Putatively benign copy number variants in subjects with idiopathic autism spectrum disorder and/or intellectual disability

2008 ◽  
Vol 123 (1-4) ◽  
pp. 79-87 ◽  
Author(s):  
Y. Qiao ◽  
C. Harvard ◽  
N. Riendeau ◽  
C. Fawcett ◽  
X. Liu ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Copy Number ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals Copy Number Variants in Extended Autism Spectrum Disorder Families Reveal Candidates Potentially Involved in Autism Risk

PLoS ONE ◽  
2011 ◽  
Vol 6 (10) ◽  
pp. e26049 ◽  
Author(s):  
Daria Salyakina ◽  
Holly N. Cukier ◽  
Joycelyn M. Lee ◽  
Stephanie Sacharow ◽  
Laura D. Nations ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Copy Number ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals Copy-Number Variants in The Contactin-5 Gene Are a Potential Risk Factor for Autism Spectrum Disorder

2021 ◽  
Author(s):  
Zoe Schmilovich ◽  
Guillaume Huguet ◽  
Qin He ◽  
Amélie Musa-Johnson ◽  
Elise Douard ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Copy Number ◽  
Statistical Power ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variants ◽  
Autistic Traits ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Small Scale ◽  
Phenotypic Data

Abstract BackgroundContactin-5 (CNTN5) is a candidate risk gene for autism spectrum disorder (ASD), yet previous attempts to associate copy-number variants (CNVs) encompassing CNTN5 with ASD-susceptibility were limited by insufficient statistical power. Here, we aim to clarify the putative association between CNTN5 CNVs and ASD-risk using large samples. MethodsFirst, we calculated the prevalence and transmission of CNTN5 CNVs in ASD across three ASD cohorts (SSC, MSSNG, and SPARK), the cases reported in the Mercati et al. study, and the BBGRE database (n = 16,607). Second, we modelled their transmission in children with ASD compared to their unaffected siblings. Third, we assessed their frequency in cases with ASD compared to unselected population controls (n = 24,898) and replicated the findings in UK Biobank (UKBB), an independent general population cohort (n = 459,855). Finally, we evaluated the clinical impact of CNTN5 CNVs by assessing their enrichment in a broad neurodevelopmental disorder (NDD) cohort, and the clinical profile of CNTN5 CNV carriers in the DECIPHER database.ResultsThe prevalence of CNTN5 exonic deletions and duplications was stable across ASD and across unselected cohorts (0.042% and 0.020%, respectively). We found a significant enrichment of intronic CNTN5 deletions CNVs in ASD compared to unselected controls (0.175% and 0.004%, respectively). CNVs in most cases with ASD (29 out of 30, 96.7%) were inherited. Parents transmitted the variants to their affected and unaffected children with the same frequency. No differences in exonic CNTN5 CNVs enrichment between cases with ASD compared to individuals with NDDs was observed. LimitationsThe lack of phenotypic data available for unaffected family members of probands with ASD limits the potential to assess whether CNTN5 CNVs segregate with other neuropsychiatric or sub-threshold autistic traits. Different genotyping or sequencing technologies may affect the differences in CNTN5 CNV prevalence across cohorts.ConclusionCNTN5 CNVs are rare inherited ASD susceptibility variants. They may also confer risk for other neuropsychiatric disorders. We offer a powerful framework to investigate candidate susceptibility variants that may not be detected through small-scale approaches. This approach may reveal more intermediate effect-size variants that are implicated in the etiology of ASD.

scholarly journals Coordination difficulties, IQ and psychopathology in children with high-risk copy number variants

2019 ◽  
pp. 1-10
Author(s):  
Adam C. Cunningham ◽  
Jeremy Hall ◽  
Michael J. Owen ◽  
Marianne B. M. van den Bree
Keyword(s):  
Autism Spectrum Disorder ◽  
Copy Number ◽  
Motor Coordination ◽  
Developmental Coordination Disorder ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Verbal Iq ◽  
Coordination Ability ◽  
Coordination Disorder

