- Email: [email protected]
De novo deletion of FMN2 in a girl with mild non-syndromic intellectual disability
European Journal of Medical Genetics 56 (2013) 686e688
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short clinical report
De novo deletion of FMN2 in a girl with mild non-syndromic intellectual disability Mohammed Almuqbil a, Fadi F. Hamdan b, Géraldine Mathonnet c, Bernard Rosenblatt a, Myriam Srour a, * a b c
Division of Pediatric Neurology, Montreal Children’s Hospital, McGill University Health Center, Canada Centre of Excellence in Neurosciences of Université de Montréal and Sainte-Justine Hospital Research Center, Canada Service de Génétique, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 March 2013 Accepted 14 October 2013 Available online 24 October 2013
We present the case of a child with mild non-syndromic intellectual disability in whom array genomic hybridization revealed a de novo heterozygous deletion involving only one gene, FMN2. FMN2 encodes FORMIN-2, a member of the formin homology family, which is primarily expressed in the developing and mature brain, and has an important role in cytoskeletal organization and actin nucleation. A heterozygous deletion of FMN2 along with 2 other genes has been recently reported in a boy with non-syndromic intellectual disability. This report provides further support for the important role of FMN2 in brain development and cognition. Ó 2013 Elsevier Masson SAS. All rights reserved.
Keywords: Chromosome 1q43 Intellectual disability FMN2 FORMIN-2
1. Introduction A growing body of work indicates that structural plasticity of dendritic spines underlies learning, memory and cognition [1,2]. The regulation of the actin cytoskeleton has a central role in axonal and spine morphogenesis, as well as in the remodeling of the postsynaptic spines during synaptic long-term plasticity [3]. We hereby report a heterozygous de novo deletion involving only the FMN2 gene in an individual with mild non-syndromic intellectual disability. FMN2 encodes FORMIN-2, a member of the formin family that is predominantly expressed in the nervous system and has an important role in actin nucleation [4]. This is the first report of an individual with a discrete heterozygous loss of FMN2, suggesting an important role of this gene in brain development and cognition.
2. Clinical description The patient is a female born to a non-consanguineous Italian couple. She has a healthy 5-year-old sister. Family history reveals that a paternal uncle and two paternal cousins had simple febrile
* Corresponding author. Montreal Children’s Hospital, McGill University, 2300 Rue Tupper, A-508, Montreal, Quebec, Canada H3H 1P3. Tel.: þ1 514 412 4466; fax: þ1 514 412 4373. E-mail address: [email protected] (M. Srour). 1769-7212/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmg.2013.10.003
seizures. Pregnancy was unremarkable. The proband was born at 39 weeks by Cesarean section for breech presentation. There were no complications and Apgar scores were normal. She developed simple febrile seizures at the age of 20 months, which resolved at the age of 6 years. She has never had any afebrile seizures. She had mild global developmental delay, with language being mainly affected. She sat at 6 months, walked at 15 months. Her first words were around the age of 2 years. She started combining two words at 3.5 years. At the current age of 8, she can recognize letters and is beginning to read simple words. She is unable to perform simple additions. She is sociable but plays with children younger than her. At the current age of 8 years, her head circumference is 50.5 cm (25th percentile for age), her height is 129.5 cm (75th percentile) and her weight is 30.1 kg (75th percentile). She is not dysmorphic and neurological examination is normal. Audiology testing, ophthalmology exam, brain MRI, karyotype and fragile X testing were normal. Initial EEG at age 20 months revealed a generalized epileptiform abnormality, but subsequent EEGs were normal. Neuropsychology evaluation for her cognitive ability using WISC-IV test at 7 years revealed that she fell within the lower end of the borderline range for her age (3rd percentile). She has difficulty with visual motor integration, and scored at the extremely low range (1st percentile) on the Visual Motor Integration test. She scored within the borderline range (4th percentile) on the Working Memory Index, upper end of the low average range on the Verbal Comprehension Index (8th percentile).
M. Almuqbil et al. / European Journal of Medical Genetics 56 (2013) 686e688
687
Fig. 1. Heterozygous deletion of FMN2. High density chromosome 1 microarray analysis shows one-copy 47.4 kb heterozygous deletion of involving the distal 3 exons of FMN2 (Chr1: 238,662,229e238,709,664, UCSC March 2006 hg18 coordinates, region between red vertical dashed lines). Probes are ordered on the x-axis and arranged with the most proximal 1q43 probes on the left and the most distal 1q43 probes on the right. Values on the y-axis represent log2 ratios of patient:control signal intensities. Genes in the region are represented by gray boxes, and vertical black tick marks below the gray boxes show the location of exons.
