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A de novo 17q21.2 duplication in a boy with developmental delay and dysmorphic features
European Journal of Medical Genetics 56 (2013) 226e228
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 17q21.2 duplication in a boy with developmental delay and dysmorphic features Céline Poirsier-Violle a, *, Azzedine Abourra a, Clarisse Baumann a, Laurence Perrin a, Yline Capri a, Cyril Mignot b, Sandrine Passemard a, c, Séverine Drunat a, Alain Verloes a, c a b c
Départment of Genetics, Univ Paris Diderot Sorbonne Paris Cité, Robert Debré Hospital, Paris, France Hôpital de la Pitié-Salpétrière, Unité de génétique clinique, Paris, France Inserm U676, Univ Paris Diderot Sorbonne Paris Cité, Robert Debré Hospital, Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 August 2012 Accepted 17 December 2012 Available online 19 January 2013
We report a boy with severe developmental delay, microcephaly and characteristic facial dysmorphism consisting in round face, hypertelorism, upslanted palpebral fissures, small nose, large mouth, micrognathia, sparse hair and eyelashes. Array-CGH revealed a de novo duplication of 103 kb within 17q21.2 not reported to date. The duplication includes 8 genes: DHX58, KAT2A, HSPB9, RAB5C, KCNH4, HCRT, GHDC and STAT5B. Three genes (KATA2, KCNH4, and STAT5B) may contribute to intellectual deficiency. Further observations will be necessary to confirm the specificity of the facial Gestalt. Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords: CGH-array Duplication 17q21.2 Intellectual disability Microcephaly
1. Clinical description Our patient is the second child of healthy non consanguineous parents. His mother and his father were 32 and 37 year-old respectively at the time of his birth. Pregnancy was uncomplicated. He was born by vaginal delivery at 40 weeks of gestation with normal growth parameters: weight 3860 g (þ1SD), length 53 cm (þ2SD) and HC 33 cm (1SD). APGAR score was 10/10. Pediatricians noted malposition of the thumbs and facial dysmorphism. Heart ultrasound scan, transfontanellar ultrasound scan and conventional karyotype were normal. At age 16 months, he had a height of 78.5 cm (median), a weight of 9700 kg (þ1SD) and a head circumference of 42 cm (4SD). The patient had microcephaly, round face, hypertelorism, upslanted palpebral fissures, small flattened nose, large mouth with down-turned corners, micrognathia, slightly posteriorly rotated ears, almost no eyebrows, sparse eyelashes and sparse hair (Fig. 1A). At the age of three years and 1 months (Fig. 1B, C), he had a height of 94 cm (median), a weight of 13,5 kg (1SD) and a head circumference of 45 cm (4SD). He had severe developmental delay: he sat alone at 21 months, walked unsupported at 30 months and had no language at age three years. No seizures were reported. He had bilateral
orchidopexy. Brain MRI, EEG, abdominal ultrasound scan, ophthalmological examination and auditory evoked potentials were normal. 2. Methods of detection Array comparative genomic hybridization (CGH) was performed using Human Genome array-CGH 180K AgilentÒ according to the manufacturer’s recommendations (Agilent Technologies, Santa Clara, CA, USA). Microarray analysis was performed using DNA Analytics Software. Results were validated with real-time quantitative PCR. Relative copy numbers were measured with two primer sets targeting KCNH4. 3. Chromosomal anomaly Microarray showed a duplication of 103 kb within 17q21.2 (USCS hg18, Mar. 2006, chromosome 17: 37,518,031e37,620,849; Fig. 2). Real-time quantitative PCR confirmed the duplication in the patient and the absence of the duplication in his parents. Due to its small size, the insertion locus could not be identified by FISH. 4. Discussion
* Corresponding author. E-mail address: [email protected] (C. Poirsier-Violle). 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmg.2012.12.005
We report a patient carrying a de novo 17q21.2 duplication with severe psychomotor delay, severe microcephaly and a striking facial
C. Poirsier-Violle et al. / European Journal of Medical Genetics 56 (2013) 226e228
227
Fig. 1. Dysmorphic features of the proband at age of 16 months (A) and 4 years (B and C). Note hypertelorism, upslanted palpebral fissures, almost no eyebrows, sparse eyelashes and sparse hair.
