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

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.govNCT00001246, “89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls.” Date of registry: 01 October 1989.

Patterns of Psychopathology and Cognition in Sex Chromosome Aneuploidy

“…Whereas the sex chromosome trisomies (XXY, XYY and XXX syndromes) are all associated with a ~ 10 point reduction in full scale IQ on average (slightly larger decrements for verbal as compared to performance IQ), reported mean IQs are typically lower in XXYY syndrome [8,19,20,30,31]. However, there is marked interindividual variability in IQ within all SCA groups [32][33][34], and it remains unclear how this is related to the co-occurring interindividual variation that has been described for psychopathology. Work in non-SCA groups suggests there can be complex correlations between clinical variation in IQ and psychopathology [35][36][37][38][39][40][41][42][43][44][45], but the few studies addressing this question in SCA have focused on individual domains of psychopathology [8], prompting the clinically important question of whether some psychiatric features are more strongly coupled to cognitive ability than others in SCA.…”

Understanding the phenotypic spectrum and family experiences of XYY syndrome: Important considerations for genetic counseling

“…Future work should also aim to distinguish possible biological and familial predictors of phenotypic variability. For example, multiple linear regression models have shown that individuals with XYY and their family members are correlated on certain traits, such as IQ, vocabulary, and social awareness (Wilson et al 2021 ). Efforts to understand the clinical utility of these models in the genetic counseling setting will be useful in providing anticipatory guidance for families.…”

A familial modeling framework for advancing precision medicine in neuropsychiatric disorders: A study in children with RASopathies

“…All participants were free from MRI contraindications. We estimated power based on previous work demonstrating a correlation between parent and child IQ in XYY syndrome (r=0.63)[34]. Using a more conservative r value of 0.50, the estimated power to detect an association between parent and child IQ for a cohort of 53 families is 0.98.…”