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Genomic Aberrations in Neurodevelopmental Disorders: Comparison
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Please note this is a comparison between Version 2 by Vivi Li and Version 1 by Toshiyuki Yamamoto.

Genomic studies are increasingly revealing that neurodevelopmental disorders are caused by underlying genomic alterations. Chromosomal microarray testing has been used to reliably detect minute changes in genomic copy numbers. The genes located in the aberrated regions identified in patients with neurodevelopmental disorders may be associated with the phenotypic features. In such cases, haploinsufficiency is considered to be the mechanism, when the deletion of a gene is related to neurodevelopmental delay. The loss-of-function mutation in such genes may be evaluated using next-generation sequencing. On the other hand, the patients with increased copy numbers of the genes may exhibit different clinical symptoms compared to those with loss-of-function mutation in the genes. In such cases, the additional copies of the genes are considered to have a dominant negative effect, inducing cell stress. In other cases, not the copy number changes, but mutations of the genes are responsible for causing the clinical symptoms. 

  • nonallelic homologous recombination (NAHR)
  • contiguous gene deletion syndrome
  • classical microdeletion syndrome
  • genome disease
  • diagnostic yield
  • exome sequencing

1. Introduction

Neurodevelopmental disorders are defined as a concept that includes a wide range of symptoms such as intellectual disability, developmental retardation, communication disorders, autism spectrum disorders, attention deficit hyperactivity disorder, learning disabilities, and motor disorders such as tics [1,2][1][2]. Cerebral palsy, epilepsy, and psychiatric disorders are also understood as peripheral diseases with the same origin. In other words, it is easy to think of the pathophysiology of many of these symptoms if wresearchers consider that some disorder of the synaptic function of the central nervous system causes various combinations of symptoms as clinical symptoms [3].
Since the completion of the Human Genome Project in 2003 (Gibbs), comprehensive genome analysis technology using the primary sequence information of the human genome has advanced, and comprehensive genome copy number analysis using microarrays and comprehensive genome analysis using next-generation sequencers have become possible. Genomic medicine using these analysis techniques has revealed the causes of neurodevelopmental disorders in children one after another [4,5][4][5]. Although the diagnostic yields in the chromosome G banding method was approximately 4%, which was the only comprehensive analysis method before the Human Genome Project, now, the diagnostic rate has increased to about 30–40% [6]. Because the genomic research of neurodevelopmental disorders is still ongoing, the involvement of the genomic alteration in neurodevelopmental disorders is not yet fully understood.

2. Different Symptoms Are Associated with Deletion and Duplication of Certain Genes

Several genes are known to show different clinical symptoms depending on their deletion or duplication (Table 21). For instance, deletion of PMP22 (located on 17p12) causes hereditary neuropathy with susceptibility to pressure palsies (MIM #162500) [12][7], while its duplication causes Charcot-Marie-Tooth disease (MIM #118220) [13][8]. Similarly, deletion of PLP1 (located on Xq22.2) causes spastic paraplegia associated with peripheral neuropathy; however, its duplication causes a congenital white matter abnormality, known as Pelizaeus-Merzbacher disease (MIM #312080) [14,15][9][10]. These differences can be attributed to different mechanisms associated with gene deletion or duplication events [16][11]. Additionally, it is believed that duplication events result in the increased expression of genes, inducing cell stress.
Table 21.
 The genes with different phenotypes in deletions and duplications.
  Deletion Duplication
PMP22 hereditary neuropathy with susceptibility to pressure palsies (HNPP) Charcot-Marie-Tooth disease
PLP1 spastic paraplegia Pelizaeus-Merzbacher disease
MECP2 Rett syndrome in female MECP2 duplication syndrome in male
Furthermore, mutation of MECP2 gene (located on Xq28) causes Rett syndrome (MIM #312750), a neurodevelopmental disorder specific to females; however, its duplication (MIM #300815) is asymptomatic in women, while causing severe intellectual disability, epilepsy, and susceptibility to infection in males [17][12]. The exact mechanism underlying MECP2 deletion or duplication is unclear to date [18][13].

