scholarly journals Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents

2020 ◽  
Vol 29 (1) ◽  
pp. 205-215
Author(s):  
Dinka Smajlagić ◽  
Ksenia Lavrichenko ◽  
Siren Berland ◽  
Øyvind Helgeland ◽  
Gun Peggy Knudsen ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Copy Number Variations ◽  
Genetic Diagnostics ◽  
Incomplete Penetrance ◽  
Inheritance Pattern ◽  
Neurodevelopmental Delay ◽  
Population Prevalence ◽  
Total Prevalence ◽  
Genomic Regions

AbstractRecurrent copy number variations (CNVs) are common causes of neurodevelopmental disorders (NDDs) and associated with a range of psychiatric traits. These CNVs occur at defined genomic regions that are particularly prone to recurrent deletions and duplications and often exhibit variable expressivity and incomplete penetrance. Robust estimates of the population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders (NDD CNVs) are lacking. Here we perform array-based CNV calling in 12,252 mother–father–child trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and analyse the inheritance pattern of 26 recurrent NDD CNVs in 13 genomic regions. We estimate the total prevalence of recurrent NDD CNVs (duplications and deletions) in live-born children to 0.48% (95% C.I.: 0.37–0.62%), i.e., ~1 in 200 newborns has either a deletion or duplication in these NDDs associated regions. Approximately a third of the newborn recurrent NDD CNVs (34%, N = 20/59) are de novo variants. We provide prevalence estimates and inheritance information for each of the 26 NDD CNVs and find higher prevalence than previously reported for 1q21.1 deletions (~1:2000), 15q11.2 duplications (~1:4000), 15q13.3 microdeletions (~1:2500), 16p11.2 proximal microdeletions (~1:2000) and 17q12 deletions (~1:4000) and lower than previously reported prevalence for the 22q11.2 deletion (~1:12,000). In conclusion, our analysis of an unselected and representative population of newborns and their parents provides a clearer picture of the rate of recurrent microdeletions/duplications implicated in neurodevelopmental delay. These results will provide an important resource for genetic diagnostics and counseling.

scholarly journals Role of Copy Number Variations in ADHD

2020 ◽  
Author(s):  
Danijela Krgović
Keyword(s):  
Autism Spectrum Disorder ◽  
Attention Deficit ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Spectrum Disorder ◽  
Genetic Diagnostics ◽  
Healthy Controls

Copy number variations (CNV) have an important role in etiology of neurodevelopmental disorders (NDD). Among them, individuals with attention-deficit and hyperactivity disorders (ADHD) have 1.33 times higher overall rate of CNVs larger than 100 kb compared to healthy controls. These CNVs are often shared with other NDDs and neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD), although duplications of 15q13.3 and 16p13.11 have been found enriched in ADHD cohorts. CNVs provide new opportunities for studying and management of psychiatric disorders including ADHD. Therefore this chapter provides a brief overview of the literature on this topic and presents the benefits of CNV genetic diagnostics in ADHD patients.

Aetiology, genes, and environment

ESC CardioMed ◽  
2018 ◽  
pp. 742-746
Author(s):  
Elisavet Fotiou ◽  
Bernard Keavney
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Recurrence Risk ◽  
Copy Number Variations ◽  
Deletion Syndrome ◽  
Clinical Genetics ◽  
Single Nucleotide ◽  
Neurodevelopmental Delay ◽  
Substantial Progress ◽  
Neurodevelopmental Abnormalities