dysmorphism that could be recognizable. The duplication of 103 kb includes 8 genes: DHX58, KAT2A, HSPB9, RAB5C, KCNH4, HCRT, GHDC and STAT5B. Two genes, DHX58 and STAT5B located at the borders, are probably interrupted by the breakpoints. Three of these genes can be considered candidates for mental retardation: KAT2A, KCNH4 and RAB5C. KAT2A (OMIM 602301) encodes a histone acetyltransferase (HAT) that serves as a coactivator for DNA-bound transcription factors. KAT2A affects expression of multiple cell cycle-related and apoptosis-related genes causing up-
or down-regulation of more than 50 transcripts [1], among which the cell-division cycle 6 protein (CDC6) which is essential for S phase progression [2]. The KAT2A/ mouse is not viable because of high levels of apoptosis leading to loss of mesodermal lineages [3]. KCNH4 (OMIM 604528) is exclusively expressed in human brain (telencephalon) and encodes a voltage-gated Kþ channel protein which plays a role in controlling cellular excitability in the nervous system [4]. RAB5C (OMIM 604037) encodes a small GTPase of the Ras superfamily which is ubiquitously expressed [5].
Fig. 2. Content of the duplicated region on chromosome 17. Black bar represents minimal duplication extension (from nucleotides 37,518,031 to 37,623,849 according to USCS hg 18 build, Mars 2006) and dotted bars maximal extension (from nucleotides 37,518,031 to 37,623,616).
228
C. Poirsier-Violle et al. / European Journal of Medical Genetics 56 (2013) 226e228
The HCRT gene encodes hypocretin, a neuropeptide expressed in brain especially in hypothalamus. Hypocretin producing neurons regulate wakefulness and feeding. Loss of hypocretin neurons is responsible for narcolepsy. But in series of 74 patients with narcolepsy, only one patient with HCRT mutation was reported [6]. Johnson et al. [7] showed an elevated level of hypocretin in cerebrospinal fluid in subject with panic disorder suggesting that hypocretin system may be involved in these disorders. STAT5B encodes a Signal Transducers and Activators of Transcription protein (STAT) activated by numerous cytokines. STAT5B is activated in human hematologic malignancies (myelo and lymphoproliferative disease). Homozygous mutations of STAT5B were reported in patients with growth hormone insensitivity and immunodeficiency [8]. We have limited information about HSPB9 whose transcript was detected only in testis in human tissues [9]. Cui et al. cloned mouse Ghdc and Dhx58 (also called Lgp1 and Lgp2 respectively) [10]. They showed that transcripts were detected with highest expression in mouse liver. DHX58 downregulates interferon production during several viruses infections. No other patient has been reported with duplication or deletion similar to our patient in the medical literature. A patient in the DECIPHER Database (case 254309) has a much wider duplication of 11.9 Mb on chromosome 17q11.2q21.3, which preclude any reasonable genotypeephenotype comparison. He had a mental retardation with cerebellar abnormalities and a facial appearance different from that of our patient. These three genes may contribute to the intellectual deficiency of our patient, and their overexpression may be the origin of the microcephaly. Further observations will be necessary to confirm the specificity of the facial Gestalt.
