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A boy with mental retardation, obesity and hypertrichosis caused by a microdeletion of 19p13.12
European Journal of Medical Genetics 53 (2010) 291e293
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short report
A boy with mental retardation, obesity and hypertrichosis caused by a microdeletion of 19p13.12 Nathalie Van der Aa*, Geert Vandeweyer, R. Frank Kooy Department of Medical Genetics, University of Antwerp, University Hospital Antwerp, Antwerp, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 May 2010 Accepted 24 May 2010 Available online 4 June 2010
We present a moderately mentally retarded boy with obesity, short stature, hypertrichosis and facial dysmorphism due to a deletion of 1.2 Mb on chromosome 19p13.2. The deletion was de novo and familial history was negative for the disorder. Genes in the deleted region possibly related to the clinical symptoms of our patient include NOTCH3 (MIM600276), causative of the vascular neurodegenerative disorder CADASIL and CASP14 (MIM605848), playing a central role in apoptosis in the inner root sheeth of the hair follicle. Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords: Microdeletion Chromosome 19p 19p13.12 deletion Mental retardation Hypertrichosis
1. Introduction Chromosome 19 is one of the most gene-dense chromosomes [3]. Chromosomal aberrations of chromosome 19 are uncommon and submicroscopic deletions have rarely been reported. Interestingly, no microdeletion or duplication syndrome has been mapped to this chromosome [6]. We here report on a boy with mental retardation, obesity and hypertrichosis caused by a microdeletion of 19p13.12. 2. Clinical report The proband is the second son of healthy non-consanguineous Caucasian parents. He was born at term after an uneventful pregnancy by spontaneous delivery. He was dysmature with a birth weight of 2.2 kg, a length of 46 cm and a head circumference of 32 cm. A mild degree of perinatal asphyxia was recorded and the boy suffered from neonatal seizures that were successfully treated. Cranial ultrasound was normal, as were abdominal ultrasound and echocardiography. He had a global developmental delay. He walked unsupported at the age of 2 years and communication skills were poor due to an expressive language delay. However he was happy and sociable as a toddler. The boy suffered from asthma and recurrent lower
* Corresponding author. Department of Medical Genetics, Prins Boudewijnlaan 43, B-2650 Edegem. Tel.: þ32 03 275 97 72; fax: þ32 03 275 97 23. E-mail address: [email protected] (N. Van der Aa). 1769-7212/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2010.05.006
respiratory tract infections as a young child. He was relatively obese (Wt on 50th centile for Ht on 3rd) and had dysmorphic features: trigonocephaly, a widow's peak with bilateral frontal upsweep, synophrys, thick eyebrows, bilateral epicanthal folds, a flat nasal bridge and prominent incisors. He had a high palate and rather large ears. His neck was short and he had hypertrichosis. An MRI of the brain revealed a rather narrow brainstem and gracile corpus callosum but was otherwise normal. Eye examination showed amblyopia of the right eye. Puberty started early, before the age of 10 years. At 15 years of age he has moderate mental retardation and is very shy, extremely insecure and anxious. He has a thick irregular skin and thick scalp hair, thick eyebrows and marked hypertrichosis on back, shoulders, abdomen and limbs (Fig. 1).
3. Molecular karyotype Using an Illumina (San Diego, CA) iScan system with a CNV370Duo Beadchip a deletion on chromosome 19p13.12 was identified in DNA from our patient. The deletion is approximately 1.2 Mb in size, with breakpoints at 14.2 Mb and 15.4 Mb (Fig. 2). It was confirmed using multiplex-ligation dependent probe amplification (MLPA) with probes in the NOTCH3, PKN1 and ZNF333 genes and not present in either of the parents (Fig. 1S). The deleted region encompasses 30 coding transcripts (Fig. 3). Deleted genes include NOTCH3 (MIM600276), causative of the vascular neurodegenerative disorder CADASIL [5]. In CADASIL, pathogenic mutations alter the number of cysteine residues in the
292
N. Van der Aa et al. / European Journal of Medical Genetics 53 (2010) 291e293
Fig. 1. A) The patient at 15 years of age, B) facial and C) profile.
extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. It has been suggested that CADASIL mutations act through gain of function mechanisms [1]. As mutations in NOTCH3 play a role in neurodegeneration, it is tempting to speculate that haploinsufficiency of this gene might contribute to the cognitive impairment in our patient. Another gene in the deleted region potentially related to the phenotype is CASP14 (MIM605848), playing a central role in apoptosis. It is highly expressed in the inner root sheath of the hair follicle and haploinsufficiency of this gene may well contribute to the hypertrichosis in our patient. 4. Discussion Isolated copy number changes in chromosome band 19p13.12 are rare. We found only two deletions overlapping with the one in our patient in the literature and in the databases for chromosomal abnormalities DECIPHER and ECARUCA (Fig. 3). A female patient reported by Jensen et al. [4] with a larger deletion has some features in common with our patient including dysmaturity and developmental delay, early puberty and minor MRI abnormalities. However, she shows no overlap in facial dysmorphism and has a cardiac defect as well as congenital hearing loss, neither of which is seen in our patient. Engels et al. [2] reported a patient with mild mental retardation, growth retardation, hearing loss and only few overlapping dysmorphic features such as synophrys and epicanthus. Several patients with duplications in part overlapping with the deletion of our patients are listed in DECIPHER. Interestingly, the
Fig. 2. Log R ratio and B allele frequency plots of DNA of our patient in the 19p13.12 region, clearly illustrating the deletion.
N. Van der Aa et al. / European Journal of Medical Genetics 53 (2010) 291e293
293
Fig. 3. The deletion in our patient compared with two deletions described previously.
duplication patient 249428 that shows the largest overlap with the deletion of our patient has tall stature, a soft skin and macrocephaly, as opposed to the short stature, hard skin and small head in our patient. We conclude that although a clinical picture of patients with 19p13.2 deletions is emerging, at this moment it is not possible to define an unambiguous genotypeephenotype correlation and state that collecting a larger set of patients with aberrations in this chromosome band along with their clinical presentation is necessary. Acknowledgements Our experimental work on genomic disorders was generously supported by grants from the Marguerite-Marie Delacroix foundation and the Belgian National Fund for Scientific Research Flanders (FWO). Appendix. Supplementary data The supplementary data associated with this article can be found in the on-line version at doi:10.1016/j.ejmg.2010.05.006. References [1] C.P. Donahue, K.S. Kosik, Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics 83 (2004) 59e65.
[2] H. Engels, A. Brockschmidt, A. Hoischen, C. Landwehr, K. Bosse, C. Walldorf, G. Toedt, B. Radlwimmer, P. Propping, P. Lichter, R.G. Weber, DNA microarray analysis identifies candidate regions and genes in unexplained mental retardation. Neurology 68 (2007) 743e750. [3] J. Grimwood, L.A. Gordon, A. Olsen, A. Terry, J. Schmutz, J. Lamerdin, U. Hellsten, D. Goodstein, O. Couronne, M. Tran-Gyamfi, A. Aerts, M. Altherr, L. Ashworth, E. Bajorek, S. Black, E. Branscomb, S. Caenepeel, A. Carrano, C. Caoile, Y.M. Chan, M. Christensen, C.A. Cleland, A. Copeland, E. Dalin, P. Dehal, M. Denys, J.C. Detter, J. Escobar, D. Flowers, D. Fotopulos, C. Garcia, A.M. Georgescu, T. Glavina, M. Gomez, E. Gonzales, M. Groza, N. Hammon, T. Hawkins, L. Haydu, I. Ho, W. Huang, S. Israni, J. Jett, K. Kadner, H. Kimball, A. Kobayashi, V. Larionov, S.H. Leem, F. Lopez, Y. Lou, S. Lowry, S. Malfatti, D. Martinez, P. McCready, C. Medina, J. Morgan, K. Nelson, M. Nolan, I. Ovcharenko, S. Pitluck, M. Pollard, A.P. Popkie, P. Predki, G. Quan, L. Ramirez, S. Rash, J. Retterer, A. Rodriguez, S. Rogers, A. Salamov, A. Salazar, X. She, D. Smith, T. Slezak, V. Solovyev, N. Thayer, H. Tice, M. Tsai, A. Ustaszewska, N. Vo, M. Wagner, J. Wheeler, K. Wu, G. Xie, J. Yang, I. Dubchak, T.S. Furey, P. DeJong, M. Dickson, D. Gordon, E.E. Eichler, L.A. Pennacchio, P. Richardson, L. Stubbs, D.S. Rokhsar, R.M. Myers, E.M. Rubin, S.M. Lucas, The DNA sequence