A Study from Turkey: Identification of Copy Number Variants in Children and Adolescents with Autism Spectrum Disorder

Abstract Recent studies suggest that copy number variations (CNVs) play a significant role in the aetiology of ASD. This study aims to investigate CNVs, which are thought to be an important factor in ASD etiology. In addition it was aimed to specify the clinical usefulness of chromosomal microarrays (CMA) in the examination of ASD patients in Turkish population. Of 47 children (60.34±25.60 months; 82.9% boys) with ASD were constructed the sample. The karyotype structure of all participants was found to be normal using conventional cytogenetic methods. DNA obtained from the venous blood samples of the participants was evaluated using SurePrint G3 ISCA V2 CGH 8x60K Array (Agilent Technologies Santa Clara, CA, USA). We have identified 8 CNVs, ranging in size from 55 kb to 6.5 Mb in 7 (5 boys) of 47 children with ASD of the 4 of 8 CNVs were classified as pathogenic, which were 9p24.3p24.2 deletion in 3 Mb size, 15q11-q13 duplication in 6.5 Mb size, 16p11.2 deletion in 598 kb size and 22q13.3 deletion in 55 kb size. According to results has been demonstrated that diagnostic yield of CMA in Turkish children with ASD was 8.5%. Our results indicate that CNVs contribute a part to the genetic aetiology of Turkish children with ASD. In accordance with the literature, these results emphasize the clinical importance of CMA to investigate the aetiology of ASD.

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Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders

Nature Communications ◽

10.1038/s41467-019-13380-2 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

L. D’Abate ◽

S. Walker ◽

R. K. C. Yuen ◽

K. Tammimies ◽

J. A. Buchanan ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

Copy Number ◽

Copy Number Variants ◽

Autism Spectrum ◽

Copy Number Variations ◽

Recurrence Prediction ◽

Common Genetic Variants ◽

Spectrum Disorders ◽

Atypical Development ◽

Research Consortium

AbstractIdentification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

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Large mosaic copy number variations confer autism risk

10.1101/2020.01.22.20017624 ◽

2020 ◽

Cited By ~ 1

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.

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Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder

Frontiers in Genetics ◽

10.3389/fgene.2018.00665 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 2

Author(s):

Yanjie Fan ◽

Xiujuan Du ◽

Xin Liu ◽

Lili Wang ◽

Fei Li ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Copy Number ◽

Autism Spectrum ◽

Copy Number Variations ◽

Spectrum Disorder ◽

Chinese Cohort

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Genotype-Phenotype correlation in Dravet Syndrome with SCN1A mutation increase efficiency of molecular diagnosis

Journal of Epilepsy and Clinical Neurophysiology ◽

10.1590/s1676-26492012000200009 ◽

2012 ◽

Vol 18 (2) ◽

pp. 60-62

Author(s):

MC Gonsales ◽

P Preto ◽

MA Montenegro ◽

MM Guerreiro ◽

I Lopes-Cendes

Keyword(s):

Protein Function ◽

Copy Number ◽

Mutation Screening ◽

Copy Number Variants ◽

Febrile Seizures ◽

Copy Number Variations ◽

Dravet Syndrome ◽

Missense Mutations ◽

The Impact ◽

Doose Syndrome

OBJECTIVES: The purpose of this study was to advance the knowledge on the clinical use of SCN1A testing for severe epilepsies within the spectrum of generalized epilepsy with febrile seizures plus by performing genetic screening in patients with Dravet and Doose syndromes and establishing genotype-phenotype correlations. METHODS: Mutation screening in SCN1A was performed in 15 patients with Dravet syndrome and 13 with Doose syndrome. Eight prediction algorithms were used to analyze the impact of the mutations in putative protein function. Furthermore, all SCN1A mutations previously published were compiled and analyzed. In addition, Multiplex Ligation-Dependent Probe Amplification (MLPA) technique was used to detect possible copy number variations within SCN1A. RESULTS: Twelve mutations were identified in patients with Dravet syndrome, while patients with Doose syndrome showed no mutations. Our results show that the most common type of mutation found is missense, and that they are mostly located in the pore region and the N- and C-terminal of the protein. No copy number variants in SCN1A were identified in our cohort. CONCLUSIONS: SCN1A testing is clinically useful for patients with Dravet syndrome, but not for those with Doose syndrome, since both syndromes do not seem to share the same genetic basis. Our results indicate that indeed missense mutations can cause severe phenotypes depending on its location and the type of amino-acid substitution. Moreover, our strategy for predicting deleterious effect of mutations using multiple computation algorithms was efficient for most of the mutations identified.

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The Role of Copy Number Variation in Psychiatric Disorders

Psychiatric Genetics ◽

10.1093/med/9780190221973.003.0006 ◽

2018 ◽

pp. 84-95

Author(s):

Elliott Rees ◽

George Kirov

Keyword(s):

Autism Spectrum Disorders ◽

Copy Number ◽

Selection Pressure ◽

Copy Number Variants ◽

Autism Spectrum ◽

High Odds ◽

Strong Selection ◽

Increase Risk ◽

Number Variation

Copy number variants (CNVs) are deletions, duplications, inversions, or translocations of large DNA segments. They can play a significant role in human disease. Thirteen CNVs have received strong statistical support for involvement in schizophrenia. They are all rare in cases (<1%), much rarer among controls, and have high odds ratios (ORs) for causing disease. The same CNVs also increase risk for autism spectrum disorders, developmental delay, and medical/physical comorbidities. The penetrance of these CNVs for any disorder is relatively high, ranging from 10% for 15q11.2 deletions to nearly 100% for deletions at 22q11.2. Strong selection pressure operates against carriers of these CNVs. Most of these are formed by non-allelic homologous recombination (NAHR), which leads to high mutation rates, thus maintaining the rates of these CNVs in the general population, despite the strong selection forces.

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Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder

Translational Psychiatry ◽

10.1038/s41398-019-0599-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 12

Author(s):

Olafur O. Gudmundsson ◽

G. Bragi Walters ◽

Andres Ingason ◽

Stefan Johansson ◽

Tetyana Zayats ◽

...

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Neurodevelopmental Disorders ◽

Copy Number ◽

Neurodevelopmental Disorder ◽

Copy Number Variant ◽

Pleiotropic Effect ◽

Autism Spectrum ◽

Copy Number Variations ◽

Hyperactivity Disorder

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5–BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 × 10−21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.

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A large data resource of genomic copy number variation across neurodevelopmental disorders

npj Genomic Medicine ◽

10.1038/s41525-019-0098-3 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 22

Author(s):

Mehdi Zarrei ◽

Christie L. Burton ◽

Worrawat Engchuan ◽

Edwin J. Young ◽

Edward J. Higginbotham ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Copy Number ◽

Population Control ◽

Large Data ◽

Autism Spectrum ◽

Copy Number Variations ◽

Genomic Disorder ◽

Rare Cnvs ◽

Data Resource ◽

Compulsive Disorder

Abstract Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

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