References [1] M. Choudhury, R.S. Pandey, D.L. Clemens, J.W. Davis, R.W. Lim, S.D. Shukla, Knock down of GCN5 histone acetyltransferase by siRNA decreases ethanolinduced histone acetylation and affects differential expression of genes in human hepatoma cells, Alcohol 45 (2011) 311e324. [2] R. Paolinelli, R. Mendoza-Maldonado, A. Cereseto, M. Giacca, Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle, Nat. Struct. Mol. Biol. 16 (2009) 412e420. [3] W. Lin, G. Srajer, Y.A. Evrard, H.M. Phan, Y. Furuta, S.Y. Dent, Developmental potential of Gcn5(/) embryonic stem cells in vivo and in vitro, Dev. Dyn. 236 (2007) 1547e1557. [4] A. Miyake, S. Takahashi, Y. Nakamura, K. Inamura, S. Matsumoto, S. Mochizuki, M. Katou, Disruption of the ether-a-go-go Kþ channel gene BEC1/KCNH3 enhances cognitive function, J. Neurosci. (2009) 14637e14645. [5] H.J. Han, K. Sudo, J. Inazawa, Y. Nakamura, Isolation and mapping of a human gene (RABL) encoding a small GTP-binding protein homologous to the Rasrelated RAB gene, Cytogenet. Cell. Genet. 73 (1996) 137e139. [6] C. Peyron, J. Faraco, W. Rogers, B. Ripley, S. Overeem, Y. Charnay, S. Nevsimalova, M. Aldrich, D. Reynolds, R. Albin, R. Li, M. Hungs, et al., A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains, Nat. Med. 6 (2000) 991e997. [7] P.L. Johnson, W. Truitt, S.D. Fitz, P.E. Minick, A. Dietrich, S. Sanghani, L. Traskman-Bendz, A.W. Goddard, L. Brundin, A. Shekhar, A key role for orexin in panic anxiety, Nat. Med. 16 (2010) 111e115. [8] V. Hwa, B. Little, P. Adiyaman, E.M. Kofoed, K.L. Pratt, G. Ocal, M. Berberoglu, R.G. Rosenfeld, Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b, J. Clin. Endocrinol. Metab. 90 (2005) 4260e4266. [9] G. Kappe, P. Verschuure, R.L.A. Philipsen, A.A. Staalduinen, P. Van de Boogaart, W.C. Boelens, W.W. De Jong, Characterization of two novel human small heat shock proteins: protein kinase-related HspB8 and testis-specific HspB9, Biochim. Biophys. Acta 1520 (2001) 1e6. [10] Y. Cui, M. Li, K.D. Walton, K. Sun, J.A. Hanover, P.A. Furth, L. Hennighausen, The Stat3/5 locus encodes novel endoplasmic reticulum and helicase-like proteins that are preferentially expressed in normal and neoplastic mammary tissue, Genomics 78 (2001) 129e134.
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 17q21.2 duplication in a boy with developmental delay and dysmorphic features Céline Poirsier-Violle a, *, Azzedine Abourra a, Clarisse Baumann a, Laurence Perrin a, Yline Capri a, Cyril Mignot b, Sandrine Passemard a, c, Séverine Drunat a, Alain Verloes a, c a b c
Départment of Genetics, Univ Paris Diderot Sorbonne Paris Cité, Robert Debré Hospital, Paris, France Hôpital de la Pitié-Salpétrière, Unité de génétique clinique, Paris, France Inserm U676, Univ Paris Diderot Sorbonne Paris Cité, Robert Debré Hospital, Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 August 2012 Accepted 17 December 2012 Available online 19 January 2013
We report a boy with severe developmental delay, microcephaly and characteristic facial dysmorphism consisting in round face, hypertelorism, upslanted palpebral fissures, small nose, large mouth, micrognathia, sparse hair and eyelashes. Array-CGH revealed a de novo duplication of 103 kb within 17q21.2 not reported to date. The duplication includes 8 genes: DHX58, KAT2A, HSPB9, RAB5C, KCNH4, HCRT, GHDC and STAT5B. Three genes (KATA2, KCNH4, and STAT5B) may contribute to intellectual deficiency. Further observations will be necessary to confirm the specificity of the facial Gestalt. Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords: CGH-array Duplication 17q21.2 Intellectual disability Microcephaly
