Browsing by Author "Bassett, Anne"
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Item A normative chart for cognitive development in a genetically selected population(2021) Fiksinski, Ania; Bearden, Carrie; Bassett, Anne; Kahn, René; Zinkstok, Janneke; Hooper, Stephen R; Tempelaar, Wanda; McDonald, Donna; Swillen, Ann; Emanuel, Beverly; Morrow, Bernice; Gur, Raquel; Chow, Eva; Van den Bree, Marianne; Vermeesch, Joris; Warren, Stephen; Owen, Michael; Van Amelsvoort, Therese; Eliez, Stephan; Gothelf, Doron; Arango, Celso; Kates, Wendy; Simon, Tony; Murphy, Kieran; Repetto, Gabriela; Heine, Damian; Vicari, Stefano; Cubells, Joseph; Armando, Marco; Philip, Nicole; Campbell, Linda; García, Sixto; Schneider, Maude; Shashi, Vandana; 22q11DS International Consortium on Brain and Behavior; Vorstman, Jacob; Breetvelt, ElemiCertain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS.Item Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs(2022) Sønderby, Ida; Ching, Christopher; Thomopoulos, Sophia; Van der Meer, Dennis; Sun, Daqiang; Villalon, Julio; Agartz, Ingrid; Amunts, Katrin; Arango, Celso; Armstrong, Nicola; Ayesa, Rosa; Bakker, Geor; Bassett, Anne; Boomsma, Dorret; Bülow, Robin; Butcher, Nancy; Calhoun, Vince; Caspers, Svenja; Chow, Eva; Cichon, Sven; Ciufolini, Simone; Craig, Michael; Crespo, Benedicto; Cunningham, Adam; Dale, Ander; Dazzan, Paola; De Zubicaray, Greig; Djurovic, Srdjan; Doherty, Joanne; Donohoe, Gary; Draganski, Bogdan; Durdle, Courtney; Ehrlich, Stefan; Emanuel, Beverly; Espeseth, Thomas; Fisher, Simon; Ge, Tian; Glahn, David; Grabe, Hans; Gur, RaquelThe Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.Publication Gathering the Stakeholder’s Perspective: Experiences and Opportunities in Rare Genetic Disease Research(2023) White, Lauren; Crowley, Blaine; Finucane, Brenda; McClellan, Emily; Donoghue, Sarah; Garcia, Sixto; Repetto, Gabriela; Fischer, Matthias; Jacquemont, Sebastien; Gur, Raquel; Maillard, Anne; Donald, Kirsten; Bassett, Anne; Swillen, Ann; McDonald, DonnaBackground: Research participant feedback is rarely collected; therefore, investigators have limited understanding regarding stakeholders’ (affected individuals/caregivers) motivation to participate. Members of the Genes to Mental Health Network (G2MH) surveyed stakeholders affected by copy number variants (CNVs) regarding perceived incentives for study participation, opinions concerning research priorities, and the necessity for future funding. Respondents were also asked about feelings of preparedness, research burden, and satisfaction with research study participation. Methods: Modified validated surveys were used to assess stakeholders´ views across three domains: (1) Research Study Enrollment, Retainment, Withdrawal, and Future Participation; (2) Overall Research Experience, Burden, and Preparedness; (3) Research Priorities and Obstacles. Top box score analyses were performed. Results: A total of 704 stakeholders´ responded from 29 countries representing 55 CNVs. The top reasons for initial participation in the research included reasons related to education and altruism. The top reasons for leaving a research study included treatment risks and side effects. The importance of sharing research findings and laboratory results with stakeholders was underscored by participants. Most stakeholders reported positive research experiences. Conclusions: This study provides important insight into how individuals and families affected with a rare CNV feel toward research participation and their overall experience in rare disease research. There are clear targets for areas of improvement for study teams, although manystakeholders reported positive research experiences. Key findings from this international survey may help advance collaborative research and improve the experience of participants, investigators, and other stakeholders moving forward.Item Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the GPR98 Locus on 5q14.3(Lippincott Williams & Wilkins, 2017) Guo, Tingwei; Repetto, Gabriela; McDonald, Donna; Chung, Jonathan; Nomaru, Hiroko; Campbell, Christopher; Blonska, Anna; Bassett, Anne; Chow, Eva; Mlynarski, Elisabeth; Swillen, Ann; Vermeesch, Joris; Devriendt, Koen; Gothelf, Doron; Carmel, Miri; Michaelovsky, Elena; Schneider, Maude; Eliez, Stephan; Antonarakis, Stylianos; Coleman, Karlene; Tomita, Aoy; Mitchell, Michael; Digilio, Cristina; Dallapiccola, Bruno; Marino, Bruno; Philip, Nicole; Busa, Tiffany; Kushan, Leila; Bearden, Carrie; Piotrowicz, Małgorzata; Hawuła, Wanda; Roberts, Amy; Tassone, Flora; Simon, Tony; van