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A de novo 1.13 Mb microdeletion in 12q13.13 associated with congenital distal arthrogryposis, intellectual disability and mild dysmorphism
European Journal of Medical Genetics 55 (2012) 437e440
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Chromosomal imbalance report
A de novo 1.13 Mb microdeletion in 12q13.13 associated with congenital distal arthrogryposis, intellectual disability and mild dysmorphism Dagur Ingi Jonsson a, b, Petur Ludvigsson c, Swaroop Aradhya d, Sunna Sigurdardottir a, b, Margret Steinarsdottir a, b, Helga Hauksdottir a, b, Jon Johannes Jonsson a, b, * a
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Reykjavik, Iceland Department of Genetics and Molecular Medicine, Landspitali e National University Hospital of Iceland, Reykjavik, Iceland Department of Pediatrics, Landspitali e National University Hospital of Iceland, Reykjavik, Iceland d GeneDx, Gaithersburg, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 August 2011 Accepted 8 March 2012 Available online 2 April 2012
A girl presented with congenital arthrogryposis, intellectual disability and mild bone-related dysmorphism. Molecular workup including the NimbleGen Human CGH 2.1M platform revealed a 1.13 Mb de novo microdeletion on chromosome 12q13.13 of paternal origin. The deletion contains 33 genes, including AAAS, AMRH2, and RARG genes as well as the HOXC gene cluster. At least one gene, CSAD, is expressed in fetal brain. The deletion partially overlaps number of reported benign CNVs and pathogenic duplications. This case appears to represent a previously unknown microdeletion syndrome and possibly the first description in humans of a disease phenotype associated with copy loss of HOXC genes. Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords: Array-CGH Microdeletion Arthrogryposis Intellectual disability HOX genes
1. Methods of detection Molecular workup comprised a standard 550 band karyotype and two types of array-CGH; a custom-designed 44K oligonuclotide array (Agilent Technologies, Santa Clara, CA) and NimbleGen Human CGH 2.1M Whole-Genome Tiling microarray v2.0D (Roche NimbleGen, Inc.). Genome localization of clones and candidate genes were based on the NCBI Build 36 using the UCSC Genome Browser. A standard blood karyotype was normal. Both microarrays revealed a hemizygous copy loss on chromosome 12q13.13. It was approximately 1.13 Mb in size between proximal probes 51.834.791 bp and 51.836.033 bp and distal probes 52.968.320 bp and 52.971.391 bp according to the 2.1M array-CGH (Fig. 1). Taqmanbased quantitative PCR analysis with a probe targeted to intron 2 of the AAAS gene (probe selected from the Roche Universal Probe Library; Roche) and FISH analysis using BAC-probes BAC-RP1165C2 and RP11-1101H10 on the patient-parent trio confirmed a de novo copy loss (data not shown). The deletion was paternal in origin
* Corresponding author. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. Tel.: þ354 824 5917; fax: þ354 525 4886. E-mail address: [email protected] (J.J. Jonsson). 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2012.03.001
according to three informative microsatellite markers; D12S1604, D12S1586 and D12S325 (data not shown). Thus the deletion occurred de novo in the paternal chromosome 12.
2. Clinical description The girl was born after a normal gestation of 41 weeks. Birth weight was 3665 g (75th percentile), length 51 cm (50th percentile) and head circumference 34,5 cm (75th percentile). She was the first child of a 27 year old Caribbean mother and a 37 year old Scandinavian father. The parents were both in good health and there was no family history of congenital malformations or intellectual disability. At birth the patient had umbilical hernia and pectus excavatum. All extremities were affected by flexion contractures including digits, hands and elbows. There was an ulnar deviation of hands and a valgus position of both ankles. Radiologic imaging after birth showed bilateral subluxation at MCP III, flexion in PIP and extension in DIP joints. Imaging of hands at 2 years and 7 months showed some growth retardation of metacarpal bones especially IV, short proximal phalanges and bone age was increased corresponding to 3 1/2 to 4 1/2 years. MRI of brain and spinal cord at 15 months was normal. When last examined at the age of 5 years her weight was 18,8 kg (50th percentile) and length 112 cm (50th
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D.I. Jonsson et al. / European Journal of Medical Genetics 55 (2012) 437e440
Fig. 1. Results from the 2.1M NimbleGen array showing an approximately 1.13 Mb deletion within 12q13.13. Breakpoints were between proximal probe 51.834.791 bp and distal probe 52.971.391 bp. Genes in the deletion area, structural variants listed in the database of genomic Variants, deletions in the three DECIPHER cases and known segmental duplications are shown. The figure is modified from Ensemble.
