Browsing by Author "Swillen, Ann"
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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.Publication Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS(2023) Repetto, Gabriela; Zhao, Yingjie; Wang, Yujue; Shi, Lijie; McDonald, Donna; Crowley, Blaine; McGinn, Daniel; Tran, Oanh; Miller, Daniella; Lin, Jhih-Rong; Zacka, Elaine; Johnston, Richard; Chow, Eva; Vorstman, Jacob; Vingerhoets, Claudia; Van Amelsvoort, Therese; Gothelf, Doron; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris; Eliez, Stephan; Schneider, Maude; Van den Bree, Marianne; Owen, Michael; Kates, Wendy; Shashi, Vandana; Schoch, Kelly; Bearden, Carrie; Digili, M. Cristina; Unolt, Marta; Putotto, Carolina; Marino, Bruno; Pontillo, Maria; Armando, Marco; Vicar, Stefano; Angkustsiri, Kathleen; Campbell, Linda; Busa, Tiffany; Heine, Damian; Murphy, Kieran; Murphy, DeclanCongenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHDItem Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects(American Society of Human Genetics by Elsevier Inc., 2020-01) Zhao, Yingjie; Diacou, Alexander; Johnston, Richard; Musfee, Fadi; McDonald-McGinn, Donna; McGinn, Daniel; Crowley, Blaine; Repetto, Gabriela; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris; Kates, Wendy; Digilio, Cristina; Unolt, Marta; Marino, Bruno; Pontillo, Maria; Armando, Marco; Di Fabio, Fabio; Vicari, Stefano; van den Bree, Marianne; Moss, Hayley; Owen, Michael; Murphy, Kieran; Murphy, Clodagh; Murphy, Declan; Schoch, Kelly; Shashi, Vandana; Tassone, FloraThe 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.Item Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects(2020) Zhao, Yingjie; Diacou, Alexander; Johnston, H. Richard; Musfee, Fadi I; McDonald-McGinn, Donna M.; McGinn, Daniel; Crowley, T. Blaine; Repetto, Gabriela; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris R; Kates, Wendy R.; Digilio, M. Cristina; Unolt, Marta; Marino, Bruno; Pontillo, Maria; Armando, Marco; Di Fabio, Fabio; Vicari, Stefano; Bree, Marianne van den; Moss, Hayley; Owen, Michael J.; Murphy, Kieran C.; Murphy, Clodagh M.; Murphy, Declan; Schoch, Kelly; Shashi, Vandana; Tassone, Flora; Simon, Tony J.; Shprintzen, Robert J.; Campbell, Linda; Philip, Nicole; Heine-Suñer, Damian; García-Miñaúr, Sixto; Fernández, Luis; Bearden, Carrie E.; Vingerhoets, Claudia; Amelsvoort, Therese van; Eliez, Stephan; Schneider, Maude; Vorstman, Jacob A. S.; Gothelf, Doron; Zackai, Elaine; Agopian, A. J.; Gur, Raquel E.; Bassett, Anne S.; Emanuel, Beverly S.; Goldmuntz, Elizabeth; Mitchell, Laura E.; Wang, Tao; Morrow, Bernice E.The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.Item Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2(2018) Guo, Tingwei; Diacou, Alexander; Nomaru, Hiroko; McDonald-McGinn, Donna M.; Hestand, Matthew; Demaerel, Wolfram; Zhang, Liangtian; Zhao, Yingjie; Ujueta, Francisco; Shan, Jidong; Montagna, Cristina; Zheng, Deyou; Crowley, Terrence B.; Kushan-Wells, Leila; Bearden, Carrie E.; Kates, Wendy R.; Gothelf, Doron; Schneider, Maude; Eliez, Stephan; Breckpot, Jeroen; Swillen, Ann; Vorstman, Jacob; Zackai, Elaine; Benavides, Felipe; Repetto, Gabriela; Emanuel, Beverly S.; Bassett, Anne S.; Vermeesch, Joris R.; Marshall, Christian R.; Morrow, Bernice E.Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22Aþ, resulting in LCR22Aþ-B or LCR22Aþ-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22Aþregion with a breakpoint in LCR22Aþ. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-Aþduplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22Aþmaps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.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 Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion(2020) Cleynen, Isabelle; Engchuan, Worrawat; Hestand, Matthew; Heung, Tracy; Holleman, Aarón M.; Johnston, Richard; Monfeuga, Thomas; McDonald McGinn, Donna M.; Gur, Raquel E.; Morrow, Bernice E.; Swillen, Ann; Vorstman, Jacob A. S; Bearden, Carrie E.; Chow, Eva W. C.; van den Bree, Marianne; Emanuel, Beverly S.; Vermeesch, Joris R.; Warren, Stephen T.; Owen, Michael J.; Chopra, Pankaj; Cutler, David J.; Duncan, Richard; Kotlar, Alex V.; Mulle, Jennifer G.; Voss, Anna J.; Zwick, Michael E.; Diacou, Alexander; Golden, Aaron; Guo, Tingwei; Lin, Jhih Rong; Wang, Tao; Zhang, Zhengdong; Zhao, Yingjie; Marshall, Marshall; Merico, Daniele; Jin, Andrea; Lilley, Brenna; Salmons, Harold I.; Oanh, Tran; Pardinas, Antonio; Repetto, GabrielaSchizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6 ). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both presentItem 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 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 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.Item Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome(2020) Davies, Robert W.; Fiksinski, Ania M.; Breetvelt, Elemi J.; Williams, Nigel M.; Hooper, Stephen R.; Monfeuga, Thomas; Bassett, Anne S.; Owen, Michael J.; Gur, Raquel E.; Morrow, Bernice E.; McDonald-McGinn, Donna M.; Swillen, Ann; Chow, Eva W. C.; Bree, Marianne van den; Emanuel, Beverly S.; Vermeesch, Joris R.; Amelsvoort, Therese van; Arango, Celso; Armando, Marco; Campbell, Linda E.; Cubells, Joseph F.; Eliez, Stephan; Garcia-Minaur, Sixto; Gothelf, Doron; Kates, Wendy R.; Murphy, Kieran C.; Murphy, Clodagh M.; Murphy, Declan G.; Philip, Nicole; Repetto, Gabriela; Shashi, Vandana; Simon, Tony J.; Suñer, Damiàn Heine; Vicari, Stefano; Scherer, Stephen W.; Bearden, Carrie E.; Vorstman, Jacob A. S.; International 22q11.2 Brain and Behavior ConsortiumThe 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.