Duin, Esther; van Amelsvoort, Thérèse; Kates, Wendy; Zackai, Elaine; Johnston, Richard; Cutler, David; Agopian, A; Goldmuntz, Elizabeth; Mitchell, Laura; Wang, Tao; Emanuel, Beverly; Morrow, Bernice; the International 22q11.2 Consortium/Brain and Behavior ConsortiumBACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort. METHODS AND RESULTS: To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, P=2.98×10-8) in an intron of the adhesion GPR98 (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with GPR98, including MEF2C (Myocyte-specific enhancer factor 2C). MEF2C is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS. CONCLUSIONS: In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.Item Neuroimaging and clinical features in adults with a 22q11.2 deletion at risk of Parkinson’s disease(Oxford University Press, 2017) Butcher, Nancy; Marras, Connie; Pondal, Margarita; Rusjan, Pablo; Boot, Erik; Christopher, Leigh; Repetto, Gabriela; Fritsch, Rosemarie; Chow, Eva; Masellis, Mario; Strafella, Antonio; Lang, Anthony; Bassett, AnneThe recurrent 22q11.2 deletion is a genetic risk factor for early-onset Parkinson's disease. Adults with the associated 22q11.2 deletion syndrome (22q11.2DS) may exhibit phenotypes that could help identify those at highest risk and reveal disease trajectories. We investigated clinical and neuroimaging features relevant to Parkinson's disease in 26 adults: 13 with 22q11.2DS at genetic risk of Parkinson's disease (mean age = 41.5 years, standard deviation = 9.7), 12 healthy age and sex-matched controls, and a 22q11.2DS patient with l-DOPA-responsive early-onset Parkinson's disease. Neuroimaging included transcranial sonography and positron emission tomography using 11C-dihydrotetrabenazine (11C-DTBZ), a radioligand that binds to the presynaptic vesicular monoamine transporter. The 22q11.2DS group without Parkinson's disease demonstrated significant motor and olfactory deficits relative to controls. Eight (61.5%) were clinically classified with parkinsonism. Transcranial sonography showed a significantly larger mean area of substantia nigra echogenicity in the 22q11.2DS risk group compared with controls (P = 0.03). The 22q11.2DS patient with Parkinson's disease showed the expected pattern of severely reduced striatal 11C-DTBZ binding. The 22q11.2DS group without Parkinson's disease however showed significantly elevated striatal 11C-DTBZ binding relative to controls (∼33%; P < 0.01). Results were similar within the 22q11.2DS group for those with (n = 7) and without (n = 6) psychotic illness. These findings suggest that manifestations of parkinsonism and/or evolution to Parkinson's disease in this genetic at-risk population may include a hyperdopaminergic mechanism. Adequately powered longitudinal studies and animal models are needed to evaluate the relevance of the observed clinical and imaging phenotypes to Parkinson's disease and other disorders that are more prevalent in 22q11.2DS, such as schizophrenia.Item Practical guidelines for managing adults with 22q11.2 deletion syndrome.(Macmillan Publishers Limited, 2015) Fung, Wai Lun; Butcher, Nancy; Costain, Gregory; Andrade, Danielle; Boot, Erik; Chow, Eva; Chung, Brian; Cytrynbaum, Cheryl; Faghfoury, Hanna; Fishman, Leona; García-Miñaúr, Sixto; George, Susan; Lang, Anthony; Repetto, Gabriela; Shugar, Andrea; Silversides, Candice; Swillen, Ann; Van Amelsvoort, Therese; McDonald-McGinn, Donna; Bassett, Anne22q11.2 Deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, estimated to affect up to 1 in 2,000 live births. Major features of this multisystem condition include congenital anomalies, developmental delay, and an array of early- and later-onset medical and psychiatric disorders. Advances in pediatric care ensure a growing population of adults with 22q11.2DS. Informed by an international panel of multidisciplinary experts and a comprehensive review of the existing literature concerning adults, we present the first set of guidelines focused on managing the neuropsychiatric, endocrine, cardiovascular, reproductive, psychosocial, genetic counseling, and other issues that are the focus of attention in adults with 22q11.2DS. We propose practical strategies for the recognition, evaluation, surveillance, and management of the associated morbidities.Item Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome(American Psychiatric Association, 2017) Bassett, Anne; Lowther, Chelsea; Merico, Daniele; Costain, Gregory; Chow, Eva; van Amelsvoort, Therese; McDonald-McGinn, Donna; Gur, Raquel; Swillen, Ann; Van