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Jay N Giedd - One of the best experts on this subject based on the ideXlab platform.
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mapping the stability of human brain asymmetry across five Sex Chromosome Aneuploidies
The Journal of Neuroscience, 2015Co-Authors: Amy Lin, Liv S Clasen, Jay N Giedd, Nancy Raitano Lee, Gregory L Wallace, Francois Lalonde, Jonathan Blumenthal, Armin RaznahanAbstract:The human brain displays stereotyped and early emerging patterns of cortical asymmetry in health. It is unclear if these asymmetries are highly sensitive to genetic and environmental variation or fundamental features of the brain that can survive severe developmental perturbations. To address this question, we mapped cortical thickness (CT) asymmetry in a group of genetically defined disorders known to impact CT development. Participants included 137 youth with one of five Sex-Chromosome Aneuploidies [SCAs; XXX (n = 28), XXY (n = 58), XYY (n = 26), XXYY (n = 20), and XXXXY (n = 5)], and 169 age-matched typically developing controls (80 female). In controls, we replicated previously reported rightward inferior frontal and leftward lateral parietal CT asymmetry. These opposing frontoparietal CT asymmetries were broadly preserved in all five SCA groups. However, we also detected foci of shifting CT asymmetry with aneuploidy, which fell almost exclusively within regions of significant CT asymmetry in controls. Specifically, X-Chromosome aneuploidy accentuated normative rightward inferior frontal asymmetries, while Y-Chromosome aneuploidy reversed normative rightward medial prefrontal and lateral temporal asymmetries. These findings indicate that (1) the stereotyped normative pattern of opposing frontoparietal CT asymmetry arises from developmental mechanisms that can withstand gross chromosomal aneuploidy and (2) X and Y Chromosomes can exert focal, nonoverlapping and directionally opposed influences on CT asymmetry within cortical regions of significant asymmetry in health. Our study attests to the resilience of developmental mechanisms that support the global patterning of CT asymmetry in humans, and motivates future research into the molecular bases and functional consequences of Sex Chromosome dosage effects on CT asymmetry.
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effects of Sex Chromosome dosage on corpus callosum morphology in supernumerary Sex Chromosome Aneuploidies
Biology of Sex Differences, 2014Co-Authors: Benjamin Wade, Jonathan D Blumenthal, Shantanu H Joshi, Martin Reuter, Arthur W Toga, Paul M Thompson, Jay N GieddAbstract:Background Supernumerary Sex Chromosome Aneuploidies (sSCA) are characterized by the presence of one or more additional Sex Chromosomes in an individual’s karyotype; they affect around 1 in 400 individuals. Although there is high variability, each sSCA subtype has a characteristic set of cognitive and physical phenotypes. Here, we investigated the differences in the morphometry of the human corpus callosum (CC) between Sex-matched controls 46,XY (N =99), 46,XX (N =93), and six unique sSCA karyotypes: 47,XYY (N =29), 47,XXY (N =58), 48,XXYY (N =20), 47,XXX (N =30), 48,XXXY (N =5), and 49,XXXXY (N =6).
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effects of Sex Chromosome dosage on corpus callosum morphology in supernumerary Sex Chromosome Aneuploidies
Biology of Sex Differences, 2014Co-Authors: Benjamin Wade, Jonathan D Blumenthal, Shantanu H Joshi, Martin Reuter, Arthur W Toga, Paul M Thompson, Jay N GieddAbstract:Supernumerary Sex Chromosome Aneuploidies (sSCA) are characterized by the presence of one or more additional Sex Chromosomes in an individual’s karyotype; they affect around 1 in 400 individuals. Although there is high variability, each sSCA subtype has a characteristic set of cognitive and physical phenotypes. Here, we investigated the differences in the morphometry of the human corpus callosum (CC) between Sex-matched controls 46,XY (N =99), 46,XX (N =93), and six unique sSCA karyotypes: 47,XYY (N =29), 47,XXY (N =58), 48,XXYY (N =20), 47,XXX (N =30), 48,XXXY (N =5), and 49,XXXXY (N =6). We investigated CC morphometry using local and global area, local curvature of the CC boundary, and between-landmark distance analysis (BLDA). We hypothesized that CC morphometry would vary differentially along a proposed spectrum of Y:X Chromosome ratio with supernumerary Y karyotypes having the largest CC areas and supernumerary X karyotypes having significantly smaller CC areas. To investigate this, we defined an sSCA spectrum based on a descending Y:X karyotype ratio: 47,XYY, 46,XY, 48,XXYY, 47,XXY, 48,XXXY, 49,XXXXY, 46,XX, 47,XXX. We similarly explored the effects of both X and Y Chromosome numbers within Sex. Results of shape-based metrics were analyzed using permutation tests consisting of 5,000 iterations. Several subregional areas, local curvature, and BLDs differed between groups. Moderate associations were found between area and curvature in relation to the spectrum and X and Y Chromosome counts. BLD was strongly associated with X Chromosome count in both male and female groups. Our results suggest that X- and Y-linked genes have differential effects on CC morphometry. To our knowledge, this is the first study to compare CC morphometry across these extremely rare groups.
