Review

Genomics of neurodevelopmental disorders

Genómica de los trastornos del desarrollo neurológico

0000-0002-4401-0054Luis Alberto Méndez Rosado^{1  *}  , 0000-0002-8549-2571Aracelis Lantigua Cruz²  , 0000-0001-7458-5396Maria Zelenova^{3  4}  , 0000-0002-4869-5361Svetlana Vorsanova^{3  4}  , 0000-0002-4134-8367Ivan Iourov^{3  4  *} 

¹Cytogenetic Laboratory of the National Center of Medical Genetic. Havana. Cuba.

²National Center of Medical Genetic. Havana. Cuba.

³Laboratory of Molecular Cytogenetics of Neuropsychiatric Diseases, Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University. Moscow 125412, Russia;

⁴Yurov’s Laboratory of Molecular Genetics and Cytogenomics of the Brain, Mental Health Research Center. Moscow 117152, Russia;

ABSTRACT

Introduction:

Neurodevelopmental disorders (NDD) are featured by a delay in the acquisition of motor functions, cognitive abilities and speech, or combined deficits in these areas with the onset before the age of 5 years. Genetic causes account for approximately a half of all NDD cases.

Objective:

to describe alterations of the genome implied in neurodevelopmental disorders and some aspects of their genetic counseling.

Methods:

Bibliographic search in Medline, Pubmed, Scielo, LILACS and Cochrane, emphasizing in the last five years, the relationship between the various genetic factors that may be involved in neurodevelopmental disorders.

Results:

Multiple genetic factors are involved in neurodevelopmental disorders, from gross ones such as chromosomal aneuploidies to more subtle ones such as variations in the number of copies in the genome. Special emphasis is placed on microdeletion-micro duplication syndromes as a relatively frequent cause of NDDs and their probable mechanisms of formation are explained.

Final Considerations:

Genetic aberrations are found in at least 30-50% of children with NDD. Conventional karyotyping allows the detection of chromosomal aberrations encompassing more than 5-7 Mb, which represent 5-10% of causative genome rearrangements in NDD. Molecular karyotyping (e.g. SNP array/array CGH) can significantly improve the yield in patients with NDD and congenital malformations.

Key words: CNV; chromosomal abnormalities; genome; genomic aberrations; microdeletions; microduplications; neurodevelopmental disorders

RESUMEN

Introducción:

Los trastornos del neurodesarrollo están caracterizados por retardo en la adquisición de las funciones motoras, habilidades cognitivas para el habla o el déficit combinado en estas áreas; se presenta en niños menores de 5 años de edad. Las causas genéticas están implicadas en más de la mitad de los pacientes con estos trastornos

Objetivo:

Examinar las alteraciones del genoma implicados en los trastornos del neurodesarrollo y algunos aspectos de su asesoramiento genético.

Métodos:

Búsqueda bibliográfica en Medline, Pubmed, Scielo, LILACS y Cochrane con énfasis en los últimos cinco años, acerca de la relación entre los variados factores genéticos que pueden estar involucrados en los trastornos del neurodesarrollo.

Resultados:

Los factores genéticos involucrados pueden ser groseros como las aneuploidías cromosómicas hasta los más sutiles como las variaciones en el número de copias en el genoma. Se describen los síndromes de microdeleción-micro duplicación como una causa relativamente frecuente de los trastornos del neurodesarrollo y se explican sus probables mecanismos de formación. Se relacionan las aneuploidías cromosómicas y las variaciones en el número de copia como causas de estos trastornos.

Consideraciones finales

. Las aberraciones genéticas se encuentran en 30-50 % de los niños con trastornos del neurodesarrollo. El cariotipo convencional permite la detección de aberraciones cromosómicas que abarcan más de 5-7 Mb, lo que representa 5-10 % de los reordenamientos genómicos causales en estos trastornos. El cariotipo molecular (por ejemplo, una matriz de SNP/ CGH de matriz) puede mejorar significativamente la certeza del diagnóstico en pacientes con trastornos del neurodesarrollo y malformaciones congénitas.

