nipples were also noted. Hematological investigations showed persistent mild thrombocytopenia with no hemorrhagic manifestations.

Patient 3

She was referred at the age of 8 years for intellectual disabilities, dysmorphisms, and thrombocytopenia. She was born at term with the following parameters: weight 2,740 g (−1 SD), length 47 cm (−1 SD) and OFC 30 cm (−3 SD). She had severe feeding difficulties. Atrial septal defect and thrombocytopenia were detected in the neonatal period. Psychomotor development was significantly delayed. At the age of 8 years, language was very poor and she had epilepsy. She exhibited behavioral problems with hyperactivity and sleeping problems. Facial appearance was remarkable with microcephaly, strabismus, bulbous tip of the nose and thin upper vermillion (Fig. 1). Brain MRI was unremarkable and she had persistent thrombocytopenia.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. CLINICAL REPORTS
  6. RESULTS
  7. DISCUSSION
  8. URLS
  9. Acknowledgements
  10. REFERENCES

A hundred Kb and 24 Kb resolution array-CGH experiments were performed and a 21q22.11q22.12 microdeletion of different size was identified in all three patients: 4.47 Mb in Patient 1, 2.9 Mb in patient 2 and 4.3 Mb in Patient 3 (Fig. 2A). The proximal breakpoint of the 21q deletion in Patient 1 is mapped in 21q22.11, between 32.21 and 32.29 Mb (last oligonucleotide present and first deleted respectively), while the distal breakpoint is located between 36.64 and 36.68 Mb in 21q22.12 (last oligonucleotide deleted and first present, respectively). The proximal breakpoint of the 21q deletion in Patient 2 is mapped in 21q22.11 between 33.43 and 33.45 Mb, while the distal breakpoint is located between 36.36 Mb and 36.37 Mb in 21q22.12. The proximal breakpoint of the 21q deletion in Patient 3 is mapped in 21q22.11, between 4.01 Mb and 34.06 Mb, while the distal breakpoint is located between 38.32 and 38.34 Mb in 21q22.13. To confirm array data, a second array experiment was performed in Patient 1, whereas FISH analysis was done in Patients 2 and 3. All rearrangements were confirmed in the patients, while the parents showed normal results, confirming the de novo origin of the rearrangements (for Patient 2 only the mother was tested, whereas father's DNA was not available). Analysis of the gene content of the 21q minimal deleted region in the three patients showed the presence of 12 known genes, three of which are known disease genes (KCNE1, KCNE2, and RUNX1) (Fig. 2B).

thumbnail image

Figure 2. A: Array CGH results indicating the 21q22.11q22.12 microdeletion. B: The deletion indicated by the array CGH experiment is mapped against the corresponding genomic region in the UCSC genome browser build 36.1 (2006). In the lower part, the extent of the deletion in the patients described in this report is compared with that in the six patients with small deletions already reported. Common deleted regions between the three present patients and the six already reported are indicated by interrupted lines. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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In addition, the array-CGH analysis showed an apparently de novo chromosome 17 interstitial duplication of 0.31 Mb in patient 1 extending from 19.58 to 19.79 Mb, which includes only three genes, ALDH3A1, ULK2, and AKAP10. Given the size and the gene content analysis it is likely that this CNV might poorly influence the patient's phenotype.

MiRNA content analysis evidenced the presence of mir-802. In order to identify mir-802 target sites we used the bioinformatic algorithm “TargetScan” (http://www.targetscan.org). Among the 125 putative mRNA targets with higher score we have selected the CBFB for its possible involvement in the modulation of the phenotype.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. CLINICAL REPORTS
  6. RESULTS
  7. DISCUSSION
  8. URLS
  9. Acknowledgements
  10. REFERENCES

To date, 11 patients with deletions of the 21q22.12 locus including RUNX1 and neighboring genes have been reported in the literature [Chettouh et al., 1995; Yao et al., 2006; Hoyer et al., 2007; Beri-Dexheimer et al., 2008; Shinawi et al., 2008; Lyle et al., 2009; Lindstrand et al., 2010; van der Crabben et al., 2010]. Three of them have large deletions with less defined breakpoints. All the others have been characterized by array-CGH and have different size deletions. Among these, one has a big deletion of 19.72 Mb, one presents a highly complex intrachromosomal rearrangement with four deleted segments and four duplicated segments on 21q [Lindstrand et al., 2010], while the others have deletions ranging from 3.66 to 0.71 Mb.

