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De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature
European Journal of Medical Genetics 55 (2012) 117e119
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short report
De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature M.D. Perrone a, *, M.S. Rocca b, I. Bruno c, F. Faletra b, V. Pecile b, P. Gasparini b a
Institute for Maternal and Child Health IRCCS “Burlo Garofalo” Trieste, Italy e University of Trieste, Italy IRCCS “Burlo Garofalo” Institute, Department of Medical Genetics, Trieste, Italy c IRCCS “Burlo Garofalo” Institute, Department of Pediatrics, Trieste, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 July 2011 Accepted 19 November 2011 Available online 2 December 2011
Patients with distal deletions of chromosome 1q have a recognizable syndrome that includes microcephaly, hypoplasia or agenesis of the corpus callosum, and psychomotor retardation. Although these symptoms have been attributed to deletions of 1q42e1q44, the minimal chromosomal region involved has not yet defined. In this report, we describe a 7 years old male with mental retardation, cryptorchid testes, short stature and alopecia carrying only an interstitial de novo deletion of 911 Kb in the 1q43 region (239,597,095e240,508,817) encompassing three genes CHRM3, RPS7P5 and FMN2. Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords: Deletion Chromosome 1 Mental retardation
1. Introduction Deletions of the long arm of chromosome 1 are relatively rare. The first published description of a patient carrying a 1q4 deletion was in 1976 [1]. There have since been over 30 cases reported in the medical literature worldwide. The deletion occurs in equal frequency in males and females. A 1q4 deletion is sometimes called “terminal 1q deletion” (the tip of the long arm of chromosome 1 is included in the deletion) or “1qter deletion” or, if itcan’t be seen down a microscope, “1qter microdeletion” [2]. Every person with a 1q4 deletion is unique and so each person will have different medical and developmental features. However, a number of common features have emerged: hypotonia in newborn babies, seizures, commonly starting in the first three years of life, learning difficulties, feeding difficulties, short stature, heart conditions often resolved without surgical intervention, microcephaly, structural anomalies of the brain (in particular corpus callosum). 2. Methods DNA was extracted from whole blood by the Bio Robot EZ1 Qiagen. Patient and his parents were screened using * Corresponding author. IRCCS Burlo Garofolo Via Dell’Istria 65/1 34137 Trieste, Italy. Tel.: þ39 040 3785538; fax: þ39 0403785540. E-mail addresses: [email protected] (M.D. Perrone), [email protected] (M.S. Rocca), [email protected] (I. Bruno), [email protected] (F. Faletra), [email protected] (V. Pecile), [email protected] (P. Gasparini). 1769-7212/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2011.11.004
HumanCytoSNP-12 BeadChip (Illumina Inc., San Diego, CA, USA). A total of 750 ng DNA was processed and the genotyping reaction steps were performed according to the manufacturer’s specifications (Infinium II; Illumina, San Diego, California, USA). The HumanCytoSNP-12 BeadChip contains nearly 300,000 genetic markers per sample that target all known cytogenetic abnormalities found in genes and disease pathways linked to mental retardation, autism, and other common chromosome anomalies. SNP copy number (log R ratio) and B-allele frequency were assessed using the software programs KaryoStudio v.1 (Illumina). The Human Genome Resources website at NCBI and the Archive EnsEMBL (biblio) have been used to study the CNV detected. 3. Clinical description The boy is the only child of a non consanguineous Italian mating. He was born at term with natural childbirth. At birth, weight was 3450 gr (50 centile, þ0,1SD) and length 34 cm (<<3 centile, <3SD), lactation was not possible for sucking difficult (hypotonia?). Motor development was delayed: he sat alone after 1 year and walked independently at 4 years. Now, the proband presents mental retardation, cryptorchid testes and short stature. Clinical examination showed alopecic patch in occipital area, clinodactyly of 5th finger, big thumb and toe, convergent strabismus, tendency to bite hands. Since the difficulty in chewing, he eats only blended food. Height (119 cm) is below the normal range (3 centile, 1,80SD), head circumference (55 cm) is above the 97 centile (þ2,3SD) and weight (21,5 kg) is on the 10 centile
118
M.D. Perrone et al. / European Journal of Medical Genetics 55 (2012) 117e119
Fig. 1. The figure shows some clinical features like strabismus and alopecia.