Palabras-clave: variaciones en el número de copias (CNV); anomalías cromosómicas; genoma; aberraciones del genoma; microdeleciones; microduplicaciones; desordenes del neurodesarrollo

Introduction

Neurodevelopmental disorders (NDD) are featured by a delay in the acquisition of motor functions, cognitive abilities and speech, or combined deficits in these areas with the onset before the age of 5 years. The prevalence may reach 1-3 %, according to different studies^1,2. Genetic causes account for approximately a half of all NDD cases; chromosomal aberrations (CA) account for 5-10%of cases^3,4. However, the extensive variability of causal genetic defects hinders the etiological diagnosis. The phenotypic effect of CA depends on the type, origin, and length of aberrations. Additionally, gene density and functional aspects of genes and their interactions with other genes and environmental modulating significantly contributes to the phenotype, as well.^5,6The aim of this work is to describe some alterations of the genome implied in neurodevelopmental disorders.

Methods

Bibliographic search in Medline, Pubmed, Scielo, LILACS and Cochrane, emphasizing in the last five years, the relationship between the various genetic factors that may be involved in neurodevelopmental disorders.

Results

Multiple genetic factors are involved in neurodevelopmental disorders, from gross ones such as chromosomal aneuploidies to subtler ones such as variations in the number of copies in the genome. Special emphasis is placed on microdeletion-micro duplication syndromes as a relatively frequent cause of NDDs and their probable mechanisms of formation are explained.

Microdeletion and microduplication syndromes

During the last decades an increasing number of so-called contiguous gene syndromes (CGSs) have been identified in patients with intellectual disability. CGSs are caused by an aberrant copy number (gain or loss) of specific chromosomal regions. Originally, CGSs were considered to encompass critical regions of two or more genes, located in a close proximity to each other. Some of these regions affect many genes but a limited number of genes may be dosage-sensitive and, thereby, causative for specific manifestations. Thus, the denomination “CGS” has been replaced by the designation “microdeletion or microduplication syndromes” (MMSs).⁷⁾ The common molecular cause of recurrent MMSs is a non-allelic homologous recombination. Repetitive elements are prone to illegitimate intra- or interchromosomal/chromatide recombination during meiosis and mitosis. The expected number of MMS is suggested to be higher than is currently known, because many of these events have a deleterious intrauterine effect.^8,9

Theoretically, there should be a reciprocal microduplication syndrome for each microdeletion syndrome. However, microdeletion syndromes are more common according to current molecular cytogenetic studies (Fig.1). The main reason for this inequality is that microduplications are supposed to have a lower clinical impact than microdeletions. Subsequently, the patients with microduplications are less commonly addressed by molecular (cyto)genetic techniques due to less severe phenotypic manifestations.^9,10

Source: ref. 7.

Fig. - Most common pathogenic findings on 5487 chromosomal microarrays.  

Additional causes for MMSs recurrence

Human non-homologous DNA recombination and end joining may occur due to double stranded breaks, which serve as a repair mechanism. This cause is less frequent and is not directly mediated by the features of the genome sequence.¹¹In addition, MMSs can be a result of meiotic recombination when one parent carries a polymorphic inversion (e.g., a heterochromatic region of chromosome 9), which leads to a recombinant gamete with a deletion or duplication in this regiondue aninverted loop formation.⁹

Chromosomal aneuploidies

The most frequent cause of chromosomal syndromes is aneuploidy, which affects no less than 0.5% of newborns.^12,13 Almost all of these conditions are associated with brain dysfunction ¹⁴ The most frequent aneuploidies among newborns are trisomy of chromosomes 21, 18, 13 and aneuploidy of sex chromosomes (gonosomes). Mosaic trisomy of chromosomes 8 and 9 (there are two cell populations (normal/trisomic) in an affected individual) are relatively common, as well (Tabla). ^14,15

