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A 15q24 microduplication, reciprocal to the recently described 15q24 microdeletion, in a boy sharing clinical features with 15q24 microdeletion syndrome patients
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MODEL
Available online at www.sciencedirect.com
European Journal of Medical Genetics 51 (2008) 520e526 http://www.elsevier.com/locate/ejmg
Original article
A 15q24 microduplication, reciprocal to the recently described 15q24 microdeletion, in a boy sharing clinical features with 15q24 microdeletion syndrome patients Ann-Britt Kiholm Lund*, Hanne Dahlgaard Hove, Maria Kirchhoff Department of Clinical Genetics, Blegdamsvej 9, 4062, Rigshospitalet, Copenhagen, Denmark Received 28 May 2008; accepted 22 July 2008 Available online 7 August 2008
Abstract A 15q24 microduplication, reciprocal to the minimal critical region for the recently described 15q24 microdeletion syndrome, was found in a 2-year-old boy by 244k Agilent oligoarray CGH analysis. The boy had global developmental delay and dysmorphic facial features, digital and genital abnormalities. The duplication was inherited from a healthy father, but was considered clinically significant, as the patient shared clinical features with 15q24 microdeletion syndrome patients. To our knowledge this is the first report of a patient with a 15q24 microduplication. Ó 2008 Elsevier Masson SAS. All rights reserved. Keywords: 15q24 Microduplication; 244k Agilent oligoarray; 15q24 Microdeletion syndrome
1. Introduction A microdeletion syndrome involving chromosome 15q24 has recently been described [6]. Consistent features of this syndrome are global developmental delay, digital abnormalities, genital abnormalities (hypospadias or micropenis), and dysmorphic facial features, including high anterior hairline, broad eyebrows, hypertelorism, downslanting palpebral fissures, long philtrum, and full lower lip [1,3,6]. * Corresponding author. Tel.: þ45 28 34 64 28. E-mail address: [email protected] (A.-B. Kiholm Lund). 1769-7212/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2008.07.008
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The size of the deletions varied from 1.7 to 3.9 Mb, with a minimal critical deletion for the syndrome of 1.7 Mb (chr15:72.15e73.85 Mb) [6]. The deletions were flanked by low-copy repeats (LCRs). LCRs predispose chromosomal regions to non-allelic homologous recombination (NAHR), leading to deletions, duplications or inversions [8]. Similar to the 15q24 deletions a number of recurrent microdeletions, e.g. deletions of 7q11.23 (WilliamseBeuren syndrome), 15q11-q13 (Prader-Willi/Angelman syndrome), 17q11.2 (Smith-Magenis syndrome), and 22q11.2 are flanked by LCRs. Microduplications reciprocal to the recurrent microdeletions mentioned above have been reported, however, so far only in a limited number of patients. We report a patient with a duplication reciprocal to the critical region of the 15q24 microdeletion syndrome. The patient has a number of phenotypical traits in common with patients with the 15q24 microdeletion syndrome. Our patient had inherited the duplication from his healthy father, whereas all investigations of parental samples for patients reported with 15q24 microdeletion syndrome, showed that the deletions had occurred de novo [1,3,6]. 2. Materials and methods 2.1. Patient recruitment The patient was referred for routine array CGH analysis due to mental retardation and dysmorphic features. 2.2. Array CGH Array CGH was performed using the Agilent Human Genome Microarray Kit 244A (Agilent Technologies, Santa Clara, CA, USA). This is a high resolution 60-mer oligonucleotide based microarray containing about 244.000 60-mer probes spanning coding and non-coding genomic sequences with median spacing of 7.4 kb and 16.5 kb, respectively. Labeling and hybridization were performed according to the protocol provided by Agilent (Protocol v4.0, June 2006). Briefly, 2 mg of patient DNA and of a sex-matched control were double-digested with AluI and RsaI (Promega, Madison, WI, USA) for 2 h at 37 C. The digested DNA was labeled by random priming using the Agilent Genomic DNA Labeling Kit Plus. Patient DNA and control DNA was labeled with Cy3-dUTP and Cy5-dUTP, respectively. Labeled products were purified by Microcon YM-30 filters (Millipore, Billerica, MA, USA). Patient and control DNAs were pooled and hybridized with 50 mg of Human Cot I DNA at 65 C with rotation for 40 h. Washing was performed according to the Agilent protocol. Arrays were analyzed using the Genepix 4200A scanner (Axon Instruments, Union City, CA, USA) and the Agilent Feature Extraction software (v9.1). Results were presented by Agilent CGH Analytics software (v3.4). DNA sequence information refers to the public UCSC database (Human Genome Browser, May 2004 Assembly (hg 17)). 3. Results 3.1. Case report The boy was the first child of Danish non-consanguineous parents. No family history of mental retardation. Delivery was induced at gestational age 39w þ 3d due to oligohydramnios.