3. Significance of Microarray in Detecting Chromosomal Aberrations

Since 2010, chromosomal microarray testing has been commonly used for detecting chromosomal aberrations, and it has helped in the diagnosis of several previously unknown chromosomal microdeletion syndromes [19,20][14][15]. Among these, a few are novel genomic diseases that are caused by LCR-mediated NAHR; one such disease is 16p11.2 microdeletion syndrome (MIM #611913) [21][16]. The 16p11.2 microdeletion is relatively frequent and is observed in approximately 1/100 patients with autism. Furthermore, deletion or duplication of 16p11.2 causes similar developmental disorders, and their clinical diagnosis is difficult, contrary to the classical microdeletion syndromes, as the patients have very few differentiating symptoms. Hence, comprehensive copy number variation (CNV) analysis by microarray is the only diagnostic method for 16p11.2 microdeletion syndrome.
The chromosomal microdeletions caused by LCR-mediated NAHR are limited, and various chromosomal aberrations detected by microarray are caused by random breakpoints (Table 32). However, even if the breakpoints are not common, the chromosomal microdeletions that can be clinically classified as the same entities due to the common clinical symptoms include the main gene(s) in the deleted region (Figure 21). Thus, the clinical symptoms can be diagnosed because of the involvement of the main gene(s) in the deleted regions.
Cells 10 02317 g002 550
Figure 21. Schematic representation of the patterns of deletions. (A) Deletions (black rectangles) caused by nonallelic homologous recombination triggered by surrounding LCRs show the same breakpoints in patients. (B) Deletions (black rectangles) with random breakpoints, however, include specific gene(s).
Table 32.
 Chromosomal regions and phenotypes.
  Regions Responsible Gene(s) Phenotypes
Microdeletions/duplications derived from NAHR    
  1q21.1 deletion/duplication   Developmental delay, distinctive features, congenital anomalies
  3q29 deletion DLG1, PAK2 Developmental delay, psychiatric symptoms
  15q13.3 deletion CHRNA7 Intellectual disability, epilepsy
  16p11.2 deletion/duplication   Developmental disorder
  17q12 deletion/duplication HNF1B Maturity onset diabetes of the young (MODY)
  17q21.31 deletion/duplication CRHR1, MAPT Developmental delay, muscular hypotonia, distinctive features
Microdeletions/duplications derived from random breakpoints    
  1q32 deletion IRF6 Van der Woude syndrome
  1q41q42 deletion DISP1 Developmental delay, epilepsy, distinctive features
  2p15-p16.1 deletion   Autism spectrum disorder
  2q23.1 deletion MBD5 Severe developmental delay, epilepsy, microcephaly
  2q33 deletion/duplication SATB2 Intellectual disability
  3p21.31 deletion BSN Developmental delay, white matter abnormality, hyperCKemia
  3q13.31 deletion ZBTB20 Language delay
  5q14 deletion MEF2C Severe developmental delay, epilepsy, brain abnormalities
  5q31.3deletion PURA, NRG2 Severe developmental delay, epilepsy
  8q24 deletion EXT1, TRPS1 Langer-Giedion syndrome
  9q22.3 deletion PTCH1 Gorlin syndrome
  10q22 deletion KAT6B Ohdo syndrome
  10q23 deletion PTEN Juvenile polyposis
  11p13 deletion WT1, PAX6 WAGR syndrome
  11p11.2 deletion EXT2, ALX4 Potocki-Shaffer syndrome
  12q24.21 deletion MED13L Intellectual disability
  13q32 deletion ZIC2 Holoprosencephaly
  15q22.2 deletion NRG2, RORA Developmental delay, epilepsy
  16q24.3 deletion ANKRD11, ZNF778 Autism spectrum disorder
  17p13.1 deletion DLG4, GABARAP Intellectual disability, epilepsy
  18q12.3 deletion SETBP1 Language delay
  18q21.2 deletion TCF4 Pitt-Hopkins syndrome
  19p13.2 deletion NFIX Malan syndrome
  Xp22.3 deletion KAL1 Kallmann syndrome
  Xp21-22 deletion CDKL5, ARX Epileptic encephalopathy
  Xp11.4 deletion CASK Developmental delay, microcephaly
  Xp11.22 deletion HUWE1 Developmental delay
  Xq11.1 deletion ARHGEF9 Developmental delay, epilepsy
  Xq28 duplication MECP2 Developmental delay, epilepsy