and biology of human chromosome 19. Nature 428 (2004) 529e535. [4] D.R. Jensen, D.M. Martin, S. Gebarski, T. Sahoo, E.K. Brundage, A.C. Chinault, E.A. Otto, M. Chaki, F. Hildebrandt, S.W. Cheung, M.M. Lesperance, A novel chromosome 19p13.12 deletion in a child with multiple congenital anomalies. Am. J. Med. Genet. A 149A (2009) 396e402. [5] A. Joutel, C. Corpechot, A. Ducros, K. Vahedi, H. Chabriat, P. Mouton, S. Alamowitch, V. Domenga, M. Cecillion, E. Marechal, J. Maciazek, C. Vayssiere, C. Cruaud, E.A. Cabanis, M.M. Ruchoux, J. Weissenbach, J.F. Bach, M.G. Bousser, E. Tournier-Lasserve, Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383 (1996) 707e710. [6] D.A. Koolen, R. Pfundt, N. de Leeuw, J.Y. Hehir-Kwa, W.M. Nillesen, I. Neefs, I. Scheltinga, E. Sistermans, D. Smeets, H.G. Brunner, A.G. van Kessel, J.A. Veltman, B.B.A. de Vries, Genomic microarrays in mental retardation: a practical workflow for diagnostic applications. Hum. Mutat. 30 (2009) 283e292.
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short report
A boy with mental retardation, obesity and hypertrichosis caused by a microdeletion of 19p13.12 Nathalie Van der Aa*, Geert Vandeweyer, R. Frank Kooy Department of Medical Genetics, University of Antwerp, University Hospital Antwerp, Antwerp, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 May 2010 Accepted 24 May 2010 Available online 4 June 2010
We present a moderately mentally retarded boy with obesity, short stature, hypertrichosis and facial dysmorphism due to a deletion of 1.2 Mb on chromosome 19p13.2. The deletion was de novo and familial history was negative for the disorder. Genes in the deleted region possibly related to the clinical symptoms of our patient include NOTCH3 (MIM600276), causative of the vascular neurodegenerative disorder CADASIL and CASP14 (MIM605848), playing a central role in apoptosis in the inner root sheeth of the hair follicle. Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords: Microdeletion Chromosome 19p 19p13.12 deletion Mental retardation Hypertrichosis
1. Introduction Chromosome 19 is one of the most gene-dense chromosomes [3]. Chromosomal aberrations of chromosome 19 are uncommon and submicroscopic deletions have rarely been reported. Interestingly, no microdeletion or duplication syndrome has been mapped to this chromosome [6]. We here report on a boy with mental retardation, obesity and hypertrichosis caused by a microdeletion of 19p13.12. 2. Clinical report The proband is the second son of healthy non-consanguineous Caucasian parents. He was born at term after an uneventful pregnancy by spontaneous delivery. He was dysmature with a birth weight of 2.2 kg, a length of 46 cm and a head circumference of 32 cm. A mild degree of perinatal asphyxia was recorded and the boy suffered from neonatal seizures that were successfully treated. Cranial ultrasound was normal, as were abdominal ultrasound and echocardiography. He had a global developmental delay. He walked unsupported at the age of 2 years and communication skills were poor due to an expressive language delay. However he was happy and sociable as a toddler. The boy suffered from asthma and recurrent lower
* Corresponding author. Department of Medical Genetics, Prins Boudewijnlaan 43, B-2650 Edegem. Tel.: þ32 03 275 97 72; fax: þ32 03 275 97 23. E-mail address: [email protected] (N. Van der Aa). 1769-7212/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2010.05.006
respiratory tract infections as a young child. He was relatively obese (Wt on 50th centile for Ht on 3rd) and had dysmorphic features: trigonocephaly, a widow's peak with bilateral frontal upsweep, synophrys, thick eyebrows, bilateral epicanthal folds, a flat nasal bridge and prominent incisors. He had a high palate and rather large ears. His neck was short and he had hypertrichosis. An MRI of the brain revealed a rather narrow brainstem and gracile corpus callosum but was otherwise normal. Eye examination showed amblyopia of the right eye. Puberty started early, before the age of 10 years. At 15 years of age he has moderate mental retardation and is very shy, extremely insecure and anxious. He has a thick irregular skin and thick scalp hair, thick eyebrows and marked hypertrichosis on back, shoulders, abdomen and limbs (Fig. 1).
