scholarly journals The Cytoscan HD Array in the Diagnosis of Neurodevelopmental Disorders

2018 ◽  
Vol 7 (3) ◽  
pp. 28 ◽  
Author(s):  
Francesca Scionti ◽  
Maria Di Martino ◽  
Licia Pensabene ◽  
Valentina Bruni ◽  
Daniela Concolino
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Snp Array ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Clinical Diagnostic Laboratory ◽  
Diagnostic Laboratory ◽  
Unknown Significance ◽  
Pathogenic Cnvs ◽  
Line Test

Submicroscopic chromosomal copy number variations (CNVs), such as deletions and duplications, account for about 15–20% of patients affected with developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorder. Most of CNVs are de novo or inherited rearrangements with clinical relevance, but there are also rare inherited imbalances with unknown significance that make difficult the clinical management and genetic counselling. Chromosomal microarrays analysis (CMA) are recognized as the first-line test for CNV detection and are now routinely used in the clinical diagnostic laboratory. The recent use of CMA platforms that combine classic copy number analysis with single-nucleotide polymorphism (SNP) genotyping has increased the diagnostic yields. Here we discuss the application of the Cytoscan high-density (HD) SNP-array for the detection of CNVs. We provide an overview of molecular analyses involved in identifying pathogenic CNVs and highlight important guidelines to establish pathogenicity of CNV.

scholarly journals Associations between Familial Rates of Psychiatric Disorders and De Novo Genetic Mutations in Autism

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Kyleen Luhrs ◽  
Tracey Ward ◽  
Caitlin M. Hudac ◽  
Jennifer Gerdts ◽  
Holly A. F. Stessman ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Copy Number ◽  
Depressive Disorders ◽  
De Novo ◽  
Familial Risk ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Genetic Etiology ◽  
Additive Contribution ◽  
Familial Risk Factors

The purpose of this study was to examine the confluence of genetic and familial risk factors in children with Autism Spectrum Disorder (ASD) with distinct de novo genetic events. We hypothesized that gene-disrupting mutations would be associated with reduced rates of familial psychiatric disorders relative to structural mutations. Participants included families of children with ASD in four groups: de novo duplication copy number variations (DUP, n=62), de novo deletion copy number variations (DEL, n=74), de novo likely gene-disrupting mutations (LGDM, n=267), and children without a known genetic etiology (NON, n=2111). Familial rates of psychiatric disorders were calculated from semistructured interviews. Results indicated overall increased rates of psychiatric disorders in DUP families compared to DEL and LGDM families, specific to paternal psychiatric histories, and particularly evident for depressive disorders. Higher rates of depressive disorders in maternal psychiatric histories were observed overall compared to paternal histories and higher rates of anxiety disorders were observed in paternal histories for LGDM families compared to DUP families. These findings support the notion of an additive contribution of genetic etiology and familial factors are associated with ASD risk and highlight critical need for continued work targeting these relationships.

scholarly journals Clinical Utility and the Yield of Single Nucleotide Polymorphism Array in Prenatal Diagnosis of Fetal Central Nervous System Abnormalities

2021 ◽  
Vol 8 ◽  
Author(s):  
Meiying Cai ◽  
Hailong Huang ◽  
Liangpu Xu ◽  
Na Lin
Keyword(s):  
Central Nervous System ◽  
Single Nucleotide Polymorphism ◽  
Copy Number ◽  
Chromosomal Abnormalities ◽  
Karyotype Analysis ◽  
Snp Array ◽  
Copy Number Variations ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pathogenic Cnvs

Applying single nucleotide polymorphism (SNP) array to identify the etiology of fetal central nervous system (CNS) abnormality, and exploring its association with chromosomal abnormalities, copy number variations, and obstetrical outcome. 535 fetuses with CNS abnormalities were analyzed using karyotype analysis and SNP array. Among the 535 fetuses with CNS abnormalities, chromosomal abnormalities were detected in 36 (6.7%) of the fetuses, which were consistent with karyotype analysis. Further, additional 41 fetuses with abnormal copy number variations (CNVs) were detected using SNP array (the detection rate of additional abnormal CNVs was 7.7%). The rate of chromosomal abnormalities, but not that of pathogenic CNVs in CNS abnormalities with other ultrasound abnormalities was significantly higher than that in isolated CNS abnormalities. The rates of chromosomal abnormalities and pathogenic CNVs in fetuses with spine malformation (50%), encephalocele (50%), subependymal cyst (20%), and microcephaly (16.7%) were higher than those with other isolated CNS abnormalities. The pregnancies for 36 cases with chromosomal abnormalities, 18 cases with pathogenic CNVs, and three cases with VUS CNVs were terminated. SNP array should be used in the prenatal diagnosis of fetuses with CNS abnormalities, which can enable better prenatal assessment and genetic counseling, and affect obstetrical outcomes.