Genetic factors predisposing to congenital heart disease (CHD) are characterized by extreme heterogeneity, comprising changes to the genome at all levels of variation from chromosomal aneuploidy to single nucleotide mutations. About 15–20% of patients with CHD have underlying genetic causes identifiable by currently standard clinical genetics laboratory testing, including patients with Down syndrome, Turner syndrome, 22q11 deletion syndrome, other chromosomal rearrangements, and multisystem conditions mediated by single nucleotide changes in particular genes (e.g. Noonan’s syndrome). Extracardiac malformations and/or neurodevelopmental abnormalities characteristic of these conditions are important diagnostic cues. Mendelian families with isolated non-syndromic CHD are very rare. In the remaining 80% of cases, CHD is apparently ‘sporadic’ and the empirical recurrence risk to a sibling of an index case in such families is approximately 3%. This low recurrence risk suggests that de novo events, that is, new mutations in affected offspring absent in the parents, are an important potential genetic cause of CHD. De novo copy number variations such as 1q21.1 duplication have been shown to contribute to aetiology in 5–10% of apparently sporadic patients. Recent studies have also shown that approximately 20% of patients without recognized syndromic presentations, but with CHD accompanied by extracardiac malformations and/or neurodevelopmental delay, may have pathogenic de novo single nucleotide changes discoverable by exome sequencing. Continuing advances in genomic technologies present the prospect of substantial progress in the understanding of the genetic predisposition to CHD, but further research in large cohort studies is required.

scholarly journals Duplication of chromosome 16p13.11-p12.3 with different expressions in the same family

2021 ◽  
Vol 24 (1) ◽  
pp. 89-94
Author(s):  
N Pop-Jordanova ◽  
T Zorcec ◽  
E Sukarova-Angelovska
Keyword(s):  
Neurodevelopmental Disorders ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Comparative Genomic ◽  
Incomplete Penetrance ◽  
Typical Development ◽  
Small Children ◽  
Neurodevelopmental Delay ◽  
Chromosomal Duplication ◽  
Older Siblings

Abstract The knowledge about genetic involvement in neurodevelopmental disorders, and especially in autism, is currently rising. To date, more than 100 gene mutations related to autistic syndromes have been described. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited. Recently, array comparative genomic hybridization (aCGH) has identified sub microscopic deletions and duplications as a common cause of mental retardation and autism. In this article we report the occurrence of the same genetic finding (chromosome 16p13.11-p12.3 duplication) in a family with four small children, where two older siblings manifested a global neurodevelopmental delay associated with an autism spectrum disorder (ASD), but younger twin brothers with the same mutation, have typical development. Genetic analysis showed that the chromosomal duplication was inherited from the father, in which phenotype and functioning are quite typical. As is known, the duplication can pass from parents to children. The 16p13.11 micro duplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance.

scholarly journals Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs

2021 ◽  
Vol 12 ◽  
Author(s):  
Martina Servetti ◽  
Livia Pisciotta ◽  
Elisa Tassano ◽  
Maria Cerminara ◽  
Lino Nobili ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Genetic Basis ◽  
De Novo ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Brain Diseases ◽  
Comparative Genomic ◽  
Incomplete Penetrance ◽  
Genetic Components ◽  
Complex Phenotypes

Neurodevelopmental disorders (NDDs) are a heterogeneous class of brain diseases, with a complex genetic basis estimated to account for up to 50% of cases. Nevertheless, genetic diagnostic yield is about 20%. Array-comparative genomic hybridization (array-CGH) is an established first-level diagnostic test able to detect pathogenic copy number variants (CNVs), however, most identified variants remain of uncertain significance (VUS). Failure of interpretation of VUSs may depend on various factors, including complexity of clinical phenotypes and inconsistency of genotype-phenotype correlations. Indeed, although most NDD-associated CNVs are de novo, transmission from unaffected parents to affected children of CNVs with high risk for NDDs has been observed. Moreover, variability of genetic components overlapped by CNVs, such as long non-coding genes, genomic regions with long-range effects, and additive effects of multiple CNVs can make CNV interpretation challenging. We report on 12 patients with complex phenotypes possibly explained by complex genetic mechanisms, including involvement of antisense genes and boundaries of topologically associating domains. Eight among the 12 patients carried two CNVs, either de novo or inherited, respectively, by each of their healthy parents, that could additively contribute to the patients’ phenotype. CNVs overlapped either known NDD-associated or novel candidate genes (PTPRD, BUD13, GLRA3, MIR4465, ABHD4, and WSCD2). Bioinformatic enrichment analyses showed that genes overlapped by the co-occurring CNVs have synergistic roles in biological processes fundamental in neurodevelopment. Double CNVs could concur in producing deleterious effects, according to a two-hit model, thus explaining the patients’ phenotypes and the incomplete penetrance, and variable expressivity, associated with the single variants. Overall, our findings could contribute to the knowledge on clinical and genetic diagnosis of complex forms of NDD.