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dosage effects of x and y Chromosomes on language and social functioning in children with supernumerary Sex Chromosome Aneuploidies implications for idiopathic language impairment and autism spectrum disorders
Journal of Child Psychology and Psychiatry, 2012Co-Authors: Nancy Raitano Lee, Liv S Clasen, Katherine C Lopez, Elizabeth I Adeyemi, Gregory L Wallace, Jonathan Blumenthal, Jay N GieddAbstract:Supernumerary Sex Chromosome Aneuploidies (referred to here as X/Y-Aneuploidies), the presence of extra X- and/or Y-Chromosomes, occur at a collective rate of ~1/475 births (Nielsen & Wohlert, 1990). Sex Chromosome trisomies (e.g., XXX, XXY, XYY) occur most frequently, each with rates of ~1/900 births, while tetra- and pentasomies (e.g., XXXX, XXXXX, XXXY, XXXXY) are considerably rarer, each with rates of ~1/85,000 births or fewer (Linden, Bender, & Robinson, 1995). There is longstanding evidence that children with X/Y-Aneuploidies have language-learning difficulties. However, only recently, attention also has been drawn to social difficulties, including autism spectrum disorder (ASD) symptomatology, in these groups (for reviews, see Leggett, Jacobs, Nation, Scerif, & Bishop, 2010; Lee, Lopez, Adeyemi, & Giedd, 2011). Given the close connection between idiopathic language impairments and ASDs and the fact no prior studies have examined language and/or social functioning in children with the X/Y tri-, tetra-, and pentasomies, the current study sought to examine both of these domains of functioning in a sample of children with XXX, XXXX, XXXXX, XYY, XXY, XXXY, and XXXXY and typically developing (TD) controls. In particular, we aimed to evaluate dosage effects of X- and Y-Chromosomes on language and social functioning in order to shed light not only on the nature of language and social difficulties in children with X/Y Aneuploidies, but also on the possible contributions of the X- and Y-Chromosomes to idiopathic language impairments and ASDs. Prospective newborn screening studies of X/Y-Aneuploidies (Walzer, Bashir, & Silbert, 1990; Ratcliffe et al., 1982, Bender et al., 1983; Netley & Rovet, 1982) and more recent reports (Bishop et al., 2011; Ross, Zeger, Kushner, Zinn, & Roeltgen, 2009) have noted increased rates of language-based learning disorders, including speech, semantic and syntactic deficits (which we refer to as ‘structural language’ or non-social language deficits) and depressed Verbal IQ scores in XXY and XXX. While these children often have lower nonverbal IQ scores than siblings, significant nonverbal learning difficulties are not commonly reported (Bender, Linden, & Robinson, 1991). For males with an additional Y-Chromosome (XYY), cognitive findings are inconsistent. Some prospective studies reported about a one standard deviation decrease in general cognitive functioning (Ratcliffe et al., 1982; Walzer et al., 1990). However, when data were pooled across early studies, no significant depression in overall cognitive abilities was found (Netley, 1986). Nevertheless, more recent research suggests that at a minimum, males with XYY have depressed verbal cognitive and structural language skills relative to TD peers (Bishop et al., 2011; Ross et al., 2009). Research on children with X-Chromosome tetra- and pentasomies (XXXX, XXXXX, XXXY, XXXXY) suggests decreases in verbal and nonverbal intellectual abilities with each additional X-Chromosome (Linden et al., 1995), such that many of these individuals have cognitive abilities in the borderline to intellectually disabled range (Visootsak, Rosner, Dykens, Tartaglia, & Graham, 2007; though Gropman et al., 2010 suggests that nonverbal cognition is relatively preserved in XXXXY despite profound language deficits). Furthermore, studies suggest significant structural language impairments in these groups (Visootsak et al., 2007), including severe dyspraxia resulting in limited to no speech in XXXXY (Gropman et al., 2010). In summary, there appears