scholarly journals Detection of Clinically Relevant Copy Number Variations and Genes in a Bangladeshi Cohort of Neurodevelopmental Disorders

2021 ◽  
Author(s):  
Hosneara Akter ◽  
Muhammad Mizanur Rahman ◽  
Shaoli Sarker ◽  
Mohammed Basiruzzaman ◽  
Mazharul Islam ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Critical Role ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Chromosomal Microarray Analysis ◽  
Potential Candidate ◽  
Female Ratio ◽  
Pathogenic Cnvs

Abstract Background: Copy number variations (CNVs) play a critical role into the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh. Methods: We have conducted genome-wide chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare chromosomal abnormalities (deletion /duplication/ rearrangements). To identify candidate genes within the rare CNVs, multiple gene constraint metrics (i.e. “Critical-Exon Genes (CEGs)”) were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using R package. Results: In our cohort, the head circumference of males are significantly greater than females (p=0.0002). Of all samples assayed, 12.26% (26/212) and 47.17% (100/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. 2.83% (6/212) pathogenic CNVs are located at the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs in comparison to males (OR=4.2; p=0.0007). ADOS-2 subset show severe social communication deficit (p=0.014) and overall ASD symptoms severity (p=0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs and identified PSMC3 gene as a potential candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability. Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis therapeutics and management of NDD patients.

scholarly journals Spontaneous mutations and transmission distortions of genic copy number variants shape the standing genetic variation in Picea glauca

2017 ◽  
Author(s):  
Atef Sahli ◽  
Isabelle Giguére ◽  
Jean Bousquet ◽  
John MacKay
Keyword(s):  
Genetic Variation ◽  
Picea Glauca ◽  
Copy Number ◽  
De Novo ◽  
Snp Array ◽  
Copy Number Variations ◽  
Spontaneous Mutations ◽  
Evolutionary Forces ◽  
Gene Space ◽  
Transmission Distortions

AbstractCopy number variations (CNVs) are large genetic variations detected among the individuals of every multicellular organism examined so far. These variations are believed to play an important role in the evolution and adaptation of species. In plants, little is known about the characteristics of CNVs, particularly regarding the rates at which they are generated and the mechanics of their transmission from a generation to the next. Here, we used SNP-array raw intensity data for 55 two-generations families (3663 individuals) to scan the gene space of the conifer tree Picea glauca (Moench) Voss for CNVs. We were particularly interested in the abundance, inheritance, spontaneous mutation rate spectrum and the evolutionary consequences they may have on the standing genetic variation of white spruce. Our findings show that CNVs affect a small proportion of the gene space and are predominantly copy number losses. CNVs were either inherited or generated through de novo events. De novo CNVs present high rates of spontaneous mutations that vary for different genes and alleles and are correlated with gene expression levels. Most of the inherited CNVs (70%) are transmitted from the parents in violation of Mendelian expectations. These transmission distortions can cause considerable frequency changes between generations and be dependent on whether the heterozygote parents contribute as male or female. Transmission distortions were also influenced by the partner genotype and the parents’ genetic background. This study provides new insights into the effects of different evolutionary forces on copy number variations based on the analysis of a perennial plant.

scholarly journals Rare Copy Number Variation Analysis in Chinese Children of Complete Atrioventricular Canal and Single Ventricle 

2021 ◽  
Author(s):  
Xingyu Zhang ◽  
Bo Wang ◽  
Guoling You ◽  
Ying Xiang ◽  
Qihua Fu ◽  
...  
Keyword(s):  
Copy Number ◽  
Trisomy 21 ◽  
Single Ventricle ◽  
Snp Array ◽  
Copy Number Variations ◽  
Chinese Children ◽  
Atrioventricular Canal ◽  
Rare Cnvs ◽  
Pathogenic Cnvs ◽  
Complete Atrioventricular

Abstract Background: Congenital heart disease (CHD) is the most common birth defects. Copy number variations (CNVs) have been proved to be important genetic factors that contribute to CHD. Here, we screened pathogenic CNVs in Chinese children with two rare types of CHD, complete atrioventricular canal (CAVC) and single ventricle (SV) .Methods：We screened CNVs in 262 sporadic CAVC cases and 259 sporadic SV cases respectively, using a customized SNP array. The detected CNVs were annotated and filtered using available databases.Results: Among 262 CAVC patients, we identified 44 rare CNVs in 43 individuals (16.4 %, 43/262), including 2 syndrome-related CNVs (7q11.23 and 8q24.3 deletion). Surprisingly, 88.6% rare CNVs (39/44) were duplications of 21q11.2-21q22.3, which were categorized as trisomy 21 (Down syndrome, DS). In CAVC with DS patients, the female to male ratio was 1.6:1 (24:15), and the rate of pulmonary hypertension (PH) was 41% (16/39). Additionally, 6 rare CNVs were identified in the SV patients (2.3%, 6/259), and none of them was trisomy 21.Conclusions: Our study identified 50 rare CNVs in 262 CAVC and 259 SV patients, representing the largest cohort of these two rare CHD types in Chinese population. The results provided strong correlation between CAVC and DS, which also showed sex difference and higher incidence of PH. The presence of rare CNVs suggests the etiology of complex CHD is incredibly diverse, and CHD candidate genes remain to be discovered.