3. Methods Oligonucleotide-based microarray comparative genomic hybridization (aCGH) analysis was performed using a whole-genome Nimblegen CGX-12 (Roche) microarray containing 135,000 oligonucleotide probes according to manufacturer’s protocol. Parental chromosomes were also studied using same microarray CGH. A chromosome 1-specific microarray CGH containing 385,000 oligonucleotides (Nimblegen 2006-09-22_HG18_CHR1_FT) was used to confirm the deletion in the proband. 4. Genomic rearrangement Whole-genome microarray CGH revealed a 7 oligonucleotides deletion on 1q43 (Chr1: 238,663,693e238,709,645, UCSC March 2006 hg 18 build) measuring approximately 46 kb and involving only the distal 3 exons of one gene, FMN2. Parental microarray was done and this deletion was determined to be de novo. The deletion in the proband was confirmed using a high density chromosome 1 microarray (Chr1: 238,662,229e238,709,664, UCSC March 2006 hg 18 build) showing a 47.4 kb deletion (see Fig. 1). No other significant copy number variant was found. 5. Discussion We report for the first time a heterozygous de-novo deletion of part of FMN2 in an individual with mild non-syndromic intellectual disability. FMN2 has 18 exons and encodes FORMIN-2, a 1722 amino-acid member of the formin homology family that has an important role in cytoskeletal organization and the establishment of cell polarity [5]. FORMIN-2 is expressed almost exclusively in the developing and mature central nervous system [5,6]. Surprisingly, mice that lack Fmn2 are phenotypically normal and have neither gross nor histological differences in brains when compared to normal mice [7]. However, behavioral and cognitive studies have not been performed. The Fmn2/ female mice have decreased fertility and there is abnormal positioning of the metaphase spindle and formation of the first polar body [7]. The heterozygous deletion found in our patient includes the distal 3 exons of FMN2 which encode two important functional domains: the distal end of the Formin Homology 2 (FH2) domain
and the carboxy terminal tail. The FH2 domain is highly conserved and is necessary and sufficient for nucleation of actin filaments [8]. It remains bound to the barbed end of the actin filament as additional subunits are added, protecting growing ends from the activity of capping proteins (for review e see Ref. [9]). In vitro studies have shown that the carboxy-tail of Fmn2 is essential for the protein’s activity and that deletion of the tail alone results in decreased actin filament nucleation rates [4]. Deletions <5 Mb encompassing FMN2 are extremely rare. The DECIPHER database reports only 1 deletion measuring <5 Mb that involves FMN2: a 410 Mb deletion (Chr1: 239,990,618e 240,400,485) in an individual in whom neither phenotype nor parental genotype is available. A recent study reports a 911 Kb deletion (Chr1: 239,587,095e240,508,817) that encompasses FMN2 as well as 2 other genes, CHRM3 and RPS7P5 [10], in a child with intellectual delay, feeding difficulties and short stature. The authors suggest that the feeding difficulties and short stature may be a result of the deletion of CHRM3, a muscarinic receptor, because mice deficient in the CHRM3 display decreased food intake, reduced body weight and low insulin levels [11]. The authors speculate that the deletion of FMN2 is likely responsible for the neurology phenotype in their patient given the known function of FMN2. Interestingly, the deletion in their proband affects the proximal portions of FMN2, and spares the distal portions that are involved in our case, suggesting that disruption of either distal or proximal domains may lead to a neurologic phenotype. In summary, we hereby report an individual with nonsyndromic intellectual disability with a small heterozygous denovo deletion that only involves FMN2. Our report provides further support for the important role of FMN2 in brain development and suggests its implication in cognition and synaptic plasticity. Competing interests All authors declare no competing interests pertaining to this paper. Acknowledgments We would like to thank the patient and her family for their participation. MS holds a CIHR clinicianescientist training award.
