Cortical Organoids Model Early Brain Development Disrupted by 16p11.2 Copy Number Variants in Autism

AbstractReciprocal deletion and duplication of 16p11.2 region is the most common copy number variation (CNV) associated with Autism Spectrum Disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV has mirror-opposite effect on neuronal maturation, proliferation, and synapse number, in concordance with its effect on brain growth in humans. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with excess of neurons and depletion of neural progenitors observed in deletions, and mirror phenotypes in duplications. Transcriptomic and proteomic profiling revealed multiple dysregulated pathways, including defects in neuron migration. Inhibition of activity of the small GTPase RhoA rescued migration deficits. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.

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Cortical organoids model early brain development disrupted by 16p11.2 copy number variants in autism

Molecular Psychiatry ◽

10.1038/s41380-021-01243-6 ◽

2021 ◽

Cited By ~ 1

Author(s):

Jorge Urresti ◽

Pan Zhang ◽

Patricia Moran-Losada ◽

Nam-Kyung Yu ◽

Priscilla D. Negraes ◽

...

Keyword(s):

Copy Number ◽

Active Form ◽

Copy Number Variants ◽

Autism Spectrum ◽

Small Gtpase ◽

Neural Progenitors ◽

Proteomic Profiling ◽

Rhoa Activity ◽

Number Variation ◽

Early Neurogenesis

AbstractReciprocal deletion and duplication of the 16p11.2 region is the most common copy number variation (CNV) associated with autism spectrum disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV dosage affects neuronal maturation, proliferation, and synapse number, in addition to its effect on organoid size. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with a significant excess of neurons and depletion of neural progenitors observed in deletions. Transcriptomic and proteomic profiling revealed multiple pathways dysregulated by the 16p11.2 CNV, including neuron migration, actin cytoskeleton, ion channel activity, synaptic-related functions, and Wnt signaling. The level of the active form of small GTPase RhoA was increased in both, deletions and duplications. Inhibition of RhoA activity rescued migration deficits, but not neurite outgrowth. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.

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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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Association testing of copy number variants in schizophrenia and autism spectrum disorders

Journal of Neurodevelopmental Disorders ◽

10.1186/1866-1955-4-15 ◽

2012 ◽

Vol 4 (1) ◽

Cited By ~ 46

Author(s):

Bernard J Crespi ◽

Helen J Crofts

Keyword(s):

Autism Spectrum Disorders ◽

Copy Number ◽

Copy Number Variants ◽

Autism Spectrum ◽

Association Testing ◽

Spectrum Disorders

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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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