to be strong evidence for structural language impairments in X/Y-Aneuploidies. However, less is known about pragmatic or more social aspects of language, including discourse, understanding of metaphor and humor, and nonverbal communication. The few studies that have been completed converge in implicating pragmatic language difficulties in X/Y trisomies using standardized (Ross et al., 2009) and experimental cognitive tasks (van Rijn et al., 2007) as well as parent report (Bishop et al., 2011). However, no study has examined pragmatic language skills in X/Y tetra- and pentasomies, or pragmatic language vis-a-vis structural language functioning in any X/Y-aneuploidy. Even less is known about the social phenotype associated with X/Y-Aneuploidies. Recent studies suggest that the addition of one X-Chromosome in males (XXY) is associated with heightened rates of ASDs and social-cognitive impairments (Bishop et al., 2011; Bruining, Swaab, Kas, & van Engeland, 2009; van Rijn, Swaab, Aleman, & Kahn, 2006). In contrast, reports of females with XXX and males with XXXY and XXXXY are not indicative of increased ASD risk (Bishop et al., 2011; Visootsak et al., 2007). Reports of males with XYY indicate that an additional Y-Chromosome may be associated with social difficulties, as these males appear to have increased rates of ASDs and ASD symptomatology (Bishop et al., 2011; Geerts, Steyaert, & Fryns, 2003). Thus, the current research sought to examine verbal and nonverbal intellectual skills, structural and pragmatic language abilities, and ASD symptomatology in a large sample of children with Sex Chromosome tri-, tetra-, and pentasomies and TD controls in order to examine X- and Y-Chromosome dosage effects on these phenotypes. Unlike previous studies investigating genotype-specific profiles, we focused on quantity of supernumerary Sex Chromosomes. Therefore, we collapsed across genotypes (e.g., +0X=XX, XY; +1X=XXX, XXY), and in the case of tetra- and pentasomies, limited sample size necessitated combining these groups (i.e., +2/3X=XXXX, XXXXX, XXXY, XXXXY; consistent with prior work by Visootsak et al., 2007) in order to answer study questions regarding X and Y dosage effects. We predict that: 1- Increased X- and Y-Chromosome number will be associated with increased intellectual impairments with a discrepantly stronger impact on verbal relative to nonverbal intelligence. 2-Supernumerary X- and Y-Chromosomes will be associated with impairments in both structural and pragmatic language; however, a supernumerary Y-Chromosome will be associated with more pronounced pragmatic than structural language deficits. 3-Elevated ASD symptomatology will be associated with X/Y-aneuploidy, but supernumerary X-Chromosome dosage effects will not be present.
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Sex Chromosome Aneuploidies a window for examining the effects of the x and y Chromosomes on speech language and social development
International review of research in developmental disabilities, 2011Co-Authors: Nancy Raitano Lee, Katherine C Lopez, Elizabeth I Adeyemi, Jay N GieddAbstract:Abstract In this chapter, the existing literature on speech, language, and social development in children with Sex Chromosome Aneuploidies (SCAs) is reviewed. Given the scarcity of studies of young children with SCAs, the topic of this volume, studies of children of all ages as well as some studies of adults are summarized in order to begin to describe the developmental unfolding of the speech, language, and social phenotypes associated with these conditions. A particular emphasis is placed on (a) hypothesized dosage effects of differing numbers of X and Y Chromosomes on these phenotypes, and (b) the importance of examining both speech/language and social development in concert, given the close and bidirectional relations between these domains of functioning in typical and atypical development.
K H Nicolaides - One of the best experts on this subject based on the ideXlab platform.