1. Clinical description Our patient is the second child of healthy non consanguineous parents. His mother and his father were 32 and 37 year-old respectively at the time of his birth. Pregnancy was uncomplicated. He was born by vaginal delivery at 40 weeks of gestation with normal growth parameters: weight 3860 g (þ1SD), length 53 cm (þ2SD) and HC 33 cm (1SD). APGAR score was 10/10. Pediatricians noted malposition of the thumbs and facial dysmorphism. Heart ultrasound scan, transfontanellar ultrasound scan and conventional karyotype were normal. At age 16 months, he had a height of 78.5 cm (median), a weight of 9700 kg (þ1SD) and a head circumference of 42 cm (4SD). The patient had microcephaly, round face, hypertelorism, upslanted palpebral fissures, small flattened nose, large mouth with down-turned corners, micrognathia, slightly posteriorly rotated ears, almost no eyebrows, sparse eyelashes and sparse hair (Fig. 1A). At the age of three years and 1 months (Fig. 1B, C), he had a height of 94 cm (median), a weight of 13,5 kg (1SD) and a head circumference of 45 cm (4SD). He had severe developmental delay: he sat alone at 21 months, walked unsupported at 30 months and had no language at age three years. No seizures were reported. He had bilateral
orchidopexy. Brain MRI, EEG, abdominal ultrasound scan, ophthalmological examination and auditory evoked potentials were normal. 2. Methods of detection Array comparative genomic hybridization (CGH) was performed using Human Genome array-CGH 180K AgilentÒ according to the manufacturer’s recommendations (Agilent Technologies, Santa Clara, CA, USA). Microarray analysis was performed using DNA Analytics Software. Results were validated with real-time quantitative PCR. Relative copy numbers were measured with two primer sets targeting KCNH4. 3. Chromosomal anomaly Microarray showed a duplication of 103 kb within 17q21.2 (USCS hg18, Mar. 2006, chromosome 17: 37,518,031e37,620,849; Fig. 2). Real-time quantitative PCR confirmed the duplication in the patient and the absence of the duplication in his parents. Due to its small size, the insertion locus could not be identified by FISH. 4. Discussion
* Corresponding author. E-mail address: [email protected] (C. Poirsier-Violle). 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmg.2012.12.005
We report a patient carrying a de novo 17q21.2 duplication with severe psychomotor delay, severe microcephaly and a striking facial
C. Poirsier-Violle et al. / European Journal of Medical Genetics 56 (2013) 226e228
227
Fig. 1. Dysmorphic features of the proband at age of 16 months (A) and 4 years (B and C). Note hypertelorism, upslanted palpebral fissures, almost no eyebrows, sparse eyelashes and sparse hair.
dysmorphism that could be recognizable. The duplication of 103 kb includes 8 genes: DHX58, KAT2A, HSPB9, RAB5C, KCNH4, HCRT, GHDC and STAT5B. Two genes, DHX58 and STAT5B located at the borders, are probably interrupted by the breakpoints. Three of these genes can be considered candidates for mental retardation: KAT2A, KCNH4 and RAB5C. KAT2A (OMIM 602301) encodes a histone acetyltransferase (HAT) that serves as a coactivator for DNA-bound transcription factors. KAT2A affects expression of multiple cell cycle-related and apoptosis-related genes causing up-
or down-regulation of more than 50 transcripts [1], among which the cell-division cycle 6 protein (CDC6) which is essential for S phase progression [2]. The KAT2A/ mouse is not viable because of high levels of apoptosis leading to loss of mesodermal lineages [3]. KCNH4 (OMIM 604528) is exclusively expressed in human brain (telencephalon) and encodes a voltage-gated Kþ channel protein which plays a role in controlling cellular excitability in the nervous system [4]. RAB5C (OMIM 604037) encodes a small GTPase of the Ras superfamily which is ubiquitously expressed [5].
Fig. 2. Content of the duplicated region on chromosome 17. Black bar represents minimal duplication extension (from nucleotides 37,518,031 to 37,623,849 according to USCS hg 18 build, Mars 2006) and dotted bars maximal extension (from nucleotides 37,518,031 to 37,623,616).