3. Molecular karyotype Using an Illumina (San Diego, CA) iScan system with a CNV370Duo Beadchip a deletion on chromosome 19p13.12 was identified in DNA from our patient. The deletion is approximately 1.2 Mb in size, with breakpoints at 14.2 Mb and 15.4 Mb (Fig. 2). It was confirmed using multiplex-ligation dependent probe amplification (MLPA) with probes in the NOTCH3, PKN1 and ZNF333 genes and not present in either of the parents (Fig. 1S). The deleted region encompasses 30 coding transcripts (Fig. 3). Deleted genes include NOTCH3 (MIM600276), causative of the vascular neurodegenerative disorder CADASIL [5]. In CADASIL, pathogenic mutations alter the number of cysteine residues in the
292
N. Van der Aa et al. / European Journal of Medical Genetics 53 (2010) 291e293
Fig. 1. A) The patient at 15 years of age, B) facial and C) profile.
extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. It has been suggested that CADASIL mutations act through gain of function mechanisms [1]. As mutations in NOTCH3 play a role in neurodegeneration, it is tempting to speculate that haploinsufficiency of this gene might contribute to the cognitive impairment in our patient. Another gene in the deleted region potentially related to the phenotype is CASP14 (MIM605848), playing a central role in apoptosis. It is highly expressed in the inner root sheath of the hair follicle and haploinsufficiency of this gene may well contribute to the hypertrichosis in our patient. 4. Discussion Isolated copy number changes in chromosome band 19p13.12 are rare. We found only two deletions overlapping with the one in our patient in the literature and in the databases for chromosomal abnormalities DECIPHER and ECARUCA (Fig. 3). A female patient reported by Jensen et al. [4] with a larger deletion has some features in common with our patient including dysmaturity and developmental delay, early puberty and minor MRI abnormalities. However, she shows no overlap in facial dysmorphism and has a cardiac defect as well as congenital hearing loss, neither of which is seen in our patient. Engels et al. [2] reported a patient with mild mental retardation, growth retardation, hearing loss and only few overlapping dysmorphic features such as synophrys and epicanthus. Several patients with duplications in part overlapping with the deletion of our patients are listed in DECIPHER. Interestingly, the
Fig. 2. Log R ratio and B allele frequency plots of DNA of our patient in the 19p13.12 region, clearly illustrating the deletion.
N. Van der Aa et al. / European Journal of Medical Genetics 53 (2010) 291e293
293
Fig. 3. The deletion in our patient compared with two deletions described previously.
duplication patient 249428 that shows the largest overlap with the deletion of our patient has tall stature, a soft skin and macrocephaly, as opposed to the short stature, hard skin and small head in our patient. We conclude that although a clinical picture of patients with 19p13.2 deletions is emerging, at this moment it is not possible to define an unambiguous genotypeephenotype correlation and state that collecting a larger set of patients with aberrations in this chromosome band along with their clinical presentation is necessary. Acknowledgements Our experimental work on genomic disorders was generously supported by grants from the Marguerite-Marie Delacroix foundation and the Belgian National Fund for Scientific Research Flanders (FWO). Appendix. Supplementary data The supplementary data associated with this article can be found in the on-line version at doi:10.1016/j.ejmg.2010.05.006. References [1] C.P. Donahue, K.S. Kosik, Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics 83 (2004) 59e65.