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analysis of cell free dna in maternal blood in screening for fetal Aneuploidies updated meta analysis
Ultrasound in Obstetrics & Gynecology, 2015Co-Authors: M M Gil, Ranjit Akolekar, Maria Soledad Quezada, Rocio Revello, K H NicolaidesAbstract:Objective To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and Sex Chromosome Aneuploidies. Methods Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for Aneuploidies between January 2011, when the first such study was published, and 4 January 2015. Results In total, 37 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for Aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. Weighted pooled detection rates (DR) and false-positive rates (FPR) in singleton pregnancies were 99.2% (95% CI, 98.5–99.6%) and 0.09% (95% CI, 0.05–0.14%), respectively, for trisomy 21, 96.3% (95% CI, 94.3–97.9%) and 0.13% (95% CI, 0.07–0.20) for trisomy 18, 91.0% (95% CI, 85.0–95.6%) and 0.13% (95% CI, 0.05–0.26%) for trisomy 13, 90.3% (95% CI, 85.7–94.2%) and 0.23% (95% CI, 0.14–0.34%) for monosomy X and 93.0% (95% CI, 85.8–97.8%) and 0.14% (95% CI, 0.06–0.24%) for Sex Chromosome Aneuploidies other than monosomy X. For twin pregnancies, the DR for trisomy 21 was 93.7% (95% CI, 83.6–99.2%) and the FPR was 0.23% (95% CI, 0.00–0.92%). Conclusion Screening for trisomy 21 by analysis of cfDNA in maternal blood is superior to that of all other traditional methods of screening, with higher DR and lower FPR. The performance of screening for trisomies 18 and 13 and Sex Chromosome Aneuploidies is considerably worse than that for trisomy 21. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
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replacing the combined test by cell free dna testing in screening for trisomies 21 18 and 13 impact on the diagnosis of other chromosomal abnormalities
Fetal Diagnosis and Therapy, 2014Co-Authors: Argyro Syngelaki, Eugene Pergament, Tessa Homfray, Ranjit Akolekar, K H NicolaidesAbstract:Objective: To estimate the proportion of other chromosomal abnormalities that could be missed if combined testing was replaced by cell-free (cf) DNA testing as the method of screening for trisomies 21, 18 and 13. Methods: The prevalence of trisomies 21, 18 or 13, Sex Chromosome Aneuploidies, triploidy and other chromosomal abnormalities was examined in pregnancies undergoing first-trimester combined screening and chorionic villus sampling (CVS). Results: In 1,831 clinically significant chromosomal abnormalities in pregnancies with combined risk for trisomies 21, 18 and 13 ≥ 1: 100, the contribution of trisomies 21, 18 or 13, Sex Chromosome Aneuploidies, triploidy and other chromosomal abnormalities at high risk of adverse outcome was 82.9, 8.2, 3.9 and 5.0%, respectively. Combined screening followed by CVS for risk ≥ 1: 10 and cfDNA testing for risk 1: 11–1: 2,500 could detect 97% of trisomy 21 and 98% of trisomies 18 and 13. Additionally, 86% of monosomy X, half of 47,XXY, 47,XYY or 47,XXX, half of other chromosomal abnormalities and one
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assessment of fetal Sex Chromosome aneuploidy using directed cell free dna analysis
Fetal Diagnosis and Therapy, 2013Co-Authors: K H Nicolaides, Thomas J Musci, Craig A Struble, Argyro Syngelaki, M M GilAbstract:Objective: To examine the performance of Chromosome-selective sequencing of cell-free (cf) DNA in maternal blood for assessment of fetal Sex Chromosome Aneuploidies. Methods: This was a case-control study of 177 stored maternal plasma samples, obtained before fetal karyotyping at 11-13 weeks of gestation, from 59 singleton pregnancies with fetal Sex Chromosome Aneuploidies (45,X, n = 49; 47,XXX, n = 6; 47,XXY, n = 1; 47,XYY, n = 3) and 118 with euploid fetuses (46,XY, n = 59; 46,XX, n = 59). Digital analysis of selected regions (DANSR™) on Chromosomes 21, 18, 13, X and Y was performed and the fetal-fraction optimized risk of trisomy evaluation (FORTE™) algorithm was used to estimate the risk for non-disomic genotypes. Performance was calculated at a risk cut-off of 1:100. Results: Analysis of cfDNA provided risk scores for 172 (97.2%) samples; 4 samples (45,X, n = 2; 46,XY, n = 1; 46,XX, n = 1) had an insufficient fetal cfDNA fraction for reliable testing and 1 case (47,XXX) failed laboratory quality control metrics. The classification was correct in 43 (91.5%) of 47 cases of 45,X, all 5 of 47,XXX, 1 of 47,XXY and 3 of 47,XYY. There were no false-positive results for monosomy X. Discussion: Analysis of cfDNA by Chromosome-selective sequencing can correctly classify fetal Sex Chromosome aneuploidy with reasonably high sensitivity.
