Genomic Aberrations in Neurodevelopmental Disorders

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1		Toshiyuki Yamamoto	+ 1522 word(s)	1522	2022-03-25 07:20:05	\|
2	format correct	Vivi Li	Meta information modification	1522	2022-03-28 03:44:52	\|

This entry is adapted from the peer-reviewed paper 10.3390/cells10092317

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]. 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 researchers 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]. 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 1). For instance, deletion of PMP22 (located on 17p12) causes hereditary neuropathy with susceptibility to pressure palsies (MIM #162500) ^[7], while its duplication causes Charcot-Marie-Tooth disease (MIM #118220) ^[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) ^[9]^[10]. These differences can be attributed to different mechanisms associated with gene deletion or duplication events ^[11]. Additionally, it is believed that duplication events result in the increased expression of genes, inducing cell stress.

Table 1. 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 ^[12]. The exact mechanism underlying MECP2 deletion or duplication is unclear to date ^[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 ^[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) ^[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 2). 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 1). Thus, the clinical symptoms can be diagnosed because of the involvement of the main gene(s) in the deleted regions.

Figure 1. 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 2. 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, researchers identified a small deletion in Xq11.1, in a patient with epileptic encephalopathy ^[17]. The deleted region contained the ARHGEF9 gene. Additionally, researchers 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) ^[18].

Further, in 2011, researchers reported two cases of 5q31 microdeletion for the first time ^[19]. Both patients exhibited common clinical symptoms with infantile epileptic encephalopathy and shared severe psychomotor development. Following researchers' study, two other studies reporting overlapping chromosomal microdeletions narrowed down the candidate gene responsible for the syndrome to be PURA ^[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 ^[22]. Hence, currently, 5q31 microdeletion syndrome is known as a PURA-related neurodevelopmental disorder.

In another study, researchers found a 15q14 microdeletion in a patient with mild neurodevelopmental disorder with ventricular septal defect and submucosal cleft palate ^[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 ^[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 ^[25]. Previously, researchers 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 ^[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 ^[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) ^[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 ^[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.

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