We compared the clinical features present in the three patients described in the present paper with those presenting relatively small overlapping deletions (Table I). Seven patients developed thrombocytopenia, with acute myelogenous leukaemia (AML) in one patient and myelodysplastic features in a second patient, whereas the hematological phenotype was not recorded in the remaining two. Low birth weight, short stature, and microcephaly are frequent features (7/9). The exceptions are Patient 4 reported by van der Crabben et al. [2010] and Patient 5, reported by Shinawi et al. [2008] who presented normal birth weight and did not show microcephaly although Patient 5 had the OFC between 5th and 10th centile. Most patients beside Patients 4 and 5 had significant developmental delay with severe impairment of language skills (7/9). It is worth noting that Patients 4 and 5 harboring the smallest deletions present milder developmental manifestations (thrombocytopenia and mild dysmorphisms). Other apparently non-specific minor and major anomalies are reported in some of them (Table I). Brain MRI was reported as unremarkable in four patients, and showed abnormal findings in three with corpus callosum agenesis in two, while for the remaining two patients no information is available. Facial changes are reported in all patients clinically described. Although some common facial features, such as downslanted palpebral fissures, low-set ears, thin upper vermillion, downturned corners of the mouth and broad nose can be identified, the facial appearance does not seem to be very specific (Table I and Fig. 1).

Table I. Clinical Findings in Patients With 21q22 Overlapping Deletions
Clinical findingsPresent patient 1Present patient 2Present patient 3van der Crabben et al. 2010Shinawi et al. 2008Bèri-Dexheimer et al. 2008Lyle et al. 2009Hoyer et al. 2007
Case 1Case 2
  • Here the first and last locus deleted are indicated in accordance with the UCSC genome browser build 36.1 (2006).

  • n.r., not reported; M, male; F, female; y, year, m, months.

  • a

    Dislocation of hips.

  • b

    Hypoplastic nails.

  • c

    Sacral dimple.

  • d

    Hypoplastic nipples.

  • e

    Inverted nipples.

  • f

    Renal cysts.

Patient no.123456789
Molecular karyotypeq22.11–q22.12q22.11–q22.12q22.11–q22.13q22.11–q22.12q22.12q22.11–q22.12q22.11–q22.12q22.11–q22.12q22.11–q22.12
Experimental methodArray 44 KArray 244 KArray 244 KArray 105 KArray 244 KArray 244 KGeneSensor array 300Bac array100 SNP array
Breakpoints (Mb)32.21–36.68 (4.47 Mb)33.45–36.37 (2.92 Mb)34.06–38.30 (4.24 Mb)34.21–35.77 (1.56 Mb)34.79–35.50 (0.71 Mb)33.83–35.64 (1.81 Mb)32.67–36.33 (3.66 Mb)34.32–35.66 (1.34 Mb)32.32–35.36 (3.04 Mb)
SexFMFMMFFn.r.n.r.
Age at assesment17 y 5 m23 y8 y5 y6 y8 y10 yn.r.n.r.
Intrauterine growth retardation++n.r.+++n.r.
Low birth weight+++25th centile+++n.r.
Failure to thrive+++++n.r.n.r.
Microcephaly+++5–10th centile++(−2.6 SD)+−?
Short stature++n.r.n.r.+++++
Developmental delay/mental retardation+++Fine motor++++
Behavioural problems+++n.r.+n.r.n.r.n.r.
Seizures++n.r.
Growth delay++n.r.n.r.+++++
Hypertelorismn.r.+n.r.+++n.r.
Epicantic folds+n.r.++n.r.
Short palpebral fissuresn.r.+n.r.+n.r.n.r.
Down-slanting palpebral fissures++n.r.+n.r.
Eye anomalies = strabism++Intermittent strabism enophthalmian.r.
Broad nasal bridge+++++++n.r.
Down-turned corners of mouth+++n.r.++ n.r.
Thin upper vermillion++n.r.++− (paternal north african ascent)n.r.n.r.
Retrognathia+n.r.PrognathismPrognathism?n.r.
Low set ears++n.r.n.r.n.r.n.r.n.r.
Heart defects++ (great vessel trasposition)+ (inter-atrial septal defect)+
Skeletal anomalies+CamptodactylyClinodactylyn.r.
Abnormal genitalia+ (absence of left testis)+ (labiamajora hypoplasia)n.r.n.r.
Ectodermal anomalies++ (small depigmentation of the skin and linea alba)+?n.r.n.r.
MRI/CT cerebral anomalies+ (corpus callosum agenesis)+ (dysgenic corpus callosum)+ (increased size of lateral ventricles)n.r.n.r.
Thrombocytopenia+++++++n.r.n.r.
MDS/AMLn.r.+n.r.n.r.
Other anomaliesabbcd  eecfn.r.n.r.
Mir-802 deletedYesYesYesNoNoNoYesNoNo
MDS/AMLNoNoNoYesYesNoNon.r.n.r.