(1,41SD). A neurological examination revealed a development delay with autistic features. MRI, ECG and abdominal ultrasound were normal. No seizures were reported. A test for fragile X syndrome was negative. Because of the mental retardation and development delay a SNPs-array analysis was performed (Fig. 1 and 2). 4. Results The SNPs-Array analysis revealed a de novo interstitial deletion of 911722 bp in the 1q43 region (chr1:239,597,095e240,508,817, genome assembly Feb. 2009 (GRCh37/hg19)). This region contains only three genes, RPS7P5 a pseudogene that is unlikely to influence the phenotype, and two genes with a known function: the first one is the FMN2 gene, involved in the development of the central nervous system and the other one is the CHRM3 gene, encoding for a muscarinic cholinergic receptor.
5. Discussion Interstitial deletions of chromosome 1q are not rare, more than 30 patients have been described [3] since the first case in 1976. The 911 Kb deletion here described encompasses a small region with only 2 coding genes. FMN2, encoding for Formin-2 and CHRM3, for a cholinergic receptor muscarinic 3. FMN2 gene plays a role in cytoskeletal organization and/or establishment of cell polarity. Moreover, Formin-2 expression is important in the development of the central nervous system and the synaptic growth [4]. Strong expression is seen in all tissues of the adult central nervous system, including the pituitary gland and spinal cord. Fetal brain also showed heavy expression [5]. Until now, FMN2 has been associated with unexplained infertility [6] or leukaemia [7], but since his CNS expression is likely that FMN2 mutation causes developmental delay. Indeed, in a case of unexplained mental retardation a FMN2 duplication was found (http://decipher.sanger.ac.uk/). So, we
Fig. 2. Area of the deletion 1q43 in our patient.
M.D. Perrone et al. / European Journal of Medical Genetics 55 (2012) 117e119
suggest that psychomotor delay of our patient might be due to alteration of FMN2 gene. Indeed, CHRM3 encodes for a muscarinic cholinergic receptor. It influences many effects of acetylcholine in the central and peripheral nervous system. Briefly, the muscarinic cholinergic receptor 3 controls smooth muscle contraction and its stimulation causes secretion of glandular tissue [8]. Yamada et al. [9] showed that mice deficient in the M3 muscarinic receptor display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic mRNA levels of melanin-concentrating hormone, normally upregulated in fasted animals leading to an increase in food intake, are significantly reduced in M3r / mice. So, we might correlate the growth delay and the low food intake of the proband with the low appetite, caused by the CHRM3 deletion. There aren’t patients described with small aberrations (duplications or deletions) that comprise these genes. It’s possible to make an interesting comparison between our case and 7 patients with terminal chromosome 1q deletion [3]. 6 of these 7 patients present microcephaly and seizures, not present in our case. This finding might be explained because their deletion zone includes genes with an important role in the cerebral development and in the neuronal excitability not deleted in our proband. The first one is RGS7, involved in synaptic vesicle exocytosis [10].and may play an important role in the rapid regulation of neuronal excitability and the cellular responses to short-lived stimulations. The second one to consider is ZNF 238, responsible to generate abnormalities in corpus callosum [11]. Finally, KMO related to behavioral disorders [12]. Indeed, microcephaly is a recurrent feature in patients with 1q43 deletion; indeed our patient shows a relative macrocephaly. In conclusion, our case improves the knowledge about the minimal region of 1q43 deletion suggesting that the loss of two coding genes involved in the developing of central nervous system(FMN2 and CHRM3) can explain some particular features. Knowledge of the pattern of this deletion-phenotype will help clinicians to diagnose this abnormality in their patients and to counsel the parents accordingly.