688
M. Almuqbil et al. / European Journal of Medical Genetics 56 (2013) 686e688
References [1] F.F. Hamdan, J. Gauthier, Y. Araki, D.T. Lin, Y. Yoshizawa, K. Higashi, A.R. Park, D. Spiegelman, S. Dobrzeniecka, A. Piton, H. Tomitori, H. Daoud, C. Massicotte, E. Henrion, O. Diallo, M. Shekarabi, C. Marineau, M. Shevell, B. Maranda, G. Mitchell, A. Nadeau, G. D’Anjou, M. Vanasse, M. Srour, R.G. Lafreniere, P. Drapeau, J.C. Lacaille, E. Kim, J.R. Lee, K. Igarashi, R.L. Huganir, G.A. Rouleau, J.L. Michaud, Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability, Am. J. Hum. Genet. 88 (2011) 306e316. [2] H. van Bokhoven, Genetic and epigenetic networks in intellectual disabilities, Annu. Rev. Genet. 45 (2011) 81e104. [3] L. Luo, Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity, Annu. Rev. Cell Dev. Biol. 18 (2002) 601e635. [4] C.L. Vizcarra, B. Kreutz, A.A. Rodal, A.V. Toms, J. Lu, W. Zheng, M.E. Quinlan, M.J. Eck, Structure and function of the interacting domains of Spire and Fmnfamily formins, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 11884e11889. [5] B. Leader, P. Leder, Formin-2, a novel formin homology protein of the cappuccino subfamily, is highly expressed in the developing and adult central nervous system, Mech. Dev. 93 (2000) 221e231.
[6] M. Katoh, M. Katoh, Characterization of FMN2 gene at human chromosome 1q43, Int. J. Mol. Med. 14 (2004) 469e474. [7] B. Leader, H. Lim, M.J. Carabatsos, A. Harrington, J. Ecsedy, D. Pellman, R. Maas, P. Leder, Formin-2, polyploidy, hypofertility and positioning of the meiotic spindle in mouse oocytes, Nat. Cell Biol. 4 (2002) 921e 928. [8] D. Pruyne, M. Evangelista, C. Yang, E. Bi, S. Zigmond, A. Bretscher, C. Boone, Role of formins in actin assembly: nucleation and barbed-end association, Science 297 (2002) 612e615. [9] S.H. Zigmond, Formin-induced nucleation of actin filaments, Curr. Opin. Cell Biol. 16 (2004) 99e105. [10] M.D. Perrone, M.S. Rocca, I. Bruno, F. Faletra, V. Pecile, P. Gasparini, De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature, Eur. J. Med. Genet. 55 (2012) 117e 119. [11] M. Yamada, T. Miyakawa, A. Duttaroy, A. Yamanaka, T. Moriguchi, 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 (2001) 207e212.
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short clinical report
De novo deletion of FMN2 in a girl with mild non-syndromic intellectual disability Mohammed Almuqbil a, Fadi F. Hamdan b, Géraldine Mathonnet c, Bernard Rosenblatt a, Myriam Srour a, * a b c
Division of Pediatric Neurology, Montreal Children’s Hospital, McGill University Health Center, Canada Centre of Excellence in Neurosciences of Université de Montréal and Sainte-Justine Hospital Research Center, Canada Service de Génétique, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 March 2013 Accepted 14 October 2013 Available online 24 October 2013
We present the case of a child with mild non-syndromic intellectual disability in whom array genomic hybridization revealed a de novo heterozygous deletion involving only one gene, FMN2. FMN2 encodes FORMIN-2, a member of the formin homology family, which is primarily expressed in the developing and mature brain, and has an important role in cytoskeletal organization and actin nucleation. A heterozygous deletion of FMN2 along with 2 other genes has been recently reported in a boy with non-syndromic intellectual disability. This report provides further support for the important role of FMN2 in brain development and cognition. Ó 2013 Elsevier Masson SAS. All rights reserved.
Keywords: Chromosome 1q43 Intellectual disability FMN2 FORMIN-2
1. Introduction A growing body of work indicates that structural plasticity of dendritic spines underlies learning, memory and cognition [1,2]. The regulation of the actin cytoskeleton has a central role in axonal and spine morphogenesis, as well as in the remodeling of the postsynaptic spines during synaptic long-term plasticity [3]. We hereby report a heterozygous de novo deletion involving only the FMN2 gene in an individual with mild non-syndromic intellectual disability. FMN2 encodes FORMIN-2, a member of the formin family that is predominantly expressed in the nervous system and has an important role in actin nucleation [4]. This is the first report of an individual with a discrete heterozygous loss of FMN2, suggesting an important role of this gene in brain development and cognition.