scholarly journals Copy number variation in pediatric multiple sclerosis

2012 ◽  
Vol 19 (8) ◽  
pp. 1014-1021 ◽  
Author(s):  
JP McElroy ◽  
LB Krupp ◽  
BA Johnson ◽  
JL McCauley ◽  
Z Qi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Early Onset ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variations ◽  
Comparative Genomic ◽  
Pediatric Multiple Sclerosis ◽  
Reported Study ◽  
Number Variation ◽  
Genomic Regions

Background: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. Objectives and methods: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. Results and discussion: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. Conclusions: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient’s disease course and prognosis.

scholarly journals Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders

2017 ◽  
Author(s):  
Sofia Stamouli ◽  
Britt-Marie Anderlid ◽  
Charlotte Willfors ◽  
Bhooma Thiruvahindrapuram ◽  
John Wei ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Single Cells ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Rare Cnvs ◽  
Number Variation ◽  
Discordant Twins ◽  
Mz Twins

AbstractHundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. Here, we sought to investigate the contribution of CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on MZ pairs discordant for autism spectrum disorder (ASD) using the PsychChip array. In our collection, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. When analyzing the burden of rare CNVs among pairs concordant and discordant for ASD/NDD in comparison with typically developed (TD) pairs, no differences were found. However, we did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p=0.02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood and, in the majority of MZ twins, do not explain the discordance of NDDs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.

scholarly journals Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders

2018 ◽  
Vol 21 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Sofia Stamouli ◽  
Britt-Marie Anderlid ◽  
Charlotte Willfors ◽  
Bhooma Thiruvahindrapuram ◽  
John Wei ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Single Cells ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Typically Developing ◽  
Rare Cnvs ◽  
Number Variation ◽  
Discordant Twins

Hundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. We sought to investigate the contribution of rare CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on postzygotic CNVs in MZ pairs discordant for autism spectrum disorder (ASD) using the Illumina Infinium PsychArray. In our sample, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. We did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system, such as a rare deletion affecting HNRNPU, in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p = .02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood, and suggests that the discordance of NDDs in our sample of twins is not explained by discordant CNVs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.

Rett-like Syndrome in a Pediatric Patient—A Challenging Diagnosis

2020 ◽  
Author(s):  
Sofia Simões Ferreira ◽  
Marta Mesquita ◽  
Joana Nunes ◽  
Isabel Alonso ◽  
Miguel Leão ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Pediatric Patient ◽  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Hand Movements ◽  
Gene Variants ◽  
Neurodevelopmental Delay ◽  
Whole Exome ◽  
Rett’S Syndrome

AbstractNeurodevelopmental disorders with features overlapping Rett's syndrome frequently remain unexplained in patients without disease-causing variants in MECP2. Variants in IQSEC2 frequently cause nonsyndromic X-linked intellectual disability (XLID), although de novo variants may cause a severe syndrome that resembles Rett and Angelman's syndrome. We report a 7-year-old girl presenting severe neurodevelopmental delay, stereotypic hand movements, hypotonia, autistic-like features, inappropriate laughing/screaming spells, and symmetrical hypomyelination. A whole exome sequencing detected a novel de novo heterozygous truncating variant within the IQSEC2 gene. Variants of IQSEC2 should be considered in patients with Rett–Angelman phenotype spectrum and autistic features when those causes were excluded.

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