119
References [1] C.B. Mankinen, J.W. Sears, V.R. Alvares, Terminal (1)(q43) long-arm deletion of chromosome no. 1 in a three-year-old female, Birth Defects Orig. Artic. Ser. 12 (5) (1976) 131e136. [2] Y. Hiraki, N. Okamoto, T. Ida, Y. Nakata, M. Kamada, Y. Kanemura, M. Yamasaki, H. Fujita, G. Nishimura, M. Kato, N. Harada, N. Matsumoto, Two new cases of pure 1q terminal deletion presenting with brain malformations, Am. J. Med. Genet. Part A 146A (2008) 1241e1247. [3] A.D. Hill, B.S. Chang, R.S. Hill, L.A. Garraway, A. Bodell, W.R. Sellers, C.A. Walsh, A 2-Mb critical region implicated in the microcephaly associated with terminal 1q deletion syndrome, Am. J. Med. Genet. A 143A (15) (2007 Aug 1) 1692e1698. [4] C. Pawson, B.A. Eaton, G.W. Davis, Formin-dependent synaptic growth: evidence that dlar signals via Diaphanous to modulate synaptic actin and dynamic pioneer microtubules, J. Neurosci. 28 (44) (2008 Oct 29) 11111e11123. [5] B. Leader, P. Leder, Formin-2, a novel forming homology protein of the cappuccino subfamily, is highly expressed in the developing and adult central nervous system, Mech. Develop. 93 (2000) 221e231. [6] D.A. Ryley, H.-H. Wu, B. Leader, A. Zimon, R. Reindollar, M.R. Grey, Characterization and mutation analysis of the human FORMIN-2 (FMN2) gene in women with unexplained infertility, Fertil. Sterility 83 (5) (2005 May). [7] C. Charfi, V. Voisin, L.C. Levros Jr., E. Edouard, E. Rassart, Gene profiling of Graffi murine leukemia virus-induced lymphoid leukemias: identification of leukemia markers and Fmn2 as a potential oncogene, Blood 117 (6) (2011 Feb 10) 1899e1910 Epub 2010 Dec 6. [8] R.M. Eglen, Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function, Auton. Autacoid. Pharmacol. 26 (3) (2006 Jul) 219e233. [9] M. Yamada, T. Miyakawa, A. Duttaroy, A. Yamanaka, T. Morigu chi, R. Makita, M. Ogawa, C.J. Chou, B. Xia, J.N. Crawley, C.C. Felder, C.X. Deng, J. Wess, Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean, Nature 410 (6825) (2001 Mar 8) 207e212. [10] R.A. Hunt, W. Edris, P.K. Chanda, B. Nieuwenhuijsen, K.H. Young, Snapin interacts with the N-terminus of regulator of G protein signaling 7, Biochem. Biophys. Res. Commun. 303 (2) (2003 Apr 4) 594e599. [11] S.C. Nagamani, A. Erez, C. Bay, A. Pettigrew, S.R. Lalani, K. Herman, B.H. Graham, M.J. Nowaczyk, M. Proud, W.J. Craigen, B. Hopkins, B. Kozel, K. Plunkett, P. Hixson, P. Stankiewicz, A. Patel, S.W. Cheung, Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43-q44, Eur. J. Hum. Genet. (2011 Sep 21). doi:10.1038/ ejhg.2011.171. [12] I. Wonodi, O.C. Stine, K.V. Sathyasaikumar, R.C. Roberts, B.D. Mitchell, L.E. Hong, Y. Kajii, G.K. Thaker, R. Schwarcz, Downregulated kynurenine 3monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes, Arch. Gen. Psychiatry 68 (7) (2011 Jul) 665e674.
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short report
De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature M.D. Perrone a, *, M.S. Rocca b, I. Bruno c, F. Faletra b, V. Pecile b, P. Gasparini b a
Institute for Maternal and Child Health IRCCS “Burlo Garofalo” Trieste, Italy e University of Trieste, Italy IRCCS “Burlo Garofalo” Institute, Department of Medical Genetics, Trieste, Italy c IRCCS “Burlo Garofalo” Institute, Department of Pediatrics, Trieste, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 July 2011 Accepted 19 November 2011 Available online 2 December 2011
Patients with distal deletions of chromosome 1q have a recognizable syndrome that includes microcephaly, hypoplasia or agenesis of the corpus callosum, and psychomotor retardation. Although these symptoms have been attributed to deletions of 1q42e1q44, the minimal chromosomal region involved has not yet defined. In this report, we describe a 7 years old male with mental retardation, cryptorchid testes, short stature and alopecia carrying only an interstitial de novo deletion of 911 Kb in the 1q43 region (239,597,095e240,508,817) encompassing three genes CHRM3, RPS7P5 and FMN2. Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords: Deletion Chromosome 1 Mental retardation