2. Clinical description The patient is a female born to a non-consanguineous Italian couple. She has a healthy 5-year-old sister. Family history reveals that a paternal uncle and two paternal cousins had simple febrile
* Corresponding author. Montreal Children’s Hospital, McGill University, 2300 Rue Tupper, A-508, Montreal, Quebec, Canada H3H 1P3. Tel.: þ1 514 412 4466; fax: þ1 514 412 4373. E-mail address: [email protected] (M. Srour). 1769-7212/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmg.2013.10.003
seizures. Pregnancy was unremarkable. The proband was born at 39 weeks by Cesarean section for breech presentation. There were no complications and Apgar scores were normal. She developed simple febrile seizures at the age of 20 months, which resolved at the age of 6 years. She has never had any afebrile seizures. She had mild global developmental delay, with language being mainly affected. She sat at 6 months, walked at 15 months. Her first words were around the age of 2 years. She started combining two words at 3.5 years. At the current age of 8, she can recognize letters and is beginning to read simple words. She is unable to perform simple additions. She is sociable but plays with children younger than her. At the current age of 8 years, her head circumference is 50.5 cm (25th percentile for age), her height is 129.5 cm (75th percentile) and her weight is 30.1 kg (75th percentile). She is not dysmorphic and neurological examination is normal. Audiology testing, ophthalmology exam, brain MRI, karyotype and fragile X testing were normal. Initial EEG at age 20 months revealed a generalized epileptiform abnormality, but subsequent EEGs were normal. Neuropsychology evaluation for her cognitive ability using WISC-IV test at 7 years revealed that she fell within the lower end of the borderline range for her age (3rd percentile). She has difficulty with visual motor integration, and scored at the extremely low range (1st percentile) on the Visual Motor Integration test. She scored within the borderline range (4th percentile) on the Working Memory Index, upper end of the low average range on the Verbal Comprehension Index (8th percentile).
M. Almuqbil et al. / European Journal of Medical Genetics 56 (2013) 686e688
687
Fig. 1. Heterozygous deletion of FMN2. High density chromosome 1 microarray analysis shows one-copy 47.4 kb heterozygous deletion of involving the distal 3 exons of FMN2 (Chr1: 238,662,229e238,709,664, UCSC March 2006 hg18 coordinates, region between red vertical dashed lines). Probes are ordered on the x-axis and arranged with the most proximal 1q43 probes on the left and the most distal 1q43 probes on the right. Values on the y-axis represent log2 ratios of patient:control signal intensities. Genes in the region are represented by gray boxes, and vertical black tick marks below the gray boxes show the location of exons.
3. Methods Oligonucleotide-based microarray comparative genomic hybridization (aCGH) analysis was performed using a whole-genome Nimblegen CGX-12 (Roche) microarray containing 135,000 oligonucleotide probes according to manufacturer’s protocol. Parental chromosomes were also studied using same microarray CGH. A chromosome 1-specific microarray CGH containing 385,000 oligonucleotides (Nimblegen 2006-09-22_HG18_CHR1_FT) was used to confirm the deletion in the proband. 4. Genomic rearrangement Whole-genome microarray CGH revealed a 7 oligonucleotides deletion on 1q43 (Chr1: 238,663,693e238,709,645, UCSC March 2006 hg 18 build) measuring approximately 46 kb and involving only the distal 3 exons of one gene, FMN2. Parental microarray was done and this deletion was determined to be de novo. The deletion in the proband was confirmed using a high density chromosome 1 microarray (Chr1: 238,662,229e238,709,664, UCSC March 2006 hg 18 build) showing a 47.4 kb deletion (see Fig. 1). No other significant copy number variant was found. 5. Discussion We report for the first time a heterozygous de-novo deletion of part of FMN2 in an individual with mild non-syndromic intellectual disability. FMN2 has 18 exons and encodes FORMIN-2, a 1722 amino-acid member of the formin homology family that has an important role in cytoskeletal organization and the establishment of cell polarity [5]. FORMIN-2 is expressed almost exclusively in the developing and mature central nervous system [5,6]. Surprisingly, mice that lack Fmn2 are phenotypically normal and have neither gross nor histological differences in brains when compared to normal mice [7]. However, behavioral and cognitive studies have not been performed. The Fmn2/ female mice have decreased fertility and there is abnormal positioning of the metaphase spindle and formation of the first polar body [7]. The heterozygous deletion found in our patient includes the distal 3 exons of FMN2 which encode two important functional domains: the distal end of the Formin Homology 2 (FH2) domain