228
C. Poirsier-Violle et al. / European Journal of Medical Genetics 56 (2013) 226e228
The HCRT gene encodes hypocretin, a neuropeptide expressed in brain especially in hypothalamus. Hypocretin producing neurons regulate wakefulness and feeding. Loss of hypocretin neurons is responsible for narcolepsy. But in series of 74 patients with narcolepsy, only one patient with HCRT mutation was reported [6]. Johnson et al. [7] showed an elevated level of hypocretin in cerebrospinal fluid in subject with panic disorder suggesting that hypocretin system may be involved in these disorders. STAT5B encodes a Signal Transducers and Activators of Transcription protein (STAT) activated by numerous cytokines. STAT5B is activated in human hematologic malignancies (myelo and lymphoproliferative disease). Homozygous mutations of STAT5B were reported in patients with growth hormone insensitivity and immunodeficiency [8]. We have limited information about HSPB9 whose transcript was detected only in testis in human tissues [9]. Cui et al. cloned mouse Ghdc and Dhx58 (also called Lgp1 and Lgp2 respectively) [10]. They showed that transcripts were detected with highest expression in mouse liver. DHX58 downregulates interferon production during several viruses infections. No other patient has been reported with duplication or deletion similar to our patient in the medical literature. A patient in the DECIPHER Database (case 254309) has a much wider duplication of 11.9 Mb on chromosome 17q11.2q21.3, which preclude any reasonable genotypeephenotype comparison. He had a mental retardation with cerebellar abnormalities and a facial appearance different from that of our patient. These three genes may contribute to the intellectual deficiency of our patient, and their overexpression may be the origin of the microcephaly. Further observations will be necessary to confirm the specificity of the facial Gestalt.
References [1] M. Choudhury, R.S. Pandey, D.L. Clemens, J.W. Davis, R.W. Lim, S.D. Shukla, Knock down of GCN5 histone acetyltransferase by siRNA decreases ethanolinduced histone acetylation and affects differential expression of genes in human hepatoma cells, Alcohol 45 (2011) 311e324. [2] R. Paolinelli, R. Mendoza-Maldonado, A. Cereseto, M. Giacca, Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle, Nat. Struct. Mol. Biol. 16 (2009) 412e420. [3] W. Lin, G. Srajer, Y.A. Evrard, H.M. Phan, Y. Furuta, S.Y. Dent, Developmental potential of Gcn5(/) embryonic stem cells in vivo and in vitro, Dev. Dyn. 236 (2007) 1547e1557. [4] A. Miyake, S. Takahashi, Y. Nakamura, K. Inamura, S. Matsumoto, S. Mochizuki, M. Katou, Disruption of the ether-a-go-go Kþ channel gene BEC1/KCNH3 enhances cognitive function, J. Neurosci. (2009) 14637e14645. [5] H.J. Han, K. Sudo, J. Inazawa, Y. Nakamura, Isolation and mapping of a human gene (RABL) encoding a small GTP-binding protein homologous to the Rasrelated RAB gene, Cytogenet. Cell. Genet. 73 (1996) 137e139. [6] C. Peyron, J. Faraco, W. Rogers, B. Ripley, S. Overeem, Y. Charnay, S. Nevsimalova, M. Aldrich, D. Reynolds, R. Albin, R. Li, M. Hungs, et al., A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains, Nat. Med. 6 (2000) 991e997. [7] P.L. Johnson, W. Truitt, S.D. Fitz, P.E. Minick, A. Dietrich, S. Sanghani, L. Traskman-Bendz, A.W. Goddard, L. Brundin, A. Shekhar, A key role for orexin in panic anxiety, Nat. Med. 16 (2010) 111e115. [8] V. Hwa, B. Little, P. Adiyaman, E.M. Kofoed, K.L. Pratt, G. Ocal, M. Berberoglu, R.G. Rosenfeld, Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b, J. Clin. Endocrinol. Metab. 90 (2005) 4260e4266. [9] G. Kappe, P. Verschuure, R.L.A. Philipsen, A.A. Staalduinen, P. Van de Boogaart, W.C. Boelens, W.W. De Jong, Characterization of two novel human small heat shock proteins: protein kinase-related HspB8 and testis-specific HspB9, Biochim. Biophys. Acta 1520 (2001) 1e6. [10] Y. Cui, M. Li, K.D. Walton, K. Sun, J.A. Hanover, P.A. Furth, L. Hennighausen, The Stat3/5 locus encodes novel endoplasmic reticulum and helicase-like proteins that are preferentially expressed in normal and neoplastic mammary tissue, Genomics 78 (2001) 129e134.