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validation of targeted sequencing of single nucleotide polymorphisms for non invasive prenatal detection of aneuploidy of Chromosomes 13 18 21 x and y
Prenatal Diagnosis, 2013Co-Authors: K H Nicolaides, Argyro Syngelaki, M M Gil, V Atanasova, Desislava MarkovaAbstract:Objective To assess the performance of cell-free DNA (cfDNA) testing in maternal blood for detection of fetal aneuploidy of Chromosomes 13, 18, 21, X, and Y using targeted sequencing of single-nucleotide polymorphisms. Methods Prospective study in 242 singleton pregnancies undergoing chorionic villus sampling at 11 to 13weeks. Maternal blood was collected before chorionic villus sampling and sent to Natera (San Carlos, CA, USA). cfDNA was isolated from maternal plasma, and targeted multiplex PCR amplification followed by sequencing of 19488 polymorphic loci covering Chromosomes 13, 18, 21, X, and Y was performed. Sequencing data were analyzed using the NATUS algorithm that determines the copy number and calculates a sample-specific accuracy for each of the five Chromosomes tested. Laboratory personnel were blinded to fetal karyotype. Results Results were provided for 229 (94.6%) of the 242 cases. Thirty-two cases were correctly identified as aneuploid, including trisomy 21 [n=25; sensitivity=100% (CI: 86.3–100%), specificity=100% (CI: 98.2–100%)], trisomy 18 (n=3), trisomy 13 (n=1), Turner syndrome (n=2), and triploidy (n=1), with no false positive or false negative results. Median accuracy was 99.9% (range: 96.0–100%). Conclusions cfDNA testing in maternal blood using targeted sequencing of polymorphic loci at Chromosomes 13, 18, 21, X, and Y holds promise for accurate detection of fetal autosomal trisomies, Sex Chromosome Aneuploidies, and triploidy. © 2013 John Wiley & Sons, Ltd.
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maternal serum pregnancy associated plasma protein a and fetal nuchal translucency thickness for the prediction of fetal trisomies in early pregnancy
Obstetrics & Gynecology, 1994Co-Authors: M L Brizot, R J M Snijders, N A Bersinger, P Kuhn, K H NicolaidesAbstract:OBJECTIVE: To determine if the risk for fetal trisomies during the first trimester of pregnancy can be derived by combining data from maternal serum pregnancy-associated plasma protein A (PAPP-A) and fetal nuchal translucency thickness. METHODS: Pregnancy-associated plasma protein A was measured in samples from 87 singleton pregnancies with fetal chromosomal abnormalities (45 trisomy 21, 19 trisomy 18, eight trisomy 13, 11 Sex Chromosome Aneuploidies, four triploidies) and 348 chromosomally normal controls at 10-13 weeks' gestation. Likelihood ratios for trisomies 21, 18, and 13 in relation to PAPP-A, in multiples of the normal median (MoM) for crown-rump length, were derived from the overlapping gaussian frequency distribution curves for normal and abnormal pregnancies. RESULTS: In the chromosomally normal group, maternal serum PAPP-A correlated significantly with fetal crown-rump length (r = 0.421, P < .0001). In the chromosomally abnormal group, the median PAPP-A was significantly lower than in the normal controls. The respective median values expressed in MoM for trisomies 21, 18, and 13 and other Aneuploidies were 0.5 MoM (90% confidence interval [CI] 0.09-1.67, z = 6.0, P < .001), 0.17 MoM (90% CI 0.06-1.45, z = 6.6, P < .001), 0.25 MoM (90% CI 0.10-0.62, z = 4.5, P < .001), and 0.72 MoM (90% CI 0.09-2.48, z = 2.2, P < .05), respectively. There was no significant linear association between PAPP-A and fetal nuchal translucency thickness in either the chromosomally normal (r = -0.01, P = .89) or abnormal groups (r = -0.19, P = .08). CONCLUSION: The risks for fetal trisomies at 10-13 weeks' gestation can be derived by combining data on maternal age, maternal serum PAPP-A, and fetal nuchal translucency thickness.