percentile). Contractures of upper extremities had decreased with physical therapy, but at the age of 6 years surgery was needed to improve ankle valgus. Bilaterally there were absent or minimal flexion lines and short metacarpal and proximal phalangeal bones (Fig. 2c). Nails of hands and feet were short. Facial features included bilateral epicanthal folds, a depressed nasal bridge, a slightly bulbous and antiverted nose, and a short philtrum (Fig. 2a and b). Motor and mental abilities developed slowly. She started to walk at 22 months and at 30 months her maturity was 10 months behind her age group according to Kuno Beller’s test [1]. Wechsler Preschool and Primary Scale of Intelligence (WPPSI) taken at 40 months showed her 2e3 standard deviations below average. At 6 years she was diagnosed with an attention deficit disorder. She speaks two languages fluently. The girl has asthma and is prone to airway infections. She has had pneumonia three times resulting in two hospitalizations. Routine blood tests and immunologic evaluations have, however, been normal.
3. Discussion We did not find any description of patients with similar symptoms or copy loss after searching databases and literature of chromosomal malformations. The copy loss included 33 genes and 2 microRNAs according to the UCSC Genome Browser build 36 (Fig. 1). Two genes, AAAS and AMRH2, are disease-associated according to OMIM. Their associated diseases, respectively, are Triple A syndrome (#MIM 231550), named after the main symptoms; achalasia, Addison disease and alacrima, and Persistent Müllerian duct syndrome (#MIM 261550), which only has an abnormal phenotype in males. Both conditions have autosomal recessive inheritance and are unlikely to play a part in the girl’s phenotype. A search in the DECIPHER database (http://decipher. sanger.ac.uk/ accessed 1.4.2011) revealed pathological copy gains in two patients (248785, 248901) that were associated with cognitive dysfunction and deformities. These copy gains extend beyond the copy loss in our patient on both sides (Fig. 1). A third
D.I. Jonsson et al. / European Journal of Medical Genetics 55 (2012) 437e440
Fig. 2. Patient at 5 years of age. a and b: Facial features included bilateral epicanthal folds, a low and flat nasal bridge, a slightly bulbous and antiverted nose, and a short philtrum. c: Bilaterally single transverse palmar creases, absent or minimal flexion lines and short metacarpal bones.
patient in DECIPHER (2055) also has a short copy gain in this area. That patient reportedly has a number of other chromosomal imbalances limiting phenotypic correlation. According to the girl’s phenotype i.e. intellectual disability, distal arthrogryposis, and bone malformations, the gene or genes responsible should have a role in bone and neuronal function during fetal growth. This fits well with known functions, and mouse phenotypes associated with the HOXC gene complex. HOX genes are highly conserved [2]. Heterozygous and homozygous copy loss of various Hoxc genes in mice cause minor structural abnormalities the most common being extra ribs connected to sternum and minor malformations of the spinal column and hindlegs [3e7]. Mice with homozygous copy loss knockout of Hoxc8 present with congenital distal contractures of front legs. This presumably results from CNS involvement since the mice show an atrophy of the anterior spinal horns [8]. Somewhat contradicting the importance of HOXC genes in fetal development, there is a reported benign CNV (Variation 3890) in the Database of Genomic Variants (DGV, http://projects.tcag.ca/variation/ accessed 1.4.2011) that covers the entire HOXC gene cluster except for HOXC13. This CNV has only been reported in three individuals, two copy losses and one copy gain, and has not been confirmed by other molecular methods [9]. There are no known imprinted genes in the copy loss area, but Luedi et al. predicted with multiple classification algorithms based on DNA sequences that most HOXC genes, and especially HOXC9 and HOCX4, are candidates for maternally expressed
