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Duplication Versus Deletion Through the Lens of 15q13.3: Clinical and Research Implications of Studying Copy Number Variants Associated with Neuropsychiatric Disorders in Induced Pluripotent Stem Cell-Derived Neurons

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Abstract

Copy number variants (CNVs), involving duplication or deletion of susceptible intervals of the human genome, underlie a range of neurodevelopmental and neuropsychiatric disorders. As accessible in vivo animal models of these disorders often cannot be generated, induced pluripotent stem cell (iPSC) models derived from patients carrying these CNVs can reveal alterations of brain development and neuronal function that contribute to these disorders. CNVs involving deletion versus duplication of a particular genomic interval often result both in distinct clinical phenotypes and in differential phenotypic penetrance. This review initially focuses on CNVs at 15q13.3, which contribute to autism spectrum disorder, attention deficit/hyperactivity disorder, and schizophrenia. Like most CNVs, deletions at 15q13.3 usually cause severe clinical phenotypes, while duplications instead result in highly variable penetrance, with some carriers exhibiting no clinical phenotype. Here, we describe cellular and molecular phenotypes seen in iPSC-derived neuronal models of 15q13.3 duplication and deletion, which may contribute both to the differential clinical consequences and phenotypic penetrance. We then relate this work to many other CNVs involving both duplication and deletion, summarizing findings from iPSC studies and their relationship to clinical phenotype. Together, this work highlights how CNVs involving duplication versus deletion can differentially alter neural development and function to contribute to neuropsychiatric disorders. iPSC-derived neuronal models of these disorders can be used both to understand the underlying neurodevelopmental alterations and to develop pharmacological or molecular approaches for phenotypic rescue that may suggest leads for patient intervention.

Graphical Abstract

Top: Deletion versus duplication of the same genomic interval results in different clinical phenotypes and degrees of phenotypic penetrance. Example findings schematized. Bottom: iPSC-derived neurons from individuals with these CNVs involving deletion versus duplication likewise often differential phenotypes (increases or decreases) in the categories shown. Figure created with BioRender.com.

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Data Availability

N/A; no datasets were generated or analyzed during the current study.

Code Availability

N/A

Abbreviations

ASD :

Autism spectrum disorder

iPSCs :

Induced pluripotent stem cells

CNV :

Copy number variant

CHRNA7 :

α-7 Nicotinic acetylcholine receptor subunit

ID :

Intellectual disability

ADHD :

Attention deficit and hyperactivity disorder

SZ :

Schizophrenia

BD :

Bipolar disorder

EPSC :

Excitatory post synaptic current

IPSC :

Inhibitory post synaptic current

ER :

Endoplasmic reticulum

GABA :

Gamma-aminobutyric acid

NPC :

Neural progenitor cell

UM :

Unaffected mother

AP :

Affected proband

UC-M :

Unrelated control-male

UC-F :

Unrelated control-female

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Funding

This work was supported by NIH grants R01NS114551 and R01MH124808 (KLK), and by NIH P50HD103525 to John N Constantino and Christina Gurnett (KLK serves as a project PI for the Model Systems Core).

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  1. Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, 63110, USA

    Irene Antony, Mishka Narasimhan, Renata Shen, Ramachandran Prakasam, Komal Kaushik, Gareth Chapman & Kristen L. Kroll

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  1. Irene Antony
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All authors contributed to the study conception and design, IA and GC outlined the manuscript, IA, GC, RP, and MN gathered the literature and sources and IA, MN, RS, RP, KK, and KLK drafted and edited the manuscript. All authors approved the final manuscript.

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Correspondence to Kristen L. Kroll.

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Irene Antony, Mishka Narasimhan, Renata Shen, Ramachandran Prakasam these authors contributed equally to this work.

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Antony, I., Narasimhan, M., Shen, R. et al. Duplication Versus Deletion Through the Lens of 15q13.3: Clinical and Research Implications of Studying Copy Number Variants Associated with Neuropsychiatric Disorders in Induced Pluripotent Stem Cell-Derived Neurons. Stem Cell Rev and Rep 19, 639–650 (2023). https://doi.org/10.1007/s12015-022-10475-0

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