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. 2023 Jan;25(1):151-154.
doi: 10.1016/j.gim.2022.09.011. Epub 2022 Nov 6.

Phenotypic shift in copy number variants: Evidence in 16p11.2 duplication syndrome

Cora M Taylor  1 , Brenda M Finucane  2 , Andres Moreno-De-Luca  2 , Lauren K Walsh  2 , Christa Lese Martin  2 , David H Ledbetter  3
Affiliations

Phenotypic shift in copy number variants: Evidence in 16p11.2 duplication syndrome

Cora M Taylor et al. Genet Med. 2023 Jan.

Abstract

Purpose: Recurrent 16p11.2 duplications produce a wide range of clinical outcomes with varying effects on cognition and social functioning. Family-based studies of copy number variants (CNVs) have revealed significant contributions of genomic background on variable expressivity. In this study, we measured the phenotypic effect of 16p11.2 duplications and quantified the modulating effect of familial background on cognitive and social outcomes.

Methods: Genomic and clinical data were ascertained from 41 probands with a 16p11.2 duplication and their first-degree relatives. Paired comparisons were completed to determine the duplication's effect on expected vs actual performance on standardized tests of intelligence (IQ) and social functioning (Social Responsiveness Scale-2). Intraclass correlations between relatives and probands were also calculated.

Results: Cognitive and social functioning were significantly lower among individuals with 16p11.2 duplications than their CNV-negative relatives, whereas intraclass correlations between the groups remained high for full-scale IQ and Social Responsiveness Scale-2 scores.

Conclusion: The 16p11.2 duplication confers deleterious effects on cognition and social functioning, whereas familial background significantly influences phenotypic expression of these traits. Understanding variable expressivity in CNV disorders has implications for anticipatory clinical care, particularly for individuals who receive a genetic diagnosis at an early age, long before the full scope of manifestations becomes evident.

Keywords: Neurodevelopment; Neuropsychiatric conditions.

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Conflict of interest statement

Conflict of Interest D.H.L. has received compensation as a consultant to Natera, Inc and owns stock in the company and is a consultant to MyOme, Inc and has received stock in the company. All other authors declare no conflicts of interest.

Figures

Figure 1:
Figure 1:
Normative Distributions of Quantitative Traits in 16p11.2 Duplications and CNV-negative Relatives
See this image and copyright information in PMC

References

    1. Chung WK, Roberts TP, Sherr EH, Snyder LG, Spiro JE. 16p11.2 deletion syndrome. Curr Opin Genet Dev. 2021;68:49–56. doi:10.1016/j.gde.2021.01.011 - DOI - PMC - PubMed
    1. D’Angelo D, Lebon S, Chen Q, et al. Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities. JAMA Psychiatry. 2016;73(1):20–30. doi:10.1001/jamapsychiatry.2015.2123 - DOI - PMC - PubMed
    1. Moreno-De-Luca A, Evans DW, Boomer KB, et al. The role of parental cognitive, behavioral, and motor profiles in clinical variability in individuals with chromosome 16p11.2 deletions. JAMA Psychiatry. 2015;72(2):119–126. doi:10.1001/jamapsychiatry.2014.2147 - DOI - PubMed
    1. Oetjens MT, Kelly MA, Sturm AC, Martin CL, Ledbetter DH. Quantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders. Nat Commun. 2019;10(1):4897. doi:10.1038/s41467-019-12869-0 - DOI - PMC - PubMed
    1. Jacquemont S, Reymond A, Zufferey F, et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature. 2011;478(7367):97–102. doi:10.1038/nature10406 - DOI - PMC - PubMed

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