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Birth weight was 2750 g (10th centile), length 48 cm (10th centile) and head circumference 34 cm (appropriate for length). Several dysmorphic features were observed at birth: hypospadias, joint contractures (possible due to oligohydramnios), and his second and fifth fingers were overlapping the third and the fourth fingers, respectively, on both hands. He had low-set, posteriorly rotated ears, broad nasal bridge, hypertelorism, downslanting palpebral fissures, long eyelashes, and epicantal folds. As he grew older, additional features became apparent, included thick upper eyelids, high-arched eyebrows, strabismus, a triangular mouth with a thick upper lip and a smooth philtrum, and a low posterior hairline. His nails on fingers and toes are hypoplastic and the finger pads are broad, but the overlapping of the fingers has gradually disappeared. His weight has increased from the 10th centile at birth to just below the 25th centile at 14 months, and it is now, at age 26 months, at the 50th centile. His length has also increased from the 10th centile to the 75th centile presently. His head circumference has been appropriate for his weight. His global development is delayed. At 14 months of age he was able to roll from back to stomach, and he learned to sit without support at 17 months. Presently, at age 26 months, he walks a few steps with support, gives good contact, but has no spoken words. On examination he is slightly hypertonic with increased deep tendon reflexes. Hearing examination showed slightly decreased hearing, possibly due to several episodes of middle ear infection. Eye examination revealed hypermetropia, astigmatism and slight strabismus (Fig. 1). Magnetic Resonance Imaging on day 6 showed agenesis of the corpus callosum, dilatation of the lateral ventricles and a small hemorrhage in the left parital region.
Fig. 1. Photograph of proband at age 26 months. Note the dysmorphic facial features.
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G-banding of blood lymphocytes and cultured skin fibroblasts showed normal male karyotype and excluded mosaicism of trisomy 18. Subtelomeric Multiplex Ligation-dependent Probe Amplification (MLPA) gave normal results. 3.2. Array CGH Array CGH investigation of the proband showed a duplication of chromosome 15q24.1q24.2 (Fig. 2). The minimum size of the duplication was 1653 kb (baseposition chr15:72185701e 73838909) and the maximum size was 1715 kb (baseposition chr15: 72141744e73856842). The size of the duplication is in accordance with the minimal critical region for the reciprocal microdeletion reported by Sharp et al.[6], and the breakpoints of the duplication are within flanking low copy repeats. Investigation of parental samples showed the proband’s father to carry an identical duplication of chromosome 15q24.1q24.2 (Fig. 2). 4. Discussion A number of recurrent microdeletions associated with well-known syndromes have been shown to arise from NAHR. Turner et al. studied germline rates of de novo meiotic deletions and duplications in four target regions for NAHR [10]. They found that the overall frequency of deletions outweighed the frequency of duplications roughly twofold. Yet, this does not explain the discrepancy between the large number of patients diagnosed with recurrent microdeletion syndromes and the few patients diagnosed with syndromes associated with reciprocal duplications.
Fig. 2. Results of 244k Agilent oligoarray analysis of chromosome 15. (A) Moving average based on a window of 20 probes. Dotted lines represent log2 ratios. (B) Detailed view of a 2.47 Mb region of chromosome 15q24 including the duplication. Arrow indicates the minimal size of the duplication (1653 kb).