M M Gil - One of the best experts on this subject based on the ideXlab platform.
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analysis of cell free dna in maternal blood in screening for fetal Aneuploidies updated meta analysis
Ultrasound in Obstetrics & Gynecology, 2015Co-Authors: M M Gil, Ranjit Akolekar, Maria Soledad Quezada, Rocio Revello, K H NicolaidesAbstract:Objective To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and Sex Chromosome Aneuploidies. Methods Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for Aneuploidies between January 2011, when the first such study was published, and 4 January 2015. Results In total, 37 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for Aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. Weighted pooled detection rates (DR) and false-positive rates (FPR) in singleton pregnancies were 99.2% (95% CI, 98.5–99.6%) and 0.09% (95% CI, 0.05–0.14%), respectively, for trisomy 21, 96.3% (95% CI, 94.3–97.9%) and 0.13% (95% CI, 0.07–0.20) for trisomy 18, 91.0% (95% CI, 85.0–95.6%) and 0.13% (95% CI, 0.05–0.26%) for trisomy 13, 90.3% (95% CI, 85.7–94.2%) and 0.23% (95% CI, 0.14–0.34%) for monosomy X and 93.0% (95% CI, 85.8–97.8%) and 0.14% (95% CI, 0.06–0.24%) for Sex Chromosome Aneuploidies other than monosomy X. For twin pregnancies, the DR for trisomy 21 was 93.7% (95% CI, 83.6–99.2%) and the FPR was 0.23% (95% CI, 0.00–0.92%). Conclusion Screening for trisomy 21 by analysis of cfDNA in maternal blood is superior to that of all other traditional methods of screening, with higher DR and lower FPR. The performance of screening for trisomies 18 and 13 and Sex Chromosome Aneuploidies is considerably worse than that for trisomy 21. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
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assessment of fetal Sex Chromosome aneuploidy using directed cell free dna analysis
Fetal Diagnosis and Therapy, 2013Co-Authors: K H Nicolaides, Thomas J Musci, Craig A Struble, Argyro Syngelaki, M M GilAbstract:Objective: To examine the performance of Chromosome-selective sequencing of cell-free (cf) DNA in maternal blood for assessment of fetal Sex Chromosome Aneuploidies. Methods: This was a case-control study of 177 stored maternal plasma samples, obtained before fetal karyotyping at 11-13 weeks of gestation, from 59 singleton pregnancies with fetal Sex Chromosome Aneuploidies (45,X, n = 49; 47,XXX, n = 6; 47,XXY, n = 1; 47,XYY, n = 3) and 118 with euploid fetuses (46,XY, n = 59; 46,XX, n = 59). Digital analysis of selected regions (DANSR™) on Chromosomes 21, 18, 13, X and Y was performed and the fetal-fraction optimized risk of trisomy evaluation (FORTE™) algorithm was used to estimate the risk for non-disomic genotypes. Performance was calculated at a risk cut-off of 1:100. Results: Analysis of cfDNA provided risk scores for 172 (97.2%) samples; 4 samples (45,X, n = 2; 46,XY, n = 1; 46,XX, n = 1) had an insufficient fetal cfDNA fraction for reliable testing and 1 case (47,XXX) failed laboratory quality control metrics. The classification was correct in 43 (91.5%) of 47 cases of 45,X, all 5 of 47,XXX, 1 of 47,XXY and 3 of 47,XYY. There were no false-positive results for monosomy X. Discussion: Analysis of cfDNA by Chromosome-selective sequencing can correctly classify fetal Sex Chromosome aneuploidy with reasonably high sensitivity.