439
imprinted genes [10]. Even though the parental origin in this case was paternal, the parental origin of the deletion could affect the phenotype. One gene, CSAD has a particularly high expression in fetal and adult brain and in the spine according to the Symatlas [11]. CSAD, however, is reported to be in a CNV region making it less probable that it plays a part in the phenotype. Six genes, RARG, SP1, ATP5G2, HOXC5, HOXC6 and CBX5, have been predicted to be very likely haploinsufficient according to Huang et al. [12]. These genes are all transcription factors, but their exact role has not been established. A functional link between SP1, ATP5G2 or CBX5 and the patients’ bone malformations or arthrogryposis is not evident. The RARG gene, however, encodes for retinoid acid receptor gamma and retinoids have been known to influence skeletogenesis in mice. Koyama et al. showed that the retinoids, among them the retinoid acid receptor gamma, play an important role in chondrocyte maturation and endochondrial ossification in the developing limb [13]. In conclusion, both the RARG gene and the HOXC genes could contribute to the patient’s phenotype. Independently and parallel to our work a case has been described by Okamoto et al. [14]. That patient, a 14 year old male, had a 1.7 Mb de novo copy loss on 12q13.1 with boundaries extending beyond the deletion in our case on both sides. He had skeletal anomalies similar to our case, camptodactyly and hand bone malformations, and additionally a kyphosis and Tetralogy of Fallot. The patient also had developmental delay, not walking before age of 5 years, and verbal expression was limited. The greater developmental delay and heart defect in this patient perhaps reflects the size difference in the deletions, 1.7 Mb versus 1.13 Mb. These cases support one another with regard to bone malformations. We conclude that the features in our patient represent a previously unrecognized syndrome presumably caused by the 1.13 Mb heterozygous copy loss on 12q13.13. This case along with the case described Okamoto et al. [14] might also be the first descriptions in humans of a disease phenotype associated with a copy loss of HOXC genes. Patient has been submitted to the DECIPHER database under case 250426. This study was approved by the National Bioethics Committee of Iceland (no. VSNb2008040022/03-15) and the Data Protection Authority (no. 2008050414LSL). Informed consent of the girls’ parents was obtained.
Acknowledgments This study makes use of data generated by the DECIPHER Consortium. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from [email protected]. Funding for that project was provided by the Wellcome Trust. Those who carried out the original analysis and collection of patient data bear no responsibility for the further analysis or interpretation. The data in this manuscript were obtained from the ISCA Consortium database (www. iscaconsortium.org), which generates this information using NCBI’s database of genomic structual variation (dbVar, www.ncbi. nlm.nih.gov/dbvar/), study nstd37.
References [1] E.K. Beller, H. Weltzer, Kuno Beller’s Utviklingsbeskrivelse af Småbörn, Dansk Psykologisk Forlag (1991). [2] T.R. Lappin, D.G. Grier, A. Thompson, H.L. Halliday, HOX GENES: seductive science, mysterious mechanisms, Ulster Medical Journal 75 (2006) 23e31. [3] H. Saegusa, N. Takahashi, S. Noguchi, H. Suemori, Targeted disruption in the mouse Hoxc-4 locus results in axial skeleton homeosis and malformation of the xiphoid process, Developmental Biology 174 (1996) 55e64. [4] A.M. Boulet, M.R. Capecchi, Targeted disruption of Hoxc-4 causes esophageal defects and vertebral transformations, Developmental Biology 177 (1996) 232e249.