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Microduplications may result in phenotypic features included in the spectrum of corresponding microdeletions, as reported for duplications of 17p11.2 and 22q11.21 [5,11]. They may also result in phenotypes with features that are in fact opposite to those of the corresponding microdeletions, as has been described for the microduplications of the Williamse Beuren syndrome locus and the Sotos syndrome locus, respectively [2,4,7,9]. The phenotypes associated with microduplications seem to be milder than those associated with microdeletions. However, due to the relative small number of patients with microduplications reported, the clinical phenotypes are not yet well defined. To our knowledge this is the first report of a patient with a 15q24 microduplication. The phenotypic features of patients with 15q24 microdeletions include global developmental delay, digital abnormalities, genital abnormalities, and dysmorphic facial features. Our patient shares a number of these features (Table 1). He has developmental delay, genital abnormalities (hypospadias), and digital abnormalities. Certain dysmorphic facial features are also comparable. This applies especially to the eyes, where our patient as well as the patients with 15q24 microdeletion has hypertelorism, downslanting palpebral fissures and thick eyelids (Fig. 3). Unlike patients carrying the deletions, our patient does not have a high frontal hairline or broad medial eyebrows. Table 1 Clinical features of the proband compared to clinical features reported in patients with 15q24 microdeletion Paper
Reported patients Size of duplication/deletion Genomic location
Inheritance Gender Age (years) Short stature Developmental delay Hypotonic Microcephaly Brain abnormalities by MRI High frontal hair line Downslanting palpebral fissures Epicantal folds Hypertelorism Strabismus Broad medial eyebrows Smooth philtrum Thick lower lip Genital anomaly Abnormalities of fingers Ear abnormalities
Microdeletion 15q24
Microduplication 15q24
Sharp et al. [6], Cushman et al. [1], Klopocki et al. [3]
Current case
7
1 1.7 Mb 72.14e73.85 Mb
1.7e3.9 Mb 72.15e76.01 Mb 72.15e76.01 Mb 72.15e73.85 Mb 70.40e74.21 Mb 72.2e75.9 Mb Two unknown Five de novo and two unknown Six male and one female 14, 15, 33, 14, 1, 11, 10 3/7 7/7 4/7 4/7 3/7, 2nd 5/7, 2nd 4/7, 2nd 2/7, 1nd 4/7, 2nd 4/7 5/7, 2nd 4/7, 2nd 5/7, 2nd 5/7 6/7 4/7, 1nd
nd e not determined or described. a The patient had a full lower lip, but this feature has gradually disappeared.
Paternal Male 2 þ þ þ þ þ þ þ þ/a þ þ þ
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Fig. 3. Photograph of our patient at age 14 months (right) and of a patient with 15q24 deletion (left) reported by Sharp et al., 2007 [6]. Printed with permission from Editorial Board of Human Molecular Genetics and the authors.
As this is the first patient reported with 15q24 duplication, and the imbalance is inherited from a healthy father, it cannot be ruled out that the patient has another genetic defect, which contributes to or actually causes his phenotype, leaving the duplication an accidental finding. However, the variability of the phenotype might be caused by reduced penetrance or multifactorial influences, as suggested by Kriek et al. in an equivalent scenario of a family with a microduplication reciprocal to the WilliamseBeuren critical region [4]. Indeed, the overlap in the phenotypes of 15q24 microdeletion syndrome patients and our patient strongly support the clinical significance of the duplication. In recent years application of array CGH for investigation of children with mental retardation and dysmorphic features has gained widespread use, and many new microdeletion/ duplication syndromes are being reported. We anticipate that more reports on patients with 15q24 microdeletions will delineate the clinical significance of this chromosomal imbalance in the near future.
Acknowledgements We gratefully acknowledge the parents of the patient for giving their consent to publish clinical data and photos.