scholarly journals Association of Copy Number Variations in Autism Spectrum Disorders: A Systematic Review

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Elif Funda Sener
Keyword(s):  
Autism Spectrum Disorders ◽  
Complex Traits ◽  
Copy Number ◽  
De Novo ◽  
Genome Structure ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Repetitive Behaviors ◽  
Wide Range ◽  
Spectrum Disorders

Autism spectrum disorders (ASDs) are characterized by language impairments, social deficits, and repetitive behaviors. The onset of symptoms occurs by the age of 3 and shows a lifelong persistence. Genetics plays a major role in the etiology of ASD. Except genetics, several potential risk factors (environmental factors and epigenetics) may contribute to ASD. Copy number variations (CNVs) are the most widespread structural variations in the human genome. These variations can alter the genome structure either by deletion or by duplication. CNVs can be de novo or inherited. Chromosomal rearrangements have been detected in 5–10% of the patients with ASD and recently copy number changes ranging from a few kilobases (kb) to several megabases (Mb) in size have been reported. Recent data have also revealed that submicroscopic CNVs can have a role in ASD, and de novo CNVs seem to be a more common risk factor in sporadic compared with inherited forms of ASD. CNVs are being implicated as a contributor to the pathophysiology of complex neurodevelopmental disorders and they can affect a wide range of human phenotypes including mental retardation (MR), autism, neuropsychiatric disorders, and susceptibility to other complex traits such as HIV, Crohn’s disease, and psoriasis. This review emphasizes the major CNVs reported to date in ASD.

scholarly journals Large mosaic copy number variations confer autism risk

2020 ◽  
Author(s):  
Maxwell A. Sherman ◽  
Rachel E. Rodin ◽  
Giulio Genovese ◽  
Caroline Dias ◽  
Alison R. Barton ◽  
...  
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Clinical Symptoms ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Chromosome 2 ◽  
Simons Simplex Collection ◽  
Post Mortem Brain ◽  
Significant Burden

AbstractAlthough germline de novo copy number variants are a known cause of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. Here, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 ASD probands and 5,500 unaffected siblings in the Simons Simplex Collection (SSC) and Simons Powering Autism Research for Knowledge (SPARK) cohorts. We detected 46 mCNVs in probands and 19 mCNVs in siblings ranging from 49 kb to 249 Mb and affecting 2.8-73.8% of cells. In both cohorts, probands carried a significant burden of large (>4 Mb) mCNVs (P = 0.043 and P = 6.6 × 10−3 in SSC and SPARK, respectively), which were present in a total of 25 probands but only 1 sibling (OR=11.4, 95% CI=1.5-84.2). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD. Event size positively correlated with severity of ASD symptoms (P = 0.016), and four probands exhibited clinical symptoms consistent with syndromes previously associated with genes or regions disrupted by their respective mosaic mutations. In analyses of post-mortem brain tissue from 60 additional probands, we further detected and experimentally validated two mCNVs including a complex 10.3 Mb duplication on chromosome 2. These results indicate that mosaic CNVs contribute a previously unexplained component of ASD risk.

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 Ανίχνευση υπομικροσκοπικών χρωμοσωμικών διαταραχών σε ασθενείς με αυτιστικές διαταραχές με την μέθοδο μικροσυστοιχιών συγκριτικού γενωμικού υβριδισμού array-CGH

2017 ◽  
Author(s):  
Βασίλης Οικονομάκης
Keyword(s):  
Copy Number ◽  
Array Cgh ◽  
De Novo ◽  
Copy Number Variations ◽  
Genomic Variants ◽  
Variants Of Unknown Significance ◽  
Unknown Significance