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D.I. Jonsson et al. / European Journal of Medical Genetics 55 (2012) 437e440
[5] H. Suemori, Hoxc-9 mutant mice show anterior transformation of the vertebrae and malformation of the sternum and ribs, Mechanical Development (1995). [6] H. Suemori, S. Noguchi, Hox C cluster genes are dispensable for overall body plan of mouse embryonic development, Developmental Biology 220 (2000) 333e342. [7] E. van Den Akker, C. Fromental-Ramain, W. de Graaff, H. Le Mouellic, P. Brulet, P. Chambon, J. Deschamps, Axial skeletal patterning in mice lacking all paralogous group 8 Hox genes, Development 128 (2001) 1911e1921. [8] L. Tiret, H. Le Mouellic, M. Maury, P. Brulet, Increased apoptosis of motoneurons and altered somatotopic maps in the brachial spinal cord of Hoxc-8deficient mice, Development 125 (1998) 279e291. [9] R. Redon, S. Ishikawa, K.R. Fitch, L. Feuk, G.H. Perry, T.D. Andrews, H. Fiegler, M.H. Shapero, A.R. Carson, W. Chen, E.K. Cho, S. Dallaire, et al., Global variation in copy number in the human genome, Nature 444 (2006) 444e454. [10] P.P. Luedi, F.S. Dietrich, J.R. Weidman, J.M. Bosko, R.L. Jirtle, A.J. Hartemink, Computational and experimental identification of novel human imprinted genes, Genome Research 17 (2007) 1723e1730.
[11] A.I. Su, T. Wiltshire, S. Batalov, H. Lapp, K.A. Ching, D. Block, J. Zhang, R. Soden, M. Hayakawa, G. Kreiman, M.P. Cooke, J.R. Walker, J.B. Hogenesch, A gene atlas of the mouse and human protein-encoding transcriptomes, Proceedings of the National Academy of Sciences of the United States of America 101 (2004) 6062e6067. [12] N. Huang, I. Lee, E.M. Marcotte, M.E. Hurles, Characterising and predicting haploinsufficiency in the human genome, PLoS Genetics 6 (2010) e1001154. [13] E. Koyama, E.B. Golden, T. Kirsch, S.L. Adams, R.A.S. Chandraratna, J.-J. Michaille, M. Pacifici, Retinoid signaling is required for chondrocyte maturation and endochondral bone formation during limb skeletogenesis, Developmental Biology 208 (1999) 375e391. [14] N. Okamoto, D. Tamura, G. Nishimura, K. Shimojima, T. Yamamoto, Submicroscopic deletion of 12q13 including HOXC sene cluster with skeletal anomalies and global developmental delay, American Journal of Medical Genetics Part A 155 (2011) 2997e3001.
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Chromosomal imbalance report
A de novo 1.13 Mb microdeletion in 12q13.13 associated with congenital distal arthrogryposis, intellectual disability and mild dysmorphism Dagur Ingi Jonsson a, b, Petur Ludvigsson c, Swaroop Aradhya d, Sunna Sigurdardottir a, b, Margret Steinarsdottir a, b, Helga Hauksdottir a, b, Jon Johannes Jonsson a, b, * a
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Reykjavik, Iceland Department of Genetics and Molecular Medicine, Landspitali e National University Hospital of Iceland, Reykjavik, Iceland Department of Pediatrics, Landspitali e National University Hospital of Iceland, Reykjavik, Iceland d GeneDx, Gaithersburg, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 August 2011 Accepted 8 March 2012 Available online 2 April 2012
A girl presented with congenital arthrogryposis, intellectual disability and mild bone-related dysmorphism. Molecular workup including the NimbleGen Human CGH 2.1M platform revealed a 1.13 Mb de novo microdeletion on chromosome 12q13.13 of paternal origin. The deletion contains 33 genes, including AAAS, AMRH2, and RARG genes as well as the HOXC gene cluster. At least one gene, CSAD, is expressed in fetal brain. The deletion partially overlaps number of reported benign CNVs and pathogenic duplications. This case appears to represent a previously unknown microdeletion syndrome and possibly the first description in humans of a disease phenotype associated with copy loss of HOXC genes. Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords: Array-CGH Microdeletion Arthrogryposis Intellectual disability HOX genes
1. Methods of detection Molecular workup comprised a standard 550 band karyotype and two types of array-CGH; a custom-designed 44K oligonuclotide array (Agilent Technologies, Santa Clara, CA) and NimbleGen Human CGH 2.1M Whole-Genome Tiling microarray v2.0D (Roche NimbleGen, Inc.). Genome localization of clones and candidate genes were based on the NCBI Build 36 using the UCSC Genome Browser. A standard blood karyotype was normal. Both microarrays revealed a hemizygous copy loss on chromosome 12q13.13. It was approximately 1.13 Mb in size between proximal probes 51.834.791 bp and 51.836.033 bp and distal probes 52.968.320 bp and 52.971.391 bp according to the 2.1M array-CGH (Fig. 1). Taqmanbased quantitative PCR analysis with a probe targeted to intron 2 of the AAAS gene (probe selected from the Roche Universal Probe Library; Roche) and FISH analysis using BAC-probes BAC-RP1165C2 and RP11-1101H10 on the patient-parent trio confirmed a de novo copy loss (data not shown). The deletion was paternal in origin
* Corresponding author. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. Tel.: þ354 824 5917; fax: þ354 525 4886. E-mail address: [email protected] (J.J. Jonsson). 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2012.03.001
according to three informative microsatellite markers; D12S1604, D12S1586 and D12S325 (data not shown). Thus the deletion occurred de novo in the paternal chromosome 12.
