Modeling familial predictors of proband outcomes in neurogenetic disorders: initial application in XYY syndrome

Kathleen E Wilson, Ari M Fish, Catherine Mankiw, Anastasia Xenophontos, Allysa Warling, Ethan Whitman, Liv Clasen, Erin Torres, Jonathan Blumenthal, Armin Raznahan, Kathleen E Wilson, Ari M Fish, Catherine Mankiw, Anastasia Xenophontos, Allysa Warling, Ethan Whitman, Liv Clasen, Erin Torres, Jonathan Blumenthal, Armin Raznahan

Abstract

Background: Disorders of gene dosage can significantly increase risk for psychopathology, but outcomes vary greatly amongst carriers of any given chromosomal aneuploidy or sub-chromosomal copy number variation (CNV). One potential path to advance precision medicine for neurogenetic disorders is modeling penetrance in probands relative to observed phenotypes in their non-carrier relatives. Here, we seek to advance this general analytic framework by developing new methods in application to XYY syndrome-a sex chromosome aneuploidy that is known to increase risk for psychopathology.

Methods: We analyzed a range of cognitive and behavioral domains in XYY probands and their non-carrier family members (n = 58 families), including general cognitive ability (FSIQ), as well as continuous measures of traits related to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Proband and relative scores were compared using covariance, regression and cluster analysis. Comparisons were made both within and across traits.

Results: Proband scores were shifted away from family scores with effect sizes varying between 0.9 and 2.4 across traits. Only FSIQ and vocabulary scores showed a significant positive correlation between probands and their non-carrier relatives across families (R2 ~ 0.4). Variability in family FSIQ also cross-predicted variability in proband ASD trait severity. Cluster analysis across all trait-relative pairings revealed that variability in parental psychopathology was more weakly coupled to their XYY versus their euploid offspring.

Conclusions: We present a suite of generalizable methods for modeling variable penetrance in aneuploidy and CNV carriers using family data. These methods update estimates of phenotypic penetrance for XYY and suggest that the predictive utility of family data is likely to vary for different traits and different gene dosage disorders.

Trial registrations: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls." Date of registry: 01 October 1989.

Keywords: Copy number variants; Modeling penetrance; Neurogenetic disorders; Precision psychiatry; Sex chromosome aneuploidies.

Conflict of interest statement

All authors were or currently are employed by the National Institute of Mental Health (NIMH). The authors have no additional competing interests to declare.

Figures

Fig. 1
Fig. 1
Annotated sample plot for simple linear regression. The univariate regression framework predicts proband outcome as a function of the family score for that measure. The model provides an offset (the difference between average family and average proband scores) and compares the regression slope to a horizontal line (m = 0) and an identity line (m = 1). This plot is for visualization purposes only and does not include any data from the study
Fig. 2
Fig. 2
Proband to family univariate analysis. a Proband to Family FSIQ Scores. b Proband to Family Vocabulary Scaled Scores. c Proband to Family Matrix Reasoning Scaled Scores. d Proband to Family SRS-2 Social Awareness Scores. Full Scale Intelligence Quotient (FSIQ). Social Responsiveness Scale Second Edition (SRS-2)
Fig. 3
Fig. 3
Cluster analyses. All measures are z-scored, and IQ measures are inverted such that a higher IQ score signifies more impairment. a Family cognitive and behavioral phenotype correlation matrix organized by family member. b Hierarchical clustering tree based on unsupervised clustering algorithm and elbow of within cluster sum of squares T 4. c Family cognitive and behavioral phenotype correlation matrix reorganized by unsupervised clustering algorithm. Proband (Pb). Sibling (Sib). Parent (Par). Full Scale Intelligence Quotient (FSIQ). Social Responsiveness Scale Second Edition (SRS-2). SRS-2 Social Awareness (Social Awar). SRS-2 Social Cognition (Social Cog). SRS-2 Social Communication (Social Comm). SRS-2 Social Motivation (Social Mot). SRS-2 Restricted Interests and Repetitive Behaviors (SRS-2 RIRB). SRS-2 DSM-5 Social Communication and Interaction (SRS-2 SCI). ADHD Inattentive Symptoms (Inatt). ADHD Hyperactive-Impulsive Symptoms (Hyp/Imp)

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