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validation of targeted sequencing of single nucleotide polymorphisms for non invasive prenatal detection of aneuploidy of Chromosomes 13 18 21 x and y
Prenatal Diagnosis, 2013Co-Authors: K H Nicolaides, Argyro Syngelaki, M M Gil, V Atanasova, Desislava MarkovaAbstract:Objective To assess the performance of cell-free DNA (cfDNA) testing in maternal blood for detection of fetal aneuploidy of Chromosomes 13, 18, 21, X, and Y using targeted sequencing of single-nucleotide polymorphisms. Methods Prospective study in 242 singleton pregnancies undergoing chorionic villus sampling at 11 to 13weeks. Maternal blood was collected before chorionic villus sampling and sent to Natera (San Carlos, CA, USA). cfDNA was isolated from maternal plasma, and targeted multiplex PCR amplification followed by sequencing of 19488 polymorphic loci covering Chromosomes 13, 18, 21, X, and Y was performed. Sequencing data were analyzed using the NATUS algorithm that determines the copy number and calculates a sample-specific accuracy for each of the five Chromosomes tested. Laboratory personnel were blinded to fetal karyotype. Results Results were provided for 229 (94.6%) of the 242 cases. Thirty-two cases were correctly identified as aneuploid, including trisomy 21 [n=25; sensitivity=100% (CI: 86.3–100%), specificity=100% (CI: 98.2–100%)], trisomy 18 (n=3), trisomy 13 (n=1), Turner syndrome (n=2), and triploidy (n=1), with no false positive or false negative results. Median accuracy was 99.9% (range: 96.0–100%). Conclusions cfDNA testing in maternal blood using targeted sequencing of polymorphic loci at Chromosomes 13, 18, 21, X, and Y holds promise for accurate detection of fetal autosomal trisomies, Sex Chromosome Aneuploidies, and triploidy. © 2013 John Wiley & Sons, Ltd.
Jonathan D Blumenthal - One of the best experts on this subject based on the ideXlab platform.
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Sex Chromosome dosage effects on gene expression in humans
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Armin Raznahan, Andrew R. Zinn, Neelroop N Parikshak, Vijayendran Chandran, Jonathan D Blumenthal, Liv S Clasen, Aaron Alexanderbloch, Danny Wangsa, Jasen Wise, Declan G MurphyAbstract:A fundamental question in the biology of Sex differences has eluded direct study in humans: How does Sex-Chromosome dosage (SCD) shape genome function? To address this, we developed a systematic map of SCD effects on gene function by analyzing genome-wide expression data in humans with diverse Sex-Chromosome Aneuploidies (XO, XXX, XXY, XYY, and XXYY). For Sex Chromosomes, we demonstrate a pattern of obligate dosage sensitivity among evolutionarily preserved X-Y homologs and update prevailing theoretical models for SCD compensation by detecting X-linked genes that increase expression with decreasing X- and/or Y-Chromosome dosage. We further show that SCD-sensitive Sex-Chromosome genes regulate specific coexpression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease. These gene coexpression results converge with analysis of transcription factor binding site enrichment and measures of gene expression in murine knockout models to spotlight the dosage-sensitive X-linked transcription factor ZFX as a key mediator of SCD effects on wider genome expression. Our findings characterize the effects of SCD broadly across the genome, with potential implications for human phenotypic variation.
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Sex Chromosome dosage effects on gene expression in humans
bioRxiv, 2017Co-Authors: Armin Raznahan, Andrew R. Zinn, Neelroop N Parikshak, Vijayendran Chandran, Jonathan D Blumenthal, Liv S Clasen, Aaron Alexanderbloch, Danny Wangsa, Jasen Wise, Declan G MurphyAbstract:A fundamental question in the biology of Sex-differences has eluded direct study in humans: how does Sex Chromosome dosage (SCD) shape genome function? To address this, we developed a systematic map of SCD effects on gene function by analyzing genome-wide expression data in humans with diverse Sex Chromosome Aneuploidies (XO, XXX, XXY, XYY, XXYY). For Sex Chromosomes, we demonstrate a pattern of obligate dosage sensitivity amongst evolutionarily preserved X-Y homologs, and revise prevailing theoretical models for SCD compensation by detecting X-linked genes whose expression increases with decreasing X- and/or Y-Chromosome dosage. We further show that SCD-sensitive Sex Chromosome genes regulate specific co-expression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease. Our findings detail wide-ranging effects of SCD on genome function with implications for human phenotypic variation.