References [1] L.J. Cushman, W. Torres-Martinez, A.M. Cherry, M.A. Manning, O. Abdul-Rahman, C.E. Anderson, H.H. Punnett, V.C. Thurston, D. Sweeney, G.H. Vance, A report of three patients with an interstitial deletion of chromosome 15q24, Am. J. Med. Genet. A 137 (2005) 65e71. [2] M. Kirchhoff, A.M. Bisgaard, M. Duno, F.J. Hansen, M. Schwartz, A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features, Eur. J. Med. Genet. 50 (2007) 256e263.
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[3] E. Klopocki, L.M. Graul-Neumann, U. Grieben, H. Tonnies, H.H. Ropers, D. Horn, S. Mundlos, R. Ullmann, A further case of the recurrent 15q24 microdeletion syndrome, detected by array CGH, Eur. J. Pediatr. (2007). [4] M. Kriek, S.J. White, K. Szuhai, J. Knijnenburg, G.J. van Ommen, J.T. den Dunnen, M.H. Breuning, Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications, Eur. J. Hum. Genet. 14 (2006) 180e189. [5] L. Potocki, K.S. Chen, S.S. Park, D.E. Osterholm, M.A. Withers, V. Kimonis, A.M. Summers, W.S. Meschino, K. Anyane-Yeboa, C.D. Kashork, L.G. Shaffer, J.R. Lupski, Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion, Nat. Genet. 24 (2000) 84e87. [6] A.J. Sharp, R.R. Selzer, J.A. Veltman, S. Gimelli, G. Gimelli, P. Striano, A. Coppola, R. Regan, S.M. Price, N.V. Knoers, P.S. Eis, H.G. Brunner, R.C. Hennekam, S.J. Knight, B.B. de Vries, O. Zuffardi, E.E. Eichler, Characterization of a recurrent 15q24 microdeletion syndrome, Hum. Mol. Genet. 16 (2007) 567e572. [7] M.J. Somerville, C.B. Mervis, E.J. Young, E.J. Seo, M. del Campo, S. Bamforth, E. Peregrine, W. Loo, M. Lilley, L.A. Perez-Jurado, C.A. Morris, S.W. Scherer, L.R. Osborne, Severe expressive-language delay related to duplication of the WilliamseBeuren locus, N. Engl. J. Med. 353 (2005) 1694e1701. [8] P. Stankiewicz, J.R. Lupski, Genome architecture, rearrangements and genomic disorders, Trends Genet. 18 (2002) 74e82. [9] M. Tassabehji, D. Donnai, WilliamseBeuren Syndrome: more or less? Segmental duplications and deletions in the WilliamseBeuren syndrome region provide new insights into language development, Eur. J. Hum. Genet. 14 (2006) 507e508. [10] D.J. Turner, M. Miretti, D. Rajan, H. Fiegler, N.P. Carter, M.L. Blayney, S. Beck, M.E. Hurles, Germline rates of de novo meiotic deletions and duplications causing several genomic disorders, Nat. Genet. 40 (2008) 90e95. [11] T.M. Yobb, M.J. Somerville, L. Willatt, H.V. Firth, K. Harrison, J. MacKenzie, N. Gallo, B.E. Morrow, L.G. Shaffer, M. Babcock, J. Chernos, F. Bernier, K. Sprysak, J. Christiansen, S. Haase, B. Elyas, M. Lilley, S. Bamforth, H.E. McDermid, Microduplication and triplication of 22q11.2: a highly variable syndrome, Am. J. Hum. Genet. 76 (2005) 865e876.