Deletion of 21q22.11q22.12 region encompassing the RUNX1 gene is a true example of contiguous gene deletion syndrome. The common deleted region in all nine patients is spanning from 34.79 to 35.36 Mb and contains four genes: RUNX1, RCAN1, CLIC6, and KCNE1, while is interesting noting that four patients appear to share a recurrent breakpoint at the distal end soon after RUNX1 gene (Fig. 2B). The analysis of the genomic structure of that region did not reveal the presence of low copy repeats (LCR) but a Non-Allelic Homologous Recombination mechanism (NAHR), due to the presence of high frequency of small DNA repeat elements can not be excluded (Fig. 2B).

Haploinsufficiency at the RUNX1 locus is responsible for the hematological phenotype. Patients harboring a point mutation or an intragenic deletion of RUNX1 exhibit thrombocytopenia and are prone to develop acute myelogenous leukemia (AML) (FPD/AML; MIM 601399) [Osato, 2004; Kuo et al., 2009]. Given this predisposition, such patients should be provided with a strict hematological follow up.

Regulator of calcineurin 1 (RCAN1) belongs to a highly conserved family of proteins that modulate the activity of calcineurin (CaN). It is a Down syndrome critical region protein that regulates long-term potentiation and memory by inhibition of phosphatase signaling and thus could play a role during central nervous system development [Hoeffer et al., 2007; Porta et al., 2007].

CLIC6 is a member of the intracellular chloride channel family and it interacts with dopamine D(2)-like receptors [Griffon et al., 2003]. Several mutations in chloride channel genes have been shown to be responsible for a variety of human diseases including myotonias, kidney stone disease, cystic fibrosis, and osteopetrosis [Riordan and Dieppe, 1989; Koch et al., 1992; Lloyd et al., 1996; Kornak et al., 2001].

KCNE1 gene encodes the potassium voltage-gated channel, whose heterozygous loss of function mutations cause the long QT syndrome 5 (LQTS5) [Splawski et al., 1997]. In none of the patients, including ours, has LQTS been reported. However, in our patient, as probably in the other reported patients, stress ECG has not been performed. In addition, except for the Patient 4 reported by Shinawi et al. [2008], the other deletions include the KCNE2 gene, responsible for LQTS6. Although cardiac conduction defects have not been found in the reported patients, given the small number of patients we recommend a cardiologic evaluation in patients with this microdeletion syndrome.

Bioinformatic analysis of the 21q22 region spanning from 32.21 to 38.30 Mb including the deleted regions of all patients allowed to point out the presence of one microRNA, mir-802. This miRNA is deleted in four out of the nine patients reported. We speculate that the presence of mir-802 could correlate with the hematological phenotype of the patients. One of the putative targets of mir-802 seems to be CBFB gene that encodes the non-DNA-binding CBFβ subunit of the CBF family which includes also the three distinct DNA binding CBFα subunits (RUNX1, RUNX2, and RUNX3). The RUNX1 and CBFb proteins associate in a heterodimeric transcription factor that is required for the development of normal hematopoiesis [Speck and Gilliland, 2002]. The way this miRNA is implicated in the hematological phenotype has yet to be addressed by expression studies. We speculate that the presence of mir-802 may correlate with a worse outcome of the hematological phenotype when RUNX1 is deleted, and act as an additional cofactor toward tumor progression together with a second inactivating RUNX1 mutational event, recently reported by Preudhomme et al. [2009].

In conclusion, considering literature data and the clinical and molecular features of the patients described here, two phenotypes related to 21q22 microdeletion including RUNX1 could be delineated: thrombocytopenia with ± mild dysmorphic features and syndromic thrombocytopenia with growth and developmental delay. Furthermore the comparison of the regions deleted in these two different phenotypes supports the hypothesis of van der Crabben et al. [2010] indicating that the haploinsufficiency of ITSN1 gene could be implicated in MR. On the other hand the presence of severe developmental and growth delay still has to be clarified in the patient (Patient 42) reported by Lyle et al. [2009] harboring a very similar deletion to that of Patients 4 and 5 (Fig. 2B).

Recently, due to the introduction of the array-CGH in the clinical practice we have seen relatively rapid descriptions of patients with 21q22 deletions. Our work further delineates the 22q22 deletion phenotype and encourages to evaluating the presence of miRNA and their target genes when phenotype–genotype correlation is attempted.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. CLINICAL REPORTS
  6. RESULTS
  7. DISCUSSION
  8. URLS
  9. Acknowledgements
  10. REFERENCES

This work is supported by Telethon grant GTB07001 to A.R. and grant from University of Siena (PAR 2006) to F.M. We are grateful to Prof. P. Jonveaux and Dr. Pr. Bruno Leheup for providing clinical information regarding patient 7. We would also like to thank all patients and parents for their precious collaboration.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. CLINICAL REPORTS
  6. RESULTS
  7. DISCUSSION
  8. URLS
  9. Acknowledgements
  10. REFERENCES
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