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effects of Sex Chromosome dosage on corpus callosum morphology in supernumerary Sex Chromosome Aneuploidies
Biology of Sex Differences, 2014Co-Authors: Benjamin Wade, Jonathan D Blumenthal, Shantanu H Joshi, Martin Reuter, Arthur W Toga, Paul M Thompson, Jay N GieddAbstract:Background Supernumerary Sex Chromosome Aneuploidies (sSCA) are characterized by the presence of one or more additional Sex Chromosomes in an individual’s karyotype; they affect around 1 in 400 individuals. Although there is high variability, each sSCA subtype has a characteristic set of cognitive and physical phenotypes. Here, we investigated the differences in the morphometry of the human corpus callosum (CC) between Sex-matched controls 46,XY (N =99), 46,XX (N =93), and six unique sSCA karyotypes: 47,XYY (N =29), 47,XXY (N =58), 48,XXYY (N =20), 47,XXX (N =30), 48,XXXY (N =5), and 49,XXXXY (N =6).
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effects of Sex Chromosome dosage on corpus callosum morphology in supernumerary Sex Chromosome Aneuploidies
Biology of Sex Differences, 2014Co-Authors: Benjamin Wade, Jonathan D Blumenthal, Shantanu H Joshi, Martin Reuter, Arthur W Toga, Paul M Thompson, Jay N GieddAbstract:Supernumerary Sex Chromosome Aneuploidies (sSCA) are characterized by the presence of one or more additional Sex Chromosomes in an individual’s karyotype; they affect around 1 in 400 individuals. Although there is high variability, each sSCA subtype has a characteristic set of cognitive and physical phenotypes. Here, we investigated the differences in the morphometry of the human corpus callosum (CC) between Sex-matched controls 46,XY (N =99), 46,XX (N =93), and six unique sSCA karyotypes: 47,XYY (N =29), 47,XXY (N =58), 48,XXYY (N =20), 47,XXX (N =30), 48,XXXY (N =5), and 49,XXXXY (N =6). We investigated CC morphometry using local and global area, local curvature of the CC boundary, and between-landmark distance analysis (BLDA). We hypothesized that CC morphometry would vary differentially along a proposed spectrum of Y:X Chromosome ratio with supernumerary Y karyotypes having the largest CC areas and supernumerary X karyotypes having significantly smaller CC areas. To investigate this, we defined an sSCA spectrum based on a descending Y:X karyotype ratio: 47,XYY, 46,XY, 48,XXYY, 47,XXY, 48,XXXY, 49,XXXXY, 46,XX, 47,XXX. We similarly explored the effects of both X and Y Chromosome numbers within Sex. Results of shape-based metrics were analyzed using permutation tests consisting of 5,000 iterations. Several subregional areas, local curvature, and BLDs differed between groups. Moderate associations were found between area and curvature in relation to the spectrum and X and Y Chromosome counts. BLD was strongly associated with X Chromosome count in both male and female groups. Our results suggest that X- and Y-linked genes have differential effects on CC morphometry. To our knowledge, this is the first study to compare CC morphometry across these extremely rare groups.
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cell free dna screening and Sex Chromosome Aneuploidies
Prenatal Diagnosis, 2015Co-Authors: Michael T Mennuti, Suchitra Chandrasekaran, Nahla Khalek, Lorraine DugoffAbstract:Cell-free DNA (cfDNA) testing is increasingly being used to screen pregnant women for fetal Aneuploidies. This technology may also identify fetal Sex and can be used to screen for Sex Chromosome Aneuploidies (SCAs). Physicians offering this screening will need to be prepared to offer comprehensive prenatal counseling about these disorders to an increasing number of patients. The purpose of this article is to consider the source of information to use for counseling, factors in parental decision-making, and the performance characteristics of cfDNA testing in screening for SCAs. Discordance between ultrasound examination and cfDNA results regarding fetal Sex is also discussed.
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cell free dna screening and Sex Chromosome Aneuploidies
Prenatal Diagnosis, 2015Co-Authors: Michael T Mennuti, Suchitra Chandrasekaran, Nahla Khalek, Lorraine DugoffAbstract:Cell-free DNA (cfDNA) testing is increasingly being used to screen pregnant women for fetal Aneuploidies. This technology may also identify fetal Sex and can be used to screen for Sex Chromosome Aneuploidies (SCAs). Physicians offering this screening will need to be prepared to offer comprehensive prenatal counseling about these disorders to an increasing number of patients. The purpose of this article is to consider the source of information to use for counseling, factors in parental decision-making, and the performance characteristics of cfDNA testing in screening for SCAs. Discordance between ultrasound examination and cfDNA results regarding fetal Sex is also discussed. © 2015 John Wiley & Sons, Ltd.