4. Genes Identified Based on Their Genomic Copy Number Changes

In 2011, wresearchers identified a small deletion in Xq11.1, in a patient with epileptic encephalopathy [22][17]. The deleted region contained the ARHGEF9 gene. Additionally, wresearchers identified a nonsense mutation in ARHGEF9 in a different patient with epileptic encephalopathy. Based on these findings, ARHGEF9 has been registered as the causative gene for developmental and epileptic encephalopathy 8 (MIM #300607) [23][18].
Further, in 2011, wresearchers reported two cases of 5q31 microdeletion for the first time [24][19]. Both patients exhibited common clinical symptoms with infantile epileptic encephalopathy and shared severe psychomotor development. Following ouresearchers' study, two other studies reporting overlapping chromosomal microdeletions narrowed down the candidate gene responsible for the syndrome to be PURA [25,26][20][21]. Finally, next-generation sequencing (NGS) of patients with severe psychomotor development and infantile epileptic encephalopathy revealed a large number of de novo mutations in PURA, confirming the association of PURA with 5q31 microdeletion syndrome [27][22]. Hence, currently, 5q31 microdeletion syndrome is known as a PURA-related neurodevelopmental disorder.
In another study, wresearchers found a 15q14 microdeletion in a patient with mild neurodevelopmental disorder with ventricular septal defect and submucosal cleft palate [28][23]. Further, the deleted region contained MEIS2, which has since been identified as the causative gene for neurodevelopmental disorders associated with cleft palate and congenital heart disease [29][24].
Hence, as discussed above, when the phenotype caused by chromosomal deletion and gene mutation is the same, it is considered to be caused by haploinsufficiency and is relatively easy to understand.

5. Genes Whose Phenotypes Are Not Affected by Genomic Copy Number Changes

ZBTB20, located at 3q13.31, has been identified as the causative gene for Primrose syndrome (MIM #259050), which is associated with severe neurodevelopmental disorders [30][25]. Previously, wresearchers found that the symptoms associated with neurodevelopmental disorders were very mild and inconsistent in the cases with 3q13 deletion compared to those observed in Primrose syndrome [31][26]. Therefore, Primrose syndrome is unlikely to be caused by haploinsufficiency of ZBTB20 and is thought to be the result of the dominant negative effect of ZBTB20 mutations. SATB2 is located at 2q33.1 and is known as the causative gene for Glass syndrome (MIM #612313), which causes characteristic symptoms, such as intellectual disability and dentition malformation. Patients with SATB2 mutations and deletions show similar symptoms [32,33][27][28]. Furthermore, HECW2 is located on the 3-Mb centromeric side of SATB2 at 2q32.3-q33.1 and has recently been identified as a causative gene for neurodevelopmental disorders with hypotonia, seizures, and absent language (NDHSAL; MIM #617268) [34,35][29][30]. However, microdeletion of 2q32.3-q33.1 is not known to cause severe developmental disorders. Hence, the neurodevelopmental disorders due to HECW2 mutations are considered to be because of the dominant negative effect [36][31]. Thus, the pathomechanism of neurodevelopmental disorders can be revealed by understanding whether the gene mutation is due to haploinsufficiency or the dominant negative effect. Therefore, it is important to compare the phenotypes of patients due to gene deletions and the gene mutations associated with the dominant negative effects.