Οι Διαταραχές Αυτιστικού Φάσματος (ΔΑΦ) ή αυτισμός είναι μία ομάδα ετερογενών ισόβιων νευροαναπτυξιακών διαταραχών που συνήθως αναπτύσσονται κατά την παιδική ηλικία και χαρακτηρίζονται από δυσκολία στην επικοινωνία, τις κοινωνικές αλληλεπιδράσεις και από επαναλαμβανόμενη συμπεριφορά, μέσα σε ένα στενό εύρος ενδιαφερόντων. Ως ηλικία έναρξης των πρώτων συμπτωμάτων ορίζεται συνήθως εκείνη πριν από τα τρία έτη με τη διάγνωση των ΔΑΦ να βασίζεται σε κριτήρια συμπεριφοράς και στη λεπτομερή κλινική εξέταση και καταγραφή των συμπτωμάτων. Το 2012, οι πιο πρόσφατες εκτιμήσεις για τον επιπολασμό στις ΗΠΑ, τοποθετούν τη συχνότητα των ΔΑΦ στο γενικό πληθυσμό σε 1/68 παιδιά ηλικίας οκτώ ετών (1,5%). Οι ΔΑΦ ανήκουν στις λεγόμενες πολυπαραγοντικές διαταραχές για τις οποίες έχουν ενοχοποιηθεί γενετικοί, επιγενετικοί, μεταβολικοί, ορμονικοί, ανοσολογικοί, νευροανατομικοί, νευροφυσιολογικοί καθώς και γαστρεντερικοί παράγοντες καθώς και άλλες συστηματικές διαταραχές και συννοσηρότητες ως πιθανοί παθογενετικοί μηχανισμοί. Η γενετική συμβολή είναι καθοριστικής σημασίας στην αιτιοπαθογένεια του αυτισμού και στην παρούσα διατριβή περιγράφονται αναλυτικά τα διάφορα μοντέλα που έχουν προταθεί για να εξηγήσουν την αυξημένη συχνότητα του αυτισμού σε συγκεκριμένες οικογένειες, καθώς επίσης και οι κύριοι νευροβιολογικοί μηχανισμοί που οδηγούν στον συγκεκριμένο φαινότυπο .Η Χρωμοσωμική Ανάλυση Μικροσυστοιχιών (ΧΑΜ) θεωρείται πλέον ως πρώτη επιλογή διαγνωστικής δοκιμασίας για την διερεύνηση ιδιοπαθών περιπτώσεων ΔΑΦ, Αναπτυξιακών Διαταραχών (ΑΔ) και Νοητικής Υστέρησης (ΝΥ). Για την παρούσα εργασία χρησιμοποιήθηκαν μικροσυστοιχίες υψηλής διακριτικής ικανότητας για τον εντοπισμό χρωμοσωμικών περιοχών αλλαγής αντιγράφων (Copy Number Variations - CNVs) σε 195 ασθενείς ΔΑΦ ελληνικής καταγωγής (126 άρρενα, 69 θήλεα). Η ΧΑΜ είχε σαν αποτέλεσμα τον εντοπισμό 65 παθολογικών CNVs, χωρίς να ληφθούν υπόψιν οι πολυμορφικές αλλαγές αριθμού αντιγράφων (Copy Number Polymorphisms - CNPs), που αλληλεπικαλύπτονται με αλληλουχίες στην ηλεκτρονική βάση δεδομένων Database of Genomic Variants (DGV), σε 51/195 ασθενείς (26,1%). Ο έλεγχος γονεϊκών γονιδιωμάτων σε 20/51 ασθενείς αποκάλυψε ότι 15 CNVs ήταν de novo, 3 ήταν πατρικής προέλευσης ενώ 2 μητρικής.Η πλειοψηφία των 65 CNVs αφορούσε μικροελλείμματα (66.1%), από τα οποία 5 βρέθηκαν στο χρωμόσωμα Χ, ενώ οι μικροδιπλασιασμοί, 7 εκ των οποίων βρέθηκαν στο χρωμόσωμα Χ, ήταν σπανιότεροι, με συχνότητα 33.8%. Τα 51 από τα 65 CNVs που βρέθηκαν στο δείγμα ελέγχου έχουν μεγάλη διαγνωστική αξία και είναι σαφώς περιγεγραμμένα στη διεθνή βιβλιογραφία, ενώ 14 CNVs (8 μικροελλείμματα και 6 μικροδιπλασιασμοί) χαρακτηρίστηκαν ως αλλαγές άγνωστης κλινικής σημασίας (Variants of Unknown Significance - VOUS) και χρήζουν περαιτέρω διερεύνησης. Από τους 51 ασθενείς 39 έφεραν ένα παθολογικό CNV, 10 έφεραν δύο παθολογικά CNVs και δύο ασθενείς έφεραν τρία παθολογικά CNVs.Επιπρόσθετα, έγινε εκτίμηση της ΧΑΜ ως διαγνωστική δοκιμασία και διερευνήθηκε η κλινική της εγκυρότητα και χρησιμότητα.

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.

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