MODEL
Available online at www.sciencedirect.com
European Journal of Medical Genetics 51 (2008) 520e526 http://www.elsevier.com/locate/ejmg
Original article
A 15q24 microduplication, reciprocal to the recently described 15q24 microdeletion, in a boy sharing clinical features with 15q24 microdeletion syndrome patients Ann-Britt Kiholm Lund*, Hanne Dahlgaard Hove, Maria Kirchhoff Department of Clinical Genetics, Blegdamsvej 9, 4062, Rigshospitalet, Copenhagen, Denmark Received 28 May 2008; accepted 22 July 2008 Available online 7 August 2008
Abstract A 15q24 microduplication, reciprocal to the minimal critical region for the recently described 15q24 microdeletion syndrome, was found in a 2-year-old boy by 244k Agilent oligoarray CGH analysis. The boy had global developmental delay and dysmorphic facial features, digital and genital abnormalities. The duplication was inherited from a healthy father, but was considered clinically significant, as the patient shared clinical features with 15q24 microdeletion syndrome patients. To our knowledge this is the first report of a patient with a 15q24 microduplication. Ó 2008 Elsevier Masson SAS. All rights reserved. Keywords: 15q24 Microduplication; 244k Agilent oligoarray; 15q24 Microdeletion syndrome
1. Introduction A microdeletion syndrome involving chromosome 15q24 has recently been described [6]. Consistent features of this syndrome are global developmental delay, digital abnormalities, genital abnormalities (hypospadias or micropenis), and dysmorphic facial features, including high anterior hairline, broad eyebrows, hypertelorism, downslanting palpebral fissures, long philtrum, and full lower lip [1,3,6]. * Corresponding author. Tel.: þ45 28 34 64 28. E-mail address: [email protected] (A.-B. Kiholm Lund). 1769-7212/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2008.07.008
A.-B. Kiholm Lund et al. / European Journal of Medical Genetics 51 (2008) 520e526
521
The size of the deletions varied from 1.7 to 3.9 Mb, with a minimal critical deletion for the syndrome of 1.7 Mb (chr15:72.15e73.85 Mb) [6]. The deletions were flanked by low-copy repeats (LCRs). LCRs predispose chromosomal regions to non-allelic homologous recombination (NAHR), leading to deletions, duplications or inversions [8]. Similar to the 15q24 deletions a number of recurrent microdeletions, e.g. deletions of 7q11.23 (WilliamseBeuren syndrome), 15q11-q13 (Prader-Willi/Angelman syndrome), 17q11.2 (Smith-Magenis syndrome), and 22q11.2 are flanked by LCRs. Microduplications reciprocal to the recurrent microdeletions mentioned above have been reported, however, so far only in a limited number of patients. We report a patient with a duplication reciprocal to the critical region of the 15q24 microdeletion syndrome. The patient has a number of phenotypical traits in common with patients with the 15q24 microdeletion syndrome. Our patient had inherited the duplication from his healthy father, whereas all investigations of parental samples for patients reported with 15q24 microdeletion syndrome, showed that the deletions had occurred de novo [1,3,6]. 2. Materials and methods 2.1. Patient recruitment The patient was referred for routine array CGH analysis due to mental retardation and dysmorphic features. 2.2. Array CGH Array CGH was performed using the Agilent Human Genome Microarray Kit 244A (Agilent Technologies, Santa Clara, CA, USA). This is a high resolution 60-mer oligonucleotide based microarray containing about 244.000 60-mer probes spanning coding and non-coding genomic sequences with median spacing of 7.4 kb and 16.5 kb, respectively. Labeling and hybridization were performed according to the protocol provided by Agilent (Protocol v4.0, June 2006). Briefly, 2 mg of patient DNA and of a sex-matched control were double-digested with AluI and RsaI (Promega, Madison, WI, USA) for 2 h at 37 C. The digested DNA was labeled by random priming using the Agilent Genomic DNA Labeling Kit Plus. Patient DNA and control DNA was labeled with Cy3-dUTP and Cy5-dUTP, respectively. Labeled products were purified by Microcon YM-30 filters (Millipore, Billerica, MA, USA). Patient and control DNAs were pooled and hybridized with 50 mg of Human Cot I DNA at 65 C with rotation for 40 h. Washing was performed according to the Agilent protocol. Arrays were analyzed using the Genepix 4200A scanner (Axon Instruments, Union City, CA, USA) and the Agilent Feature Extraction software (v9.1). Results were presented by Agilent CGH Analytics software (v3.4). DNA sequence information refers to the public UCSC database (Human Genome Browser, May 2004 Assembly (hg 17)). 3. Results 3.1. Case report The boy was the first child of Danish non-consanguineous parents. No family history of mental retardation. Delivery was induced at gestational age 39w þ 3d due to oligohydramnios.