and the carboxy terminal tail. The FH2 domain is highly conserved and is necessary and sufficient for nucleation of actin filaments [8]. It remains bound to the barbed end of the actin filament as additional subunits are added, protecting growing ends from the activity of capping proteins (for review e see Ref. [9]). In vitro studies have shown that the carboxy-tail of Fmn2 is essential for the protein’s activity and that deletion of the tail alone results in decreased actin filament nucleation rates [4]. Deletions <5 Mb encompassing FMN2 are extremely rare. The DECIPHER database reports only 1 deletion measuring <5 Mb that involves FMN2: a 410 Mb deletion (Chr1: 239,990,618e 240,400,485) in an individual in whom neither phenotype nor parental genotype is available. A recent study reports a 911 Kb deletion (Chr1: 239,587,095e240,508,817) that encompasses FMN2 as well as 2 other genes, CHRM3 and RPS7P5 [10], in a child with intellectual delay, feeding difficulties and short stature. The authors suggest that the feeding difficulties and short stature may be a result of the deletion of CHRM3, a muscarinic receptor, because mice deficient in the CHRM3 display decreased food intake, reduced body weight and low insulin levels [11]. The authors speculate that the deletion of FMN2 is likely responsible for the neurology phenotype in their patient given the known function of FMN2. Interestingly, the deletion in their proband affects the proximal portions of FMN2, and spares the distal portions that are involved in our case, suggesting that disruption of either distal or proximal domains may lead to a neurologic phenotype. In summary, we hereby report an individual with nonsyndromic intellectual disability with a small heterozygous denovo deletion that only involves FMN2. Our report provides further support for the important role of FMN2 in brain development and suggests its implication in cognition and synaptic plasticity. Competing interests All authors declare no competing interests pertaining to this paper. Acknowledgments We would like to thank the patient and her family for their participation. MS holds a CIHR clinicianescientist training award.
688
M. Almuqbil et al. / European Journal of Medical Genetics 56 (2013) 686e688
References [1] F.F. Hamdan, J. Gauthier, Y. Araki, D.T. Lin, Y. Yoshizawa, K. Higashi, A.R. Park, D. Spiegelman, S. Dobrzeniecka, A. Piton, H. Tomitori, H. Daoud, C. Massicotte, E. Henrion, O. Diallo, M. Shekarabi, C. Marineau, M. Shevell, B. Maranda, G. Mitchell, A. Nadeau, G. D’Anjou, M. Vanasse, M. Srour, R.G. Lafreniere, P. Drapeau, J.C. Lacaille, E. Kim, J.R. Lee, K. Igarashi, R.L. Huganir, G.A. Rouleau, J.L. Michaud, Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability, Am. J. Hum. Genet. 88 (2011) 306e316. [2] H. van Bokhoven, Genetic and epigenetic networks in intellectual disabilities, Annu. Rev. Genet. 45 (2011) 81e104. [3] L. Luo, Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity, Annu. Rev. Cell Dev. Biol. 18 (2002) 601e635. [4] C.L. Vizcarra, B. Kreutz, A.A. Rodal, A.V. Toms, J. Lu, W. Zheng, M.E. Quinlan, M.J. Eck, Structure and function of the interacting domains of Spire and Fmnfamily formins, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 11884e11889. [5] B. Leader, P. Leder, Formin-2, a novel formin homology protein of the cappuccino subfamily, is highly expressed in the developing and adult central nervous system, Mech. Dev. 93 (2000) 221e231.
[6] M. Katoh, M. Katoh, Characterization of FMN2 gene at human chromosome 1q43, Int. J. Mol. Med. 14 (2004) 469e474. [7] B. Leader, H. Lim, M.J. Carabatsos, A. Harrington, J. Ecsedy, D. Pellman, R. Maas, P. Leder, Formin-2, polyploidy, hypofertility and positioning of the meiotic spindle in mouse oocytes, Nat. Cell Biol. 4 (2002) 921e 928. [8] D. Pruyne, M. Evangelista, C. Yang, E. Bi, S. Zigmond, A. Bretscher, C. Boone, Role of formins in actin assembly: nucleation and barbed-end association, Science 297 (2002) 612e615. [9] S.H. Zigmond, Formin-induced nucleation of actin filaments, Curr. Opin. Cell Biol. 16 (2004) 99e105. [10] M.D. Perrone, M.S. Rocca, I. Bruno, F. Faletra, V. Pecile, P. Gasparini, De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature, Eur. J. Med. Genet. 55 (2012) 117e 119. [11] M. Yamada, T. Miyakawa, A. Duttaroy, A. Yamanaka, T. Moriguchi, 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 (2001) 207e212.