[2] H. Engels, A. Brockschmidt, A. Hoischen, C. Landwehr, K. Bosse, C. Walldorf, G. Toedt, B. Radlwimmer, P. Propping, P. Lichter, R.G. Weber, DNA microarray analysis identifies candidate regions and genes in unexplained mental retardation. Neurology 68 (2007) 743e750. [3] J. Grimwood, L.A. Gordon, A. Olsen, A. Terry, J. Schmutz, J. Lamerdin, U. Hellsten, D. Goodstein, O. Couronne, M. Tran-Gyamfi, A. Aerts, M. Altherr, L. Ashworth, E. Bajorek, S. Black, E. Branscomb, S. Caenepeel, A. Carrano, C. Caoile, Y.M. Chan, M. Christensen, C.A. Cleland, A. Copeland, E. Dalin, P. Dehal, M. Denys, J.C. Detter, J. Escobar, D. Flowers, D. Fotopulos, C. Garcia, A.M. Georgescu, T. Glavina, M. Gomez, E. Gonzales, M. Groza, N. Hammon, T. Hawkins, L. Haydu, I. Ho, W. Huang, S. Israni, J. Jett, K. Kadner, H. Kimball, A. Kobayashi, V. Larionov, S.H. Leem, F. Lopez, Y. Lou, S. Lowry, S. Malfatti, D. Martinez, P. McCready, C. Medina, J. Morgan, K. Nelson, M. Nolan, I. Ovcharenko, S. Pitluck, M. Pollard, A.P. Popkie, P. Predki, G. Quan, L. Ramirez, S. Rash, J. Retterer, A. Rodriguez, S. Rogers, A. Salamov, A. Salazar, X. She, D. Smith, T. Slezak, V. Solovyev, N. Thayer, H. Tice, M. Tsai, A. Ustaszewska, N. Vo, M. Wagner, J. Wheeler, K. Wu, G. Xie, J. Yang, I. Dubchak, T.S. Furey, P. DeJong, M. Dickson, D. Gordon, E.E. Eichler, L.A. Pennacchio, P. Richardson, L. Stubbs, D.S. Rokhsar, R.M. Myers, E.M. Rubin, S.M. Lucas, The DNA sequence and biology of human chromosome 19. Nature 428 (2004) 529e535. [4] D.R. Jensen, D.M. Martin, S. Gebarski, T. Sahoo, E.K. Brundage, A.C. Chinault, E.A. Otto, M. Chaki, F. Hildebrandt, S.W. Cheung, M.M. Lesperance, A novel chromosome 19p13.12 deletion in a child with multiple congenital anomalies. Am. J. Med. Genet. A 149A (2009) 396e402. [5] A. Joutel, C. Corpechot, A. Ducros, K. Vahedi, H. Chabriat, P. Mouton, S. Alamowitch, V. Domenga, M. Cecillion, E. Marechal, J. Maciazek, C. Vayssiere, C. Cruaud, E.A. Cabanis, M.M. Ruchoux, J. Weissenbach, J.F. Bach, M.G. Bousser, E. Tournier-Lasserve, Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383 (1996) 707e710. [6] D.A. Koolen, R. Pfundt, N. de Leeuw, J.Y. Hehir-Kwa, W.M. Nillesen, I. Neefs, I. Scheltinga, E. Sistermans, D. Smeets, H.G. Brunner, A.G. van Kessel, J.A. Veltman, B.B.A. de Vries, Genomic microarrays in mental retardation: a practical workflow for diagnostic applications. Hum. Mutat. 30 (2009) 283e292.