522
A.-B. Kiholm Lund et al. / European Journal of Medical Genetics 51 (2008) 520e526
Birth weight was 2750 g (10th centile), length 48 cm (10th centile) and head circumference 34 cm (appropriate for length). Several dysmorphic features were observed at birth: hypospadias, joint contractures (possible due to oligohydramnios), and his second and fifth fingers were overlapping the third and the fourth fingers, respectively, on both hands. He had low-set, posteriorly rotated ears, broad nasal bridge, hypertelorism, downslanting palpebral fissures, long eyelashes, and epicantal folds. As he grew older, additional features became apparent, included thick upper eyelids, high-arched eyebrows, strabismus, a triangular mouth with a thick upper lip and a smooth philtrum, and a low posterior hairline. His nails on fingers and toes are hypoplastic and the finger pads are broad, but the overlapping of the fingers has gradually disappeared. His weight has increased from the 10th centile at birth to just below the 25th centile at 14 months, and it is now, at age 26 months, at the 50th centile. His length has also increased from the 10th centile to the 75th centile presently. His head circumference has been appropriate for his weight. His global development is delayed. At 14 months of age he was able to roll from back to stomach, and he learned to sit without support at 17 months. Presently, at age 26 months, he walks a few steps with support, gives good contact, but has no spoken words. On examination he is slightly hypertonic with increased deep tendon reflexes. Hearing examination showed slightly decreased hearing, possibly due to several episodes of middle ear infection. Eye examination revealed hypermetropia, astigmatism and slight strabismus (Fig. 1). Magnetic Resonance Imaging on day 6 showed agenesis of the corpus callosum, dilatation of the lateral ventricles and a small hemorrhage in the left parital region.
Fig. 1. Photograph of proband at age 26 months. Note the dysmorphic facial features.
A.-B. Kiholm Lund et al. / European Journal of Medical Genetics 51 (2008) 520e526
523
G-banding of blood lymphocytes and cultured skin fibroblasts showed normal male karyotype and excluded mosaicism of trisomy 18. Subtelomeric Multiplex Ligation-dependent Probe Amplification (MLPA) gave normal results. 3.2. Array CGH Array CGH investigation of the proband showed a duplication of chromosome 15q24.1q24.2 (Fig. 2). The minimum size of the duplication was 1653 kb (baseposition chr15:72185701e 73838909) and the maximum size was 1715 kb (baseposition chr15: 72141744e73856842). The size of the duplication is in accordance with the minimal critical region for the reciprocal microdeletion reported by Sharp et al.[6], and the breakpoints of the duplication are within flanking low copy repeats. Investigation of parental samples showed the proband’s father to carry an identical duplication of chromosome 15q24.1q24.2 (Fig. 2). 4. Discussion A number of recurrent microdeletions associated with well-known syndromes have been shown to arise from NAHR. Turner et al. studied germline rates of de novo meiotic deletions and duplications in four target regions for NAHR [10]. They found that the overall frequency of deletions outweighed the frequency of duplications roughly twofold. Yet, this does not explain the discrepancy between the large number of patients diagnosed with recurrent microdeletion syndromes and the few patients diagnosed with syndromes associated with reciprocal duplications.
Fig. 2. Results of 244k Agilent oligoarray analysis of chromosome 15. (A) Moving average based on a window of 20 probes. Dotted lines represent log2 ratios. (B) Detailed view of a 2.47 Mb region of chromosome 15q24 including the duplication. Arrow indicates the minimal size of the duplication (1653 kb).