2. Clinical description The girl was born after a normal gestation of 41 weeks. Birth weight was 3665 g (75th percentile), length 51 cm (50th percentile) and head circumference 34,5 cm (75th percentile). She was the first child of a 27 year old Caribbean mother and a 37 year old Scandinavian father. The parents were both in good health and there was no family history of congenital malformations or intellectual disability. At birth the patient had umbilical hernia and pectus excavatum. All extremities were affected by flexion contractures including digits, hands and elbows. There was an ulnar deviation of hands and a valgus position of both ankles. Radiologic imaging after birth showed bilateral subluxation at MCP III, flexion in PIP and extension in DIP joints. Imaging of hands at 2 years and 7 months showed some growth retardation of metacarpal bones especially IV, short proximal phalanges and bone age was increased corresponding to 3 1/2 to 4 1/2 years. MRI of brain and spinal cord at 15 months was normal. When last examined at the age of 5 years her weight was 18,8 kg (50th percentile) and length 112 cm (50th
438
D.I. Jonsson et al. / European Journal of Medical Genetics 55 (2012) 437e440
Fig. 1. Results from the 2.1M NimbleGen array showing an approximately 1.13 Mb deletion within 12q13.13. Breakpoints were between proximal probe 51.834.791 bp and distal probe 52.971.391 bp. Genes in the deletion area, structural variants listed in the database of genomic Variants, deletions in the three DECIPHER cases and known segmental duplications are shown. The figure is modified from Ensemble.
percentile). Contractures of upper extremities had decreased with physical therapy, but at the age of 6 years surgery was needed to improve ankle valgus. Bilaterally there were absent or minimal flexion lines and short metacarpal and proximal phalangeal bones (Fig. 2c). Nails of hands and feet were short. Facial features included bilateral epicanthal folds, a depressed nasal bridge, a slightly bulbous and antiverted nose, and a short philtrum (Fig. 2a and b). Motor and mental abilities developed slowly. She started to walk at 22 months and at 30 months her maturity was 10 months behind her age group according to Kuno Beller’s test [1]. Wechsler Preschool and Primary Scale of Intelligence (WPPSI) taken at 40 months showed her 2e3 standard deviations below average. At 6 years she was diagnosed with an attention deficit disorder. She speaks two languages fluently. The girl has asthma and is prone to airway infections. She has had pneumonia three times resulting in two hospitalizations. Routine blood tests and immunologic evaluations have, however, been normal.
3. Discussion We did not find any description of patients with similar symptoms or copy loss after searching databases and literature of chromosomal malformations. The copy loss included 33 genes and 2 microRNAs according to the UCSC Genome Browser build 36 (Fig. 1). Two genes, AAAS and AMRH2, are disease-associated according to OMIM. Their associated diseases, respectively, are Triple A syndrome (#MIM 231550), named after the main symptoms; achalasia, Addison disease and alacrima, and Persistent Müllerian duct syndrome (#MIM 261550), which only has an abnormal phenotype in males. Both conditions have autosomal recessive inheritance and are unlikely to play a part in the girl’s phenotype. A search in the DECIPHER database (http://decipher. sanger.ac.uk/ accessed 1.4.2011) revealed pathological copy gains in two patients (248785, 248901) that were associated with cognitive dysfunction and deformities. These copy gains extend beyond the copy loss in our patient on both sides (Fig. 1). A third
D.I. Jonsson et al. / European Journal of Medical Genetics 55 (2012) 437e440
Fig. 2. Patient at 5 years of age. a and b: Facial features included bilateral epicanthal folds, a low and flat nasal bridge, a slightly bulbous and antiverted nose, and a short philtrum. c: Bilaterally single transverse palmar creases, absent or minimal flexion lines and short metacarpal bones.
