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

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.

Modeling Familial Predictors of Proband Outcomes in Neurogenetic Disorders: Initial Application in XYY Syndrome

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 suggests 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: 01/10/1989.

Modeling Familial Predictors of Proband Outcomes in Neurogenetic Disorders: Initial Application in XYY Syndrome

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 suggests 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: 01/10/1989.

The Level of Free Fetal DNA as Precise Noninvasive Marker for Chromosomal Aneuploidies: First Results from BALTIC Region

Background and objectives: Noninvasive prenatal testing (NIPT), which has been introduced clinically since 2011, uses the circulating cell-free fetal DNA in the maternal blood to evaluate the risk of a chromosomal anomaly. The aim of this study was to examine the effectiveness of NIPT using a single nucleotide polymorphism method. Materials and Methods: A retrospective study was conducted between 2013 and 2019. The Natera Panorama test was used to analyze the risk of trisomies 21, 18, 13, X monosomy, trisomy, and other sex chromosome abnormalities. A positive result of NIPT for aneuploidy was confirmed by invasive testing. Results: 850 women with a singleton pregnancy participated in the study. The median fetal fraction was 9.0%. The fetal fraction was lower in the no-call group (3.1%) compared with the group that received a call (9.1%) (p < 0.001). A positive correlation was determined between the gestational age and the fetal fraction (r = 0.180, p < 0.001). The overall positive predictive value (PPV) of NIPT for trisomy 21 (n = 9), trisomy 18 (n = 3) and XYY syndrome (n = 1) was 100%. Conclusions: The results of present study showed 100% PPV effectiveness of NIPT Panorama test detecting trisomies of 21 and 18 chromosomes, as well as XYY syndrome in the studied cohort. Therefore, NIPT due to its high PPV, significantly reduces the need for invasive testing, thereby reducing the risk of miscarriage and stillbirth.

Parental willing to take invasive diagnosis after Expanded Noninvasive Prenatal Testing (expanded NIPT) in a cohort of 24768 cases

BackgroundThe main aims of the study were to investigate the performance of expanded noninvasive prenatal test (expanded NIPT) in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RATs) and copy number variations (CNVs) and parental willing to taking invasive prenatal diagnosis after expanded NIPT in China.ResultsOf the 24,736 cases, successful follow-up was conducted in 92.2% (411/446) cases. The sensitivity of expanded NIPT test was 98.61%,90.91% and 100% and specificity was 99.91%,99.95% and 99.87% for the detection of trisomies 21, 18 and 13 respectively. Expanded NIPT detected 45, XO, 47, XXX, 47, XXY, XYY syndrome, RATs and CNVs with positive predictive values of 57.39%, 19.61%, 75%, 79.41%, 77.78%, 10% and 56.25% respectively. The women carrying fetuses with T21/T18/T13 underwent invasive prenatal diagnosis and terminated their pregnancies at higher rates than those positive for SCAs, RATs and CNVs.ConclusionsOur study demonstrates that the expanded NIPT detects fetal trisomies 21,18 and 13 with high sensitivity and specificity. The accuracy of detecting SCAs, RATs and CNVs is still relatively poor and needed to be improved. With a positive expanded NIPT result, the women at high risk for common trisomies are more willing to take invasive prenatal diagnosis and terminate their pregnancies.* the first two authors contribute equally to this study.

47, XYY Syndrome and its Association with Male Infertility: Case Report

47, XYY syndrome is one of the most common sex chromosomal anomaly found in humans after Klinfelter syndrome (47, XXY). It is frequently associated with infertility in males. This syndrome has an extra Y chromosome (XYY) due to non-disjunction of the Y chromosome in paternal meiotic II. The presence of an extra Y chromosome causes hormonal disbalance in the gonads that responsible for abnormal function of human chorionic gonadotropin. In our case of infertile men with severe oligozoospermia that also confirm by conventional cytogenetic analysis of the peripheral blood lymphocytes revealed the constitutional karyotype of 47, XYY. This report is likely to be helpful for counselling and early management of such infertile males.