References

  1. Savatt, J.M.; Myers, S.M. Genetic Testing in Neurodevelopmental Disorders. Front. Pediatr. 2021, 9, 526779.
  2. Blesson, A.; Cohen, J.S. Genetic Counseling in Neurodevelopmental Disorders. Cold Spring Harb. Perspect. Med. 2020, 10, a036533.
  3. Henstridge, C.M.; Pickett, E.; Spires-Jones, T.L. Synaptic pathology: A shared mechanism in neurological disease. Ageing Res. Rev. 2016, 28, 72–84.
  4. Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 2017, 542, 433–438.
  5. Moyses-Oliveira, M.; Yadav, R.; Erdin, S.; Talkowski, M.E. New gene discoveries highlight functional convergence in autism and related neurodevelopmental disorders. Curr. Opin. Genet. Dev. 2020, 65, 195–206.
  6. Yamamoto, T.; Imaizumi, T.; Yamamoto-Shimojima, K.; Lu, Y.; Yanagishita, T.; Shimada, S.; Chong, P.F.; Kira, R.; Ueda, R.; Ishiyama, A.; et al. Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders. Brain Dev. 2019, 41, 776–782.
  7. Pantera, H.; Shy, M.E.; Svaren, J. Regulating PMP22 expression as a dosage sensitive neuropathy gene. Brain Res. 2020, 1726, 146491.
  8. Marinko, J.T.; Carter, B.D.; Sanders, C.R. Direct relationship between increased expression and mistrafficking of the Charcot-Marie-Tooth-associated protein PMP22. J. Biol. Chem. 2020, 295, 11963–11970.
  9. Inoue, K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 2005, 6, 1–16.
  10. Inoue, K. Pelizaeus-Merzbacher Disease: Molecular and Cellular Pathologies and Associated Phenotypes. Adv. Exp. Med. Biol. 2019, 1190, 201–216.
  11. Yamamoto, T.; Shimojima, K. Pelizaeus-Merzbacher disease as a chromosomal disorder. Congenit Anom. 2013, 53, 3–8.
  12. Yamamoto, T.; Shimojima, K.; Shimada, S.; Yokochi, K.; Yoshitomi, S.; Yanagihara, K.; Imai, K.; Okamoto, N. Clinical impacts of genomic copy number gains at Xq28. Hum. Genome Var. 2014, 1, 14001.
  13. Vermudez, S.A.D.; Gogliotti, R.G.; Arthur, B.; Buch, A.; Morales, C.; Moxley, Y.; Rajpal, H.; Conn, P.J.; Niswender, C.M. Profiling beneficial and potential adverse effects of MeCP2 overexpression in a hypomorphic Rett syndrome mouse model. Genes Brain Behav. 2021, e12752.
  14. Battaglia, A.; Doccini, V.; Bernardini, L.; Novelli, A.; Loddo, S.; Capalbo, A.; Filippi, T.; Carey, J.C. Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features. Eur. J. Paediatr. Neurol. 2013, 17, 589–599.
  15. Miller, D.T.; Adam, M.P.; Aradhya, S.; Biesecker, L.G.; Brothman, A.R.; Carter, N.P.; Church, D.M.; Crolla, J.A.; Eichler, E.E.; Epstein, C.J.; et al. Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am. J. Hum. Genet. 2010, 86, 749–764.
  16. Kumar, R.A.; KaraMohamed, S.; Sudi, J.; Conrad, D.F.; Brune, C.; Badner, J.A.; Gilliam, T.C.; Nowak, N.J.; Cook, E.H., Jr.; Dobyns, W.B.; et al. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 2008, 17, 628–638.
  17. Shimojima, K.; Sugawara, M.; Shichiji, M.; Mukaida, S.; Takayama, R.; Imai, K.; Yamamoto, T. Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy. J. Hum. Genet. 2011, 56, 561–565.
  18. Alber, M.; Kalscheuer, V.M.; Marco, E.; Sherr, E.; Lesca, G.; Till, M.; Gradek, G.; Wiesener, A.; Korenke, C.; Mercier, S.; et al. ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation. Neurol. Genet. 2017, 3, e148.