patient in DECIPHER (2055) also has a short copy gain in this area. That patient reportedly has a number of other chromosomal imbalances limiting phenotypic correlation. According to the girl’s phenotype i.e. intellectual disability, distal arthrogryposis, and bone malformations, the gene or genes responsible should have a role in bone and neuronal function during fetal growth. This fits well with known functions, and mouse phenotypes associated with the HOXC gene complex. HOX genes are highly conserved [2]. Heterozygous and homozygous copy loss of various Hoxc genes in mice cause minor structural abnormalities the most common being extra ribs connected to sternum and minor malformations of the spinal column and hindlegs [3e7]. Mice with homozygous copy loss knockout of Hoxc8 present with congenital distal contractures of front legs. This presumably results from CNS involvement since the mice show an atrophy of the anterior spinal horns [8]. Somewhat contradicting the importance of HOXC genes in fetal development, there is a reported benign CNV (Variation 3890) in the Database of Genomic Variants (DGV, http://projects.tcag.ca/variation/ accessed 1.4.2011) that covers the entire HOXC gene cluster except for HOXC13. This CNV has only been reported in three individuals, two copy losses and one copy gain, and has not been confirmed by other molecular methods [9]. There are no known imprinted genes in the copy loss area, but Luedi et al. predicted with multiple classification algorithms based on DNA sequences that most HOXC genes, and especially HOXC9 and HOCX4, are candidates for maternally expressed
439
imprinted genes [10]. Even though the parental origin in this case was paternal, the parental origin of the deletion could affect the phenotype. One gene, CSAD has a particularly high expression in fetal and adult brain and in the spine according to the Symatlas [11]. CSAD, however, is reported to be in a CNV region making it less probable that it plays a part in the phenotype. Six genes, RARG, SP1, ATP5G2, HOXC5, HOXC6 and CBX5, have been predicted to be very likely haploinsufficient according to Huang et al. [12]. These genes are all transcription factors, but their exact role has not been established. A functional link between SP1, ATP5G2 or CBX5 and the patients’ bone malformations or arthrogryposis is not evident. The RARG gene, however, encodes for retinoid acid receptor gamma and retinoids have been known to influence skeletogenesis in mice. Koyama et al. showed that the retinoids, among them the retinoid acid receptor gamma, play an important role in chondrocyte maturation and endochondrial ossification in the developing limb [13]. In conclusion, both the RARG gene and the HOXC genes could contribute to the patient’s phenotype. Independently and parallel to our work a case has been described by Okamoto et al. [14]. That patient, a 14 year old male, had a 1.7 Mb de novo copy loss on 12q13.1 with boundaries extending beyond the deletion in our case on both sides. He had skeletal anomalies similar to our case, camptodactyly and hand bone malformations, and additionally a kyphosis and Tetralogy of Fallot. The patient also had developmental delay, not walking before age of 5 years, and verbal expression was limited. The greater developmental delay and heart defect in this patient perhaps reflects the size difference in the deletions, 1.7 Mb versus 1.13 Mb. These cases support one another with regard to bone malformations. We conclude that the features in our patient represent a previously unrecognized syndrome presumably caused by the 1.13 Mb heterozygous copy loss on 12q13.13. This case along with the case described Okamoto et al. [14] might also be the first descriptions in humans of a disease phenotype associated with a copy loss of HOXC genes. Patient has been submitted to the DECIPHER database under case 250426. This study was approved by the National Bioethics Committee of Iceland (no. VSNb2008040022/03-15) and the Data Protection Authority (no. 2008050414LSL). Informed consent of the girls’ parents was obtained.