Table- Genetic syndromes associated with different kinds of brain dysfunction 

Copy number variations

Numerous human genome loci are prone to submicroscopic copy number variations (CNVs). These CNVs are located in euchromatic regions and dispersed over the entire human genome. CNVs(gain/loss of submicroscopic regions) can either lead to clinical manifestations or lack detectable phenotypic consequences.^7,16 Several features of CNVs support their role in disease pathogenesis. Although less abundant than SNPs, they account for a larger nucleotide variation than SNPs because encompassing larger DNA sequences in the absolute size.¹⁷ Spanning thousands of nucleotide bases, CNVs often encompass and disrupt functional DNA sequences. Moreover, there appears to be enrichment in CNVs affecting “environmental sensor” genes, i.e. genes that are not necessarily critical for early embryonic development, but are involved in perceiving and interacting with the environment.^18,19 he way how CNVs change their size when passed from one generation to the next, i.e. how specific DNA-regions are lost or amplified within a CNV, is not as yet completely understood. This may result from unequal crossing-over events in low copy repeat regions ^{(5, 16)}, or from altered reparation after DNA-break and/or replication stress (e.g. non-allelic homologous recombination, microhomology-mediated break-induced replication, or chromothripsis).^{7,20,21,22,23,24} The most known disease-causing CNVs are 17q21.31microdeletions (Koolen-De Vries syndrome.²⁵ reciprocal 17q21.31 microduplications,^26,27 17q23.1q23.2 microdeletions²⁸ and 3q13 microdeletions.²⁹ Some microdeletion and microduplication syndromes are not caused by recurrent CNVs, but individuals witht he aberrations present with similar phenotypes,³⁰ which allows for the definition of smallest regions of overlap, or critical regions, for the syndrome, which are likely to contain disease-causing genes (e.g. 1q43q44, 1q41q42 and 1q24q25 microdeletions).^31,32,33

Genetic counseling

Genetic counseling in cases of CNVs with reduced penetrance and variable expressivity can be particularly difficult.³⁴ If a parent carries the CNV, there is a 50% -inheritance-chance for off spring, but the establishment of additional risk factors in the family as well as the likelihood of having another affected childr equires more sophisticated (bioinformatics) analysis. For at least some recurrent CNVs, there are estimates either for penetrance, for any clinical phenotype or for psychiatric disorders, such as schizophrenia.^35-36 The penetrance analysis shows that not all CNVs confer equal risk. steimates for the requency of carriers with significantly abnormal phenotypes range from ~10% for 15q11.2 BP1-BP2 microdeletion syndrome to~60% for distal 16p11.2 microdeletions.³⁵⁾ Unfortunately, it remains difficult to predict the severity of phenotypic outcomes, although some researchers suggest that there may be protective actors (e.g. gender)³⁷.Furthermore, it is important to note that “penetrance” is quite relative; there may still be negative CNV effects among the so-called healthy parents or controls. This is supported by recent studies of general populations reporting negative effects of the CNVs, including cognitive impairments, other neuropsychiatric features, alterations in body weight, and reduced fertility.^38,39 Therefore, it is likely that most of these CNV shave some type of negative impact on an individual’s development and neurologic functioning, although these impacts may not be always evident. Another notable feature of recurrent CNVs is variable expressivity. Same CNVs may be identified in populations of patients with intellectual disability, autism, and schizophrenia. Such effects may indicate that there are shared etiologies among NDD.^40,41,42,43 Several studies have demonstrated the applicability of this assumption by comparing parental neurocognitive function to their children with de novo risk factor CNVs, showing a correlation between lower levels of parental functioning in specific domains (such as IQ and social responsiveness) scores and more significant impairments in those domains among their off spring.^44,45.46

Final considerations

Genetic aberrations are found in at least 30-50% of children with NDD. Conventional karyotyping allows the detection of chromosomal aberrations en compassing more than 5-7 Mb, which represent 5-10% of causative genome rearrangements in NDD. Molecular karyotyping (e.g. SNP array/array CGH) can significantly improve the yield in patients with NDD and congenital malformations, which is repeatedly shown by systematic cohort studies. Recommendation: Cuban NDD cohorts have not yet been studied by these high-resolution techniques. The application of molecular karyotyping to the cohort can help in revealing new genetic aberrations and can provide effective genetic counseling.

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Abbreviations

NDD - Neurodevelopmental disorders

CA - Chromosomal aberrations

CNVs - copy number variations

CGSs - Contiguous gene syndromes

MMSs - Microdeletion or microduplication syndromes

Received: July 17, 2019; Accepted: August 26, 2020

^*Correspondence: [e-mail]

^*Correspondence: [e-mail] or [e-mail]

None. The investigation was supported by Russian Foundation for Basic Research (RFBR) and Ministerio de Ciencia Tecnologías y Medio Ambiente (CITMA) of Cuba, according to the research project №18-515-34005.

Luis Alberto Méndez Rosado: Conceived the manuscript, bibliographical revision, wrote the first draw of the paper.

Ivan Iourov: bibliographical revision, wrote the final version of paper.

Aracelis Lantigua Cruz, Maria Zelenova, SvetlanaVorsanova. bibliographical revision, participation in the design of the article.

All authors participated in the final review of the manuscript and agree with the scientific content and objetives of the paper.