Abstract Background The prevalence and impact of motor coordination difficulties in children with copy number variants associated with neurodevelopmental disorders (ND-CNVs) remains unknown. This study aims to advance understanding of motor coordination difficulties in children with ND-CNVs and establish relationships between intelligence quotient (IQ) and psychopathology. Methods 169 children with an ND-CNV (67% male, median age = 8.88 years, range 6.02–14.81) and 72 closest-in-age unaffected siblings (controls; 55% male, median age = 10.41 years, s.d. = 3.04, range 5.89–14.75) were assessed with the Developmental Coordination Disorder Questionnaire, alongside psychiatric interviews and standardised assessments of IQ. Results The children with ND-CNVs had poorer coordination ability (b = 28.98, p < 0.001) and 91% of children with an ND-CNV screened positive for suspected developmental coordination disorder, compared to 19% of controls (OR = 42.53, p < 0.001). There was no difference in coordination ability between ND-CNV genotypes (F = 1.47, p = 0.184). Poorer coordination in children with ND-CNV was associated with more attention deficit hyperactivity disorder (ADHD) (β = −0.18, p = 0.021) and autism spectrum disorder trait (β = −0.46, p < 0.001) symptoms, along with lower full-scale (ß = 0.21, p = 0.011), performance (β = −0.20, p = 0.015) and verbal IQ (β = 0.17, p = 0.036). Mediation analysis indicated that coordination ability was a full mediator of anxiety symptoms (69% mediated, p = 0.012), and a partial mediator of ADHD (51%, p = 0.001) and autism spectrum disorder trait symptoms (66%, p < 0.001) as well as full scale IQ (40%, p = 0.002), performance IQ (40%, p = 0.005) and verbal IQ (38%, p = 0.006) scores. Conclusions The findings indicate that poor motor coordination is highly prevalent and closely linked to risk of mental health disorder and lower intellectual function in children with ND-CNVs. Future research should explore whether early interventions for poor coordination ability could ameliorate neurodevelopmental risk.

scholarly journals Association of new deletion/duplication region at chromosome 1p21 with intellectual disability, severe speech deficit and autism spectrum disorder-like behavior: an all-in approach to solving the DPYD enigma

2015 ◽  
Vol 6 (1) ◽  
pp. 59-86 ◽  
Author(s):  
Lukrecija Brečević ◽  
Martina Rinčić ◽  
Željka Krsnik ◽  
Goran Sedmak ◽  
Ahmed B. Hamid ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Copy Number ◽  
Dihydropyrimidine Dehydrogenase ◽  
Copy Number Gain ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Severe Toxicity ◽  
Microdeletion Syndrome ◽  
Major Player

AbstractWe describe an as yet unreported neocentric small supernumerary marker chromosome (sSMC) derived from chromosome 1p21.3p21.2. It was present in 80% of the lymphocytes in a male patient with intellectual disability, severe speech deficit, mild dysmorphic features, and hyperactivity with elements of autism spectrum disorder (ASD). Several important neurodevelopmental genes are affected by the 3.56 Mb copy number gain of 1p21.3p21.2, which may be considered reciprocal in gene content to the recently recognized 1p21.3 microdeletion syndrome. Both 1p21.3 deletions and the presented duplication display overlapping symptoms, fitting the same disorder category. Contribution of coding and non-coding genes to the phenotype is discussed in the light of cellular and intercellular homeostasis disequilibrium. In line with this the presented 1p21.3p21.2 copy number gain correlated to 1p21.3 microdeletion syndrome verifies the hypothesis of a cumulative effect of the number of deregulated genes - homeostasis disequilibrium leading to overlapping phenotypes between microdeletion and microduplication syndromes. Although miR-137 appears to be the major player in the 1p21.3p21.2 region, deregulation of the DPYD (dihydropyrimidine dehydrogenase) gene may potentially affect neighboring genes underlying the overlapping symptoms present in both the copy number loss and copy number gain of 1p21. Namely, the all-in approach revealed that DPYD is a complex gene whose expression is epigenetically regulated by long non-coding RNAs (lncRNAs) within the locus. Furthermore, the long interspersed nuclear element-1 (LINE-1) L1MC1 transposon inserted in DPYD intronic transcript 1 (DPYD-IT1) lncRNA with its parasites, TcMAR-Tigger5b and pair of Alu repeats appears to be the “weakest link” within the DPYD gene liable to break. Identification of the precise mechanism through which DPYD is epigenetically regulated, and underlying reasons why exactly the break (FRA1E) happens, will consequently pave the way toward preventing severe toxicity to the antineoplastic drug 5-fluorouracil (5-FU) and development of the causative therapy for the dihydropyrimidine dehydrogenase deficiency.

scholarly journals A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Livia O. Loureiro ◽  
Jennifer L. Howe ◽  
Miriam S. Reuter ◽  
Alana Iaboni ◽  
Kristina Calli ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Copy Number ◽  
De Novo ◽  
Sequence Data ◽  
Copy Number Variants ◽  
Somatic Mosaicism ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Variable Expression ◽  
Genomic Location

AbstractAutism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention.

Rare copy number variants are common in young children with autism spectrum disorder

2015 ◽  
Vol 104 (6) ◽  
pp. 610-618 ◽  
Author(s):  
Mats Anders Eriksson ◽  
Agne Liedén ◽  
Joakim Westerlund ◽  
Anna Bremer ◽  
Josephine Wincent ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Young Children ◽  
Copy Number ◽  
Copy Number Variants ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Young Children With Autism
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