1. Introduction Deletions of the long arm of chromosome 1 are relatively rare. The first published description of a patient carrying a 1q4 deletion was in 1976 [1]. There have since been over 30 cases reported in the medical literature worldwide. The deletion occurs in equal frequency in males and females. A 1q4 deletion is sometimes called “terminal 1q deletion” (the tip of the long arm of chromosome 1 is included in the deletion) or “1qter deletion” or, if itcan’t be seen down a microscope, “1qter microdeletion” [2]. Every person with a 1q4 deletion is unique and so each person will have different medical and developmental features. However, a number of common features have emerged: hypotonia in newborn babies, seizures, commonly starting in the first three years of life, learning difficulties, feeding difficulties, short stature, heart conditions often resolved without surgical intervention, microcephaly, structural anomalies of the brain (in particular corpus callosum). 2. Methods DNA was extracted from whole blood by the Bio Robot EZ1 Qiagen. Patient and his parents were screened using * Corresponding author. IRCCS Burlo Garofolo Via Dell’Istria 65/1 34137 Trieste, Italy. Tel.: þ39 040 3785538; fax: þ39 0403785540. E-mail addresses: [email protected] (M.D. Perrone), [email protected] (M.S. Rocca), [email protected] (I. Bruno), [email protected] (F. Faletra), [email protected] (V. Pecile), [email protected] (P. Gasparini). 1769-7212/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2011.11.004
HumanCytoSNP-12 BeadChip (Illumina Inc., San Diego, CA, USA). A total of 750 ng DNA was processed and the genotyping reaction steps were performed according to the manufacturer’s specifications (Infinium II; Illumina, San Diego, California, USA). The HumanCytoSNP-12 BeadChip contains nearly 300,000 genetic markers per sample that target all known cytogenetic abnormalities found in genes and disease pathways linked to mental retardation, autism, and other common chromosome anomalies. SNP copy number (log R ratio) and B-allele frequency were assessed using the software programs KaryoStudio v.1 (Illumina). The Human Genome Resources website at NCBI and the Archive EnsEMBL (biblio) have been used to study the CNV detected. 3. Clinical description The boy is the only child of a non consanguineous Italian mating. He was born at term with natural childbirth. At birth, weight was 3450 gr (50 centile, þ0,1SD) and length 34 cm (<<3 centile, <3SD), lactation was not possible for sucking difficult (hypotonia?). Motor development was delayed: he sat alone after 1 year and walked independently at 4 years. Now, the proband presents mental retardation, cryptorchid testes and short stature. Clinical examination showed alopecic patch in occipital area, clinodactyly of 5th finger, big thumb and toe, convergent strabismus, tendency to bite hands. Since the difficulty in chewing, he eats only blended food. Height (119 cm) is below the normal range (3 centile, 1,80SD), head circumference (55 cm) is above the 97 centile (þ2,3SD) and weight (21,5 kg) is on the 10 centile
118
M.D. Perrone et al. / European Journal of Medical Genetics 55 (2012) 117e119
Fig. 1. The figure shows some clinical features like strabismus and alopecia.
(1,41SD). A neurological examination revealed a development delay with autistic features. MRI, ECG and abdominal ultrasound were normal. No seizures were reported. A test for fragile X syndrome was negative. Because of the mental retardation and development delay a SNPs-array analysis was performed (Fig. 1 and 2). 4. Results The SNPs-Array analysis revealed a de novo interstitial deletion of 911722 bp in the 1q43 region (chr1:239,597,095e240,508,817, genome assembly Feb. 2009 (GRCh37/hg19)). This region contains only three genes, RPS7P5 a pseudogene that is unlikely to influence the phenotype, and two genes with a known function: the first one is the FMN2 gene, involved in the development of the central nervous system and the other one is the CHRM3 gene, encoding for a muscarinic cholinergic receptor.
5. Discussion Interstitial deletions of chromosome 1q are not rare, more than 30 patients have been described [3] since the first case in 1976. The 911 Kb deletion here described encompasses a small region with only 2 coding genes. FMN2, encoding for Formin-2 and CHRM3, for a cholinergic receptor muscarinic 3. FMN2 gene plays a role in cytoskeletal organization and/or establishment of cell polarity. Moreover, Formin-2 expression is important in the development of the central nervous system and the synaptic growth [4]. Strong expression is seen in all tissues of the adult central nervous system, including the pituitary gland and spinal cord. Fetal brain also showed heavy expression [5]. Until now, FMN2 has been associated with unexplained infertility [6] or leukaemia [7], but since his CNS expression is likely that FMN2 mutation causes developmental delay. Indeed, in a case of unexplained mental retardation a FMN2 duplication was found (http://decipher.sanger.ac.uk/). So, we
Fig. 2. Area of the deletion 1q43 in our patient.