den Bree, Marianne; Murphy, Kieran; Gothelf, Doron; Bearden, Carrie; Eliez, Stephan; Kates, Wendy; Philip, Nicole; Sashi, Vandana; Campbell, Linda; Vorstman, Jacob; Cubells, Joseph; Repetto, Gabriela; Simon, Tony; Boot, Erik; Heung, Tracy; Evers, Rens; Vingerhoets, Claudia; van Duin, Esther; Zackai, Elaine; Vergaelen, Elfi; Devriendt, Koen; Vermeesch, Joris; Owen, Michael; Murphy, Clodagh; Michaelovosky, Elena; Kushan, Leila; Schneider, Maude; Fremont, Wanda; Busa, Tiffany; Hooper, Stephen; McCabe, Kathryn; Duijff, Sasja; Isaev, Karin; Pellecchia, Giovanna; Wei, John; Gazzellone, Matthew; Scherer, Stephen; Emanuel, Beverly; Guo, Tingwei; Morrow, Bernice; Marshall, Christian; International 22q11.2DS Brain and Behavior ConsortiumOBJECTIVE: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. METHOD: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. RESULTS: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. CONCLUSIONS: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.Publication Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome(2024) Repetto, Gabriela; Ge, Ruiyang; Ching, Christopher; Bassett, Anne; Kushan, Leila; Antshe, Kevin; Van Amelsvoort, Therese; Bakker, Geor; Butcher, Nancy; Campbell, Linda; Chow, Eva; Craig, Michael; Crossley, Nicolas; Cunningham, Adam; Daly, Eileen; Doherty, Joanne; Durdle, Courtney; Emanuel, Beverly; Fiksinski, Ania; Forsyth, Jennifer; Fremont, Wanda; Goodrich-Hunsaker, Naomi; Gudbrandsen, Maria; Gur, Raquel; Jalbrzikowski, Maria; Kates, Wendy; Lin, Amy; Linden, David; McCabe, Kathryn; McDonald, Donna; Moss, Hayley; Murphy, Declan; Murphy, Kieran; Owen, Michael; Villalon, Julio; Roalf, David; Ruparel, Kosha; Schmitt, J. Eric; Schuite, Sanne; Angkustsiri, Kathleen22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.Publication Updated clinical practice recommendations for managing adults with 22q11.2 deletion syndrome(2023) Boot, Erik; Óskarsdóttir, Sólveig; C Y Loo, Joanne; Crowley, Terrence; Orchanian, Ani; Andrade, Danielle; Arganbright, Jill; Castelein, René; Cserti-Gazdewich, Christine; De Reuver, Steven; Fiksinski, Ania; Klingberg, Gunilla; Lang, Anthony; Mascarenhas, Maria; Moss, Edward; Anna, Beata; Oechslin, Erwin; Palmer, Lisa; Repetto, Gabriela; D Reyes, Nikolai; Schneider, Maude; Silversides, Candice; Sullivan, Kathleen; Swillen, Ann; Van Amelsvoort, Therese; Van Batavia, Jason; Vingerhoets, Claudia; McDonald, Donna; Bassett, AnneThis review aimed to update the clinical practice guidelines for managing adults with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society recruited expert clinicians worldwide to revise the original clinical practice guidelines for adults in a stepwise process according to best practices: (1) a systematic literature search (1992-2021), (2) study selection and synthesis by clinical experts from 8 countries, covering 24 subspecialties, and (3) formulation of consensus recommendations based on the literature and further shaped by patient advocate survey results. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text review, with 2318 meeting inclusion criteria (clinical care relevance to 22q11.2DS) including 894 with potential relevance to adults. The evidence base remains limited. Thus multidisciplinary recommendations represent statements of current best practice for this evolving field, informed by the available literature. These recommendations provide guidance for the recognition, evaluation, surveillance, and management of the many emerging and chronic 22q11.2DS-associated multisystem morbidities relevant to adults. The recommendations also address key genetic counseling and psychosocial considerations for the increasing numbers of adults with this complex condition.Publication Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome(2023) Óskarsdóttir, Sólveig; Boot, Erik; Blaine Crowley, Terrence; Loo, Joanne; Arganbright, Jill; Armando, Marco; Baylis, Adriane; Breetvelt, Elemi; Castelein, René; Chadehumbe, Madeline; Cielo, Christopher; De Reuver, Steven; Eliez, Stephan; Fiksinsk, Ania; Forbes, Brian; Gallagher, Emily; Hopkins, Sarah; Jackson, Oksana; Levitz-Katz, Lorraine; Klingberg, Gunilla; Lambert, Michele; Marino, Bruno; Mascarenhas, Maria; Moldenhauer, Julie; Moss, Edward; Nowakowska, Beata; Orchanian-Cheff, Ani; Putotto, Carolina; Repetto, Gabriela; Schindewolf, Erica; Schneider, Maude; Solot, Cynthia; Sullivan, Kathleen; Swillen, Ann; Unolt, Marta; Van Batavia, Jason; Vingerhoets, Claudia; Vorstman, Jacob; Bassett, Anne; McDonald, DonnaThis review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.