cells Review Genomic Aberrations Associated with the Pathophysiological Mechanisms of Neurodevelopmental Disorders Toshiyuki Yamamoto Institute of Medical Genetics, Tokyo Women’s Medical University, Tokyo 162-8666, Japan; [email protected] Abstract: 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. This can be explained by the dominant negative effects of the gene mutations. Currently, the diagnostic yield of genomic alterations using comprehensive analysis is less than 50%, indicating the existence of more subtle alterations or genomic changes in the untranslated regions. Copy-neutral inversions and insertions may be related. Hence, better analytical algorithms specialized for the detection of such alterations are required for Citation: Yamamoto, T. Genomic higher diagnostic yields. Aberrations Associated with the Pathophysiological Mechanisms of Keywords: nonallelic homologous recombination (NAHR); contiguous gene deletion syndrome; Neurodevelopmental Disorders. Cells 2021, 10, 2317. https://doi.org/ classical microdeletion syndrome; genome disease; diagnostic yield; exome sequencing 10.3390/cells10092317 Academic Editors: Koh-ichi Nagata and Orly Reiner 1. Introduction Neurodevelopmental disorders are defined as a concept that includes a wide range Received: 26 July 2021 of symptoms such as intellectual disability, developmental retardation, communication Accepted: 3 September 2021 disorders, autism spectrum disorders, attention deficit hyperactivity disorder, learning Published: 4 September 2021 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, Publisher’s Note: MDPI stays neutral it is easy to think of the pathophysiology of many of these symptoms if we consider with regard to jurisdictional claims in that some disorder of the synaptic function of the central nervous system causes various published maps and institutional affil- combinations of symptoms as clinical symptoms [3]. iations. 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. Copyright: © 2021 by the author. Genomic medicine using these analysis techniques has revealed the causes of neurode- Licensee MDPI, Basel, Switzerland. velopmental disorders in children one after another [4,5]. Although the diagnostic yields This article is an open access article in the chromosome G banding method was approximately 4%, which was the only com- distributed under the terms and prehensive analysis method before the Human Genome Project, now, the diagnostic rate conditions of the Creative Commons has increased to about 30–40% [6]. Because the genomic research of neurodevelopmental Attribution (CC BY) license (https:// disorders is still ongoing, the involvement of the genomic alteration in neurodevelopmental creativecommons.org/licenses/by/ disorders is not yet fully understood. 4.0/). Cells 2021, 10, 2317. https://doi.org/10.3390/cells10092317 https://www.mdpi.com/journal/cells Cells 2021, 10, 2317 2 of 11 Here, the genetic factors of neurodevelopmental disorders and the current state of diagnosis by genomic medicine are outlined. 2. Chromosomal Deletions Genomic copy number variations often contribute to neurodevelopmental disorders, indicating that many genes important for neurogenesis are copy-number-dependent. In general, 22q11.2 microdeletion (MIM #192430) is the most frequently observed genomic alteration, occurring in one in three-thousand live births [7]. The 22q11.2 microdeletion is caused by nonallelic homologous recombination (NAHR) facilitated by the low-copy repeats (LCRs) present at both ends of the deletions (Figure1). Similar to the 22q11.2 microdeletion, several other microdeletions are mediated by the LCRs (Table1). Due to Cells 2021, 10, 2317 2 of 11 these characteristics of the genome, microdeletion syndromes resulting from the adjacent LCRs are sometimes called “genome diseases”. Furthermore, the microdeletion syndromes, identified before the Human Genome Project, are characterized by prominent phenotypic featuresnostic rate and has are increased relatively to easy about to 30–40% diagnose [6]. [ 8Because]. Therefore, the genomic these areresearch called of “classical neurode- microdeletionvelopmental disorders syndromes”. is still ongoing, the involvement of the genomic alteration in neu- rodevelopmentalFor instance, patientsdisorders with is not 22q11.2 yet fully microdeletion understood. syndrome often present with tetral- ogy ofHere, Fallot, the as genetic a congenital factors heart of neurodevelopmental disease (Table1). Additionally, disorders patientsand the withcurrent Williams- state of Beurendiagnosis syndrome by genomic (MIM medicine #194050) are and outlined. Smith-Magenis syndrome (MIM #182290) also present with congenital heart diseases associated with supraclavicular stenosis and ven- tricular2. Chromosomal septal defect, Deletions respectively. In addition to congenital heart diseases, patients with theseGenomic syndromes copy exhibit number distinctive variations features, often cont whichribute provide to neurodevelopmental important clues for disorders, clinical diagnosis.indicating Furthermore,that many genes the variableimportant phenotypes for neurogenesis in these are disease copy-number-dependent. groups are caused by In thegeneral, deletion 22q11.2 of multiple microdeletion adjacent (MIM genes, #192430) leading is to the the most term frequently “continuous observed gene deletiongenomic syndrome”.alteration, occurring in one in three-thousand live births [7]. The 22q11.2 microdeletion is caused“Classical by nonallelic microdeletion homologous syndromes” recombination or “genome (NAHR) diseases” facilitated are often by the associated low-copy with re- variouspeats (LCRs) levels present of neurodevelopmental at both ends of the abnormalities, deletions (Figure because 1). Similar the deleted to the region 22q11.2 contains micro- genesdeletion, related several to neurodevelopment, other microdeletions which are m areediated copy-number-dependent. by the LCRs (Table 1). Furthermore, Due to these acharacteristics condition where of the heterozygous genome, microdeletion deletions or syndromes loss of homologous resulting from alleles the occur adjacent and LCRs the remainingare sometimes functional called copy “genome of the genediseases”. is incapable Furthermore, of producing the microdeletion a sufficient gene syndromes, product requiredidentified for before maintaining the Human the normal Genome function Project, is are referred characterized to as haploinsufficiency. by prominent phenotypic Haploin- sufficiencyfeatures and of genesare relatively related easy to neurodevelopment to diagnose [8]. Therefore, is an essential these mechanismare called “classical in classical mi- microdeletion syndromes. crodeletion syndromes”. Figure 1. Schematic representation of the mechanism of nonallelic homologous recombination. Figure 1. Schematic representation of the mechanism of nonallelic homologous recombination. De- Deletions and duplications of the regions of interest (grey rectangles) can be caused by nonallelic letions and duplications of the regions of interest (grey rectangles) can be caused by nonallelic ho- homologousmologous recombination recombination triggered triggered by by the the presence presence of of low-copy low-copy repeats repeats (LCRs). (LCRs). Table 1. Classical microdeletion syndromes and reciprocal duplications. Chromosomal Deletions Duplications Regions Microdeletion Microduplication Main Clinical Features Main Clinical Features Syndromes Syndromes 22q11.2 deletion Tetralogy of Fallot, language delay, 22q11.2 duplication 22q11.2 ADHD syndrome distinctive facial features syndrome Williams- Supraventricular stenosis, Speech delay and 7q11.23 duplication 7q11.23 Beuren syn- intellectual disability, distinctive autism spectrum syndrome drome facial features behaviors Intellectual disability, Prader-Willi Developmental delay, hypotonia, 15q11 15q11 duplication autism spectrum syndrome obesity behaviors Cells 2021, 10, 2317 3 of 11 Table 1. Classical microdeletion syndromes and reciprocal duplications. Chromosomal Deletions Duplications Regions Microdeletion Microduplication Main Clinical Features Main Clinical Features Syndromes Syndromes