M.D. Perrone et al. / European Journal of Medical Genetics 55 (2012) 117e119
suggest that psychomotor delay of our patient might be due to alteration of FMN2 gene. Indeed, CHRM3 encodes for a muscarinic cholinergic receptor. It influences many effects of acetylcholine in the central and peripheral nervous system. Briefly, the muscarinic cholinergic receptor 3 controls smooth muscle contraction and its stimulation causes secretion of glandular tissue [8]. Yamada et al. [9] showed that mice deficient in the M3 muscarinic receptor display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic mRNA levels of melanin-concentrating hormone, normally upregulated in fasted animals leading to an increase in food intake, are significantly reduced in M3r / mice. So, we might correlate the growth delay and the low food intake of the proband with the low appetite, caused by the CHRM3 deletion. There aren’t patients described with small aberrations (duplications or deletions) that comprise these genes. It’s possible to make an interesting comparison between our case and 7 patients with terminal chromosome 1q deletion [3]. 6 of these 7 patients present microcephaly and seizures, not present in our case. This finding might be explained because their deletion zone includes genes with an important role in the cerebral development and in the neuronal excitability not deleted in our proband. The first one is RGS7, involved in synaptic vesicle exocytosis [10].and may play an important role in the rapid regulation of neuronal excitability and the cellular responses to short-lived stimulations. The second one to consider is ZNF 238, responsible to generate abnormalities in corpus callosum [11]. Finally, KMO related to behavioral disorders [12]. Indeed, microcephaly is a recurrent feature in patients with 1q43 deletion; indeed our patient shows a relative macrocephaly. In conclusion, our case improves the knowledge about the minimal region of 1q43 deletion suggesting that the loss of two coding genes involved in the developing of central nervous system(FMN2 and CHRM3) can explain some particular features. Knowledge of the pattern of this deletion-phenotype will help clinicians to diagnose this abnormality in their patients and to counsel the parents accordingly.
119
References [1] C.B. Mankinen, J.W. Sears, V.R. Alvares, Terminal (1)(q43) long-arm deletion of chromosome no. 1 in a three-year-old female, Birth Defects Orig. Artic. Ser. 12 (5) (1976) 131e136. [2] Y. Hiraki, N. Okamoto, T. Ida, Y. Nakata, M. Kamada, Y. Kanemura, M. Yamasaki, H. Fujita, G. Nishimura, M. Kato, N. Harada, N. Matsumoto, Two new cases of pure 1q terminal deletion presenting with brain malformations, Am. J. Med. Genet. Part A 146A (2008) 1241e1247. [3] A.D. Hill, B.S. Chang, R.S. Hill, L.A. Garraway, A. Bodell, W.R. Sellers, C.A. Walsh, A 2-Mb critical region implicated in the microcephaly associated with terminal 1q deletion syndrome, Am. J. Med. Genet. A 143A (15) (2007 Aug 1) 1692e1698. [4] C. Pawson, B.A. Eaton, G.W. Davis, Formin-dependent synaptic growth: evidence that dlar signals via Diaphanous to modulate synaptic actin and dynamic pioneer microtubules, J. Neurosci. 28 (44) (2008 Oct 29) 11111e11123. [5] B. Leader, P. Leder, Formin-2, a novel forming homology protein of the cappuccino subfamily, is highly expressed in the developing and adult central nervous system, Mech. Develop. 93 (2000) 221e231. [6] D.A. Ryley, H.-H. Wu, B. Leader, A. Zimon, R. Reindollar, M.R. Grey, Characterization and mutation analysis of the human FORMIN-2 (FMN2) gene in women with unexplained infertility, Fertil. Sterility 83 (5) (2005 May). [7] C. Charfi, V. Voisin, L.C. Levros Jr., E. Edouard, E. Rassart, Gene profiling of Graffi murine leukemia virus-induced lymphoid leukemias: identification of leukemia markers and Fmn2 as a potential oncogene, Blood 117 (6) (2011 Feb 10) 1899e1910 Epub 2010 Dec 6. [8] R.M. Eglen, Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function, Auton. Autacoid. Pharmacol. 26 (3) (2006 Jul) 219e233. [9] M. Yamada, T. Miyakawa, A. Duttaroy, A. Yamanaka, T. Morigu chi, R. Makita, M. Ogawa, C.J. Chou, B. Xia, J.N. Crawley, C.C. Felder, C.X. Deng, J. Wess, Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean, Nature 410 (6825) (2001 Mar 8) 207e212. [10] R.A. Hunt, W. Edris, P.K. Chanda, B. Nieuwenhuijsen, K.H. Young, Snapin interacts with the N-terminus of regulator of G protein signaling 7, Biochem. Biophys. Res. Commun. 303 (2) (2003 Apr 4) 594e599. [11] S.C. Nagamani, A. Erez, C. Bay, A. Pettigrew, S.R. Lalani, K. Herman, B.H. Graham, M.J. Nowaczyk, M. Proud, W.J. Craigen, B. Hopkins, B. Kozel, K. Plunkett, P. Hixson, P. Stankiewicz, A. Patel, S.W. Cheung, Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43-q44, Eur. J. Hum. Genet. (2011 Sep 21). doi:10.1038/ ejhg.2011.171. [12] I. Wonodi, O.C. Stine, K.V. Sathyasaikumar, R.C. Roberts, B.D. Mitchell, L.E. Hong, Y. Kajii, G.K. Thaker, R. Schwarcz, Downregulated kynurenine 3monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes, Arch. Gen. Psychiatry 68 (7) (2011 Jul) 665e674.