  19. Shimojima, K.; Isidor, B.; Le Caignec, C.; Kondo, A.; Sakata, S.; Ohno, K.; Yamamoto, T. A new microdeletion syndrome of 5q31.3 characterized by severe developmental delays, distinctive facial features, and delayed myelination. Am. J. Med. Genet. A 2011, 155, 732–736.
  20. Hosoki, K.; Ohta, T.; Natsume, J.; Imai, S.; Okumura, A.; Matsui, T.; Harada, N.; Bacino, C.A.; Scaglia, F.; Jones, J.Y.; et al. Clinical phenotype and candidate genes for the 5q31.3 microdeletion syndrome. Am. J. Med. Genet. A 2012, 158a, 1891–1896.
  21. Brown, N.; Burgess, T.; Forbes, R.; McGillivray, G.; Kornberg, A.; Mandelstam, S.; Stark, Z. 5q31.3 Microdeletion syndrome: Clinical and molecular characterization of two further cases. Am. J. Med. Genet. A 2013, 161a, 2604–2608.
  22. Lalani, S.R.; Zhang, J.; Schaaf, C.P.; Brown, C.W.; Magoulas, P.; Tsai, A.C.; El-Gharbawy, A.; Wierenga, K.J.; Bartholomew, D.; Fong, C.T.; et al. Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. Am. J. Hum. Genet. 2014, 95, 579–583.
  23. Shimojima, K.; Ondo, Y.; Okamoto, N.; Yamamoto, T. A 15q14 microdeletion involving MEIS2 identified in a patient with autism spectrum disorder. Hum. Genome Var. 2017, 4, 17029.
  24. Fujita, A.; Isidor, B.; Piloquet, H.; Corre, P.; Okamoto, N.; Nakashima, M.; Tsurusaki, Y.; Saitsu, H.; Miyake, N.; Matsumoto, N. De novo MEIS2 mutation causes syndromic developmental delay with persistent gastro-esophageal reflux. J. Hum. Genet. 2016, 61, 835–838.
  25. Yamamoto-Shimojima, K.; Imaizumi, T.; Akagawa, H.; Kanno, H.; Yamamoto, T. Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation. Am. J. Med. Genet. A 2020, 182, 521–526.
  26. Shimojima, K.; Saito, K.; Yamamoto, T. A de novo 1.9-Mb interstitial deletion of 3q13.2q13.31 in a girl with dysmorphic features, muscle hypotonia, and developmental delay. Am. J. Med. Genet. A 2009, 149a, 1818–1822.
  27. Leoyklang, P.; Suphapeetiporn, K.; Siriwan, P.; Desudchit, T.; Chaowanapanja, P.; Gahl, W.A.; Shotelersuk, V. Heterozygous nonsense mutation SATB2 associated with cleft palate, osteoporosis, and cognitive defects. Hum. Mutat. 2007, 28, 732–738.
  28. Rosenfeld, J.A.; Ballif, B.C.; Lucas, A.; Spence, E.J.; Powell, C.; Aylsworth, A.S.; Torchia, B.A.; Shaffer, L.G. Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome. PLoS ONE 2009, 4, e6568.
  29. Berko, E.R.; Cho, M.T.; Eng, C.; Shao, Y.; Sweetser, D.A.; Waxler, J.; Robin, N.H.; Brewer, F.; Donkervoort, S.; Mohassel, P.; et al. De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia. J. Med. Genet. 2017, 54, 84–86.
  30. Halvardson, J.; Zhao, J.J.; Zaghlool, A.; Wentzel, C.; Georgii-Hemming, P.; Månsson, E.; Ederth Sävmarker, H.; Brandberg, G.; Soussi Zander, C.; Thuresson, A.C.; et al. Mutations in HECW2 are associated with intellectual disability and epilepsy. J. Med. Genet. 2016, 53, 697–704.
  31. Yanagishita, T.; Hirade, T.; Shimojima Yamamoto, K.; Funatsuka, M.; Miyamoto, Y.; Maeda, M.; Yanagi, K.; Kaname, T.; Nagata, S.; Nagata, M.; et al. HECW2-related disorder in four Japanese patients. Am. J. Med. Genet. A 2021.
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