524
A.-B. Kiholm Lund et al. / European Journal of Medical Genetics 51 (2008) 520e526
Microduplications may result in phenotypic features included in the spectrum of corresponding microdeletions, as reported for duplications of 17p11.2 and 22q11.21 [5,11]. They may also result in phenotypes with features that are in fact opposite to those of the corresponding microdeletions, as has been described for the microduplications of the Williamse Beuren syndrome locus and the Sotos syndrome locus, respectively [2,4,7,9]. The phenotypes associated with microduplications seem to be milder than those associated with microdeletions. However, due to the relative small number of patients with microduplications reported, the clinical phenotypes are not yet well defined. To our knowledge this is the first report of a patient with a 15q24 microduplication. The phenotypic features of patients with 15q24 microdeletions include global developmental delay, digital abnormalities, genital abnormalities, and dysmorphic facial features. Our patient shares a number of these features (Table 1). He has developmental delay, genital abnormalities (hypospadias), and digital abnormalities. Certain dysmorphic facial features are also comparable. This applies especially to the eyes, where our patient as well as the patients with 15q24 microdeletion has hypertelorism, downslanting palpebral fissures and thick eyelids (Fig. 3). Unlike patients carrying the deletions, our patient does not have a high frontal hairline or broad medial eyebrows. Table 1 Clinical features of the proband compared to clinical features reported in patients with 15q24 microdeletion Paper
Reported patients Size of duplication/deletion Genomic location
Inheritance Gender Age (years) Short stature Developmental delay Hypotonic Microcephaly Brain abnormalities by MRI High frontal hair line Downslanting palpebral fissures Epicantal folds Hypertelorism Strabismus Broad medial eyebrows Smooth philtrum Thick lower lip Genital anomaly Abnormalities of fingers Ear abnormalities
Microdeletion 15q24
Microduplication 15q24
Sharp et al. [6], Cushman et al. [1], Klopocki et al. [3]
Current case
7
1 1.7 Mb 72.14e73.85 Mb
1.7e3.9 Mb 72.15e76.01 Mb 72.15e76.01 Mb 72.15e73.85 Mb 70.40e74.21 Mb 72.2e75.9 Mb Two unknown Five de novo and two unknown Six male and one female 14, 15, 33, 14, 1, 11, 10 3/7 7/7 4/7 4/7 3/7, 2nd 5/7, 2nd 4/7, 2nd 2/7, 1nd 4/7, 2nd 4/7 5/7, 2nd 4/7, 2nd 5/7, 2nd 5/7 6/7 4/7, 1nd
nd e not determined or described. a The patient had a full lower lip, but this feature has gradually disappeared.
Paternal Male 2 þ þ þ þ þ þ þ þ/a þ þ þ
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525
Fig. 3. Photograph of our patient at age 14 months (right) and of a patient with 15q24 deletion (left) reported by Sharp et al., 2007 [6]. Printed with permission from Editorial Board of Human Molecular Genetics and the authors.
As this is the first patient reported with 15q24 duplication, and the imbalance is inherited from a healthy father, it cannot be ruled out that the patient has another genetic defect, which contributes to or actually causes his phenotype, leaving the duplication an accidental finding. However, the variability of the phenotype might be caused by reduced penetrance or multifactorial influences, as suggested by Kriek et al. in an equivalent scenario of a family with a microduplication reciprocal to the WilliamseBeuren critical region [4]. Indeed, the overlap in the phenotypes of 15q24 microdeletion syndrome patients and our patient strongly support the clinical significance of the duplication. In recent years application of array CGH for investigation of children with mental retardation and dysmorphic features has gained widespread use, and many new microdeletion/ duplication syndromes are being reported. We anticipate that more reports on patients with 15q24 microdeletions will delineate the clinical significance of this chromosomal imbalance in the near future.
Acknowledgements We gratefully acknowledge the parents of the patient for giving their consent to publish clinical data and photos.
References [1] L.J. Cushman, W. Torres-Martinez, A.M. Cherry, M.A. Manning, O. Abdul-Rahman, C.E. Anderson, H.H. Punnett, V.C. Thurston, D. Sweeney, G.H. Vance, A report of three patients with an interstitial deletion of chromosome 15q24, Am. J. Med. Genet. A 137 (2005) 65e71. [2] M. Kirchhoff, A.M. Bisgaard, M. Duno, F.J. Hansen, M. Schwartz, A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features, Eur. J. Med. Genet. 50 (2007) 256e263.
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