Acknowledgments This study makes use of data generated by the DECIPHER Consortium. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from [email protected]. Funding for that project was provided by the Wellcome Trust. Those who carried out the original analysis and collection of patient data bear no responsibility for the further analysis or interpretation. The data in this manuscript were obtained from the ISCA Consortium database (www. iscaconsortium.org), which generates this information using NCBI’s database of genomic structual variation (dbVar, www.ncbi. nlm.nih.gov/dbvar/), study nstd37.
References [1] E.K. Beller, H. Weltzer, Kuno Beller’s Utviklingsbeskrivelse af Småbörn, Dansk Psykologisk Forlag (1991). [2] T.R. Lappin, D.G. Grier, A. Thompson, H.L. Halliday, HOX GENES: seductive science, mysterious mechanisms, Ulster Medical Journal 75 (2006) 23e31. [3] H. Saegusa, N. Takahashi, S. Noguchi, H. Suemori, Targeted disruption in the mouse Hoxc-4 locus results in axial skeleton homeosis and malformation of the xiphoid process, Developmental Biology 174 (1996) 55e64. [4] A.M. Boulet, M.R. Capecchi, Targeted disruption of Hoxc-4 causes esophageal defects and vertebral transformations, Developmental Biology 177 (1996) 232e249.
440
D.I. Jonsson et al. / European Journal of Medical Genetics 55 (2012) 437e440
[5] H. Suemori, Hoxc-9 mutant mice show anterior transformation of the vertebrae and malformation of the sternum and ribs, Mechanical Development (1995). [6] H. Suemori, S. Noguchi, Hox C cluster genes are dispensable for overall body plan of mouse embryonic development, Developmental Biology 220 (2000) 333e342. [7] E. van Den Akker, C. Fromental-Ramain, W. de Graaff, H. Le Mouellic, P. Brulet, P. Chambon, J. Deschamps, Axial skeletal patterning in mice lacking all paralogous group 8 Hox genes, Development 128 (2001) 1911e1921. [8] L. Tiret, H. Le Mouellic, M. Maury, P. Brulet, Increased apoptosis of motoneurons and altered somatotopic maps in the brachial spinal cord of Hoxc-8deficient mice, Development 125 (1998) 279e291. [9] R. Redon, S. Ishikawa, K.R. Fitch, L. Feuk, G.H. Perry, T.D. Andrews, H. Fiegler, M.H. Shapero, A.R. Carson, W. Chen, E.K. Cho, S. Dallaire, et al., Global variation in copy number in the human genome, Nature 444 (2006) 444e454. [10] P.P. Luedi, F.S. Dietrich, J.R. Weidman, J.M. Bosko, R.L. Jirtle, A.J. Hartemink, Computational and experimental identification of novel human imprinted genes, Genome Research 17 (2007) 1723e1730.
[11] A.I. Su, T. Wiltshire, S. Batalov, H. Lapp, K.A. Ching, D. Block, J. Zhang, R. Soden, M. Hayakawa, G. Kreiman, M.P. Cooke, J.R. Walker, J.B. Hogenesch, A gene atlas of the mouse and human protein-encoding transcriptomes, Proceedings of the National Academy of Sciences of the United States of America 101 (2004) 6062e6067. [12] N. Huang, I. Lee, E.M. Marcotte, M.E. Hurles, Characterising and predicting haploinsufficiency in the human genome, PLoS Genetics 6 (2010) e1001154. [13] E. Koyama, E.B. Golden, T. Kirsch, S.L. Adams, R.A.S. Chandraratna, J.-J. Michaille, M. Pacifici, Retinoid signaling is required for chondrocyte maturation and endochondral bone formation during limb skeletogenesis, Developmental Biology 208 (1999) 375e391. [14] N. Okamoto, D. Tamura, G. Nishimura, K. Shimojima, T. Yamamoto, Submicroscopic deletion of 12q13 including HOXC sene cluster with skeletal anomalies and global developmental delay, American Journal of Medical Genetics Part A 155 (2011) 2997e3001.