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

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.

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

Psychological Medicine ◽

10.1017/s0033291719003210 ◽

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.

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Biological Overlap of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: Evidence From Copy Number Variants

Journal of the American Academy of Child & Adolescent Psychiatry ◽

10.1016/j.jaac.2014.03.004 ◽

2014 ◽

Vol 53 (7) ◽

pp. 761-770.e26 ◽

Cited By ~ 62

Author(s):

Joanna Martin ◽

Miriam Cooper ◽

Marian L. Hamshere ◽

Andrew Pocklington ◽

Stephen W. Scherer ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Copy Number ◽

Copy Number Variants ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Hyperactivity Disorder

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Autism spectrum disorder: unbroken mirror neurons; rare copy number variants

Autism Research ◽

10.1002/aur.149 ◽

2010 ◽

Vol 3 (4) ◽

pp. 196-197 ◽

Cited By ~ 1

Author(s):

Edwin H. Cook

Keyword(s):

Autism Spectrum Disorder ◽

Copy Number ◽

Mirror Neurons ◽

Copy Number Variants ◽

Autism Spectrum ◽

Spectrum Disorder

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

Acta Paediatrica ◽

10.1111/apa.12969 ◽

2015 ◽

Vol 104 (6) ◽

pp. 610-618 ◽

Cited By ~ 8

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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A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

npj Genomic Medicine ◽

10.1038/s41525-021-00254-0 ◽

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.

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