Unraveling the genomic architecture of supernumerary (iso-) dicentric chromosomes in Dup15q syndrome: Insight from a systematic literature-based study

Unraveling the genomic architecture of supernumerary (iso-) dicentric chromosomes in Dup15q syndrome: Insight from a systematic literature-based study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Unraveling the genomic architecture of supernumerary (iso-) dicentric chromosomes in Dup15q syndrome: Insight from a systematic literature-based study Sebastian Burkart, Markus Ries, Verena Romero, Karin Burau, Christian P. Schaaf, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5833554/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Chromosomal aberrations, particularly copy-number variations (CNVs), are prevalent in neurodevelopmental disorders (NDD) and significantly contribute to their pathogenesis. Copy-number gains (CN gains) in 15q11-q13, primarily consisting of a pseudo (iso-)dicentric chromosome 15 [ (i)dic(15) ] or an interstitial duplication, are among the most frequent CNVs in NDD. The associated Dup15q syndrome is an early onset neurodevelopmental disorder characterized by global developmental delay, behavioral issues, and seizures with a variable onset and expression of symptoms. While a correlation between number of 15q11-q13 CN gain and symptom severity has been proposed, it fails to fully explain the wide phenotypic variability observed. We conducted a comprehensive systematic literature-based analysis of the supernumerary (i)dic(15), generating the largest literature-based cohort consisting of patient-level genotype data for Dup15q syndrome to date. Our findings identified symmetric BP3:BP3 and asymmetric BP4:BP5 (i)dic(15) configurations as the most common (i)dic(15) formations, likely arising from distinct mechanisms and potentially driving characteristic genotype-phenotype outcomes. Additionally, we identified a significant gap within the molecular characterization of (i)dic(15), particularly regarding information on nucleotide-level breakpoint, genomic structure, and differentially imprinted genes, being important aspects for genotype-phenotype predictions. Our findings provide critical insight into the molecular architecture of (i)dic(15), offering valuable implications for understanding pathomechanisms and guidance for future research into the molecular and clinical aspects of Dup15q syndrome. Dup15q syndrome pseudo (iso-)dicentric chromosome 15 [ (i)dic(15) ] literature-based genotype data curation Figures Figure 1 Figure 2 Figure 3 Introduction Chromosomal aberrations, particularly copy-number variations (CNVs), are frequent genetic alterations in neurodevelopmental disorders (NDDs), yet the comprehensive study of their structure and impact on genome-wide gene expression remains underexplored. Copy-number gains within the chromosomal 15q11.2-q13.1 region are among the most common chromosomal aberrations in NDD, closely linked to Dup15q syndrome, an infantile-onset neurodevelopmental disorder (Battaglia 2008; Depienne et al. 2009; Lusk et al. 1993; Wang et al. 2004). In approximately 75% of the cases, Dup15q syndrome is caused by a supernumerary pseudo (iso-)dicentric chromosome 15 [ (i)dic(15) ], while interstitial tandem CN gains account for the remaining 25%. Dup15q syndrome encompasses a wide spectrum of clinical manifestations, including hypotonia, developmental delay ranging from mild to severe, behavioral abnormalities, sleep disturbances, and epilepsy. The phenotypic severity of Dup15q syndrome seems to be determined by CNV number (triplications or tetraplications of the 15q11.2-q13.1 region) and localization of the additional genetic material (interstitial copy number gain or (i)dic(15)). However, dosage effects of this region alone do not fully explain the clinical variability observed in Dup15q syndrome (Urraca et al. 2013). This suggests that additional pathomechanisms like size, structural variations, parental derivation, and epigenetic modifications (e.g., DNA methylation profiles) play significant roles in disease manifestation and expression (Elamin et al. 2023; Parijs et al. 2024; Punt et al. 2022). The 15q11.2-q13.1 region is unique within the human genome, containing abundant repetitive sequences and imprinted genes that exhibit parent-of-origin-specific expression (Cook et al. 1997; Hogart et al. 2010; Parijs et al. 2024). CNVs within this region are largely driven by low-copy repeat (LCR)-mediated recombination events, facilitated by recurrent breakpoint regions (BP1–BP5) located proximally on 15q. The distinct syndromic outcomes of CN-gains in this region are influenced by parent-of-origin effects, with maternally imprinted CN-gains being associated with significantly higher disease burden (Christian et al. 1999; Cox and Butler 2015; Mignon-Ravix et al. 2007; Pujana et al. 2002; Roberts et al. 2003). There is a high medical need for a comprehensive understanding of the molecular structure of (i)dic(15), which is essential for an in-depth insight to the complex pathomechanisms and advancing clinical predictions in Dup15q syndrome, however, this remains considerably underexplored. To close this gap, we conducted a comprehensive literature-based analysis of the supernumerary (i)dic(15) chromosome in Dup15q syndrome, with the following objectives: To create an accessible set of genotype data from (i)dic(15) cases derived from the existing literature. To assess the quality and completeness of available genetic data and to identify gaps for future research. To elucidate the current knowledge of the molecular architecture of (i)dic(15) by mapping the distribution and frequency of chromosomal breakpoints within recurrent regions (BP1–BP5). To analyze the current knowledge of the parental origin of (i)dic(15). This systematic literature-based case-level analysis allows novel data-driven insight into Dup15q syndrome, such as the molecular architecture of (i)dic(15), and helps identifying and closing further gaps in the current knowledge. Methods Selection Process A comprehensive and systematic literature review in compliance with PRISMA criteria was conducted to identify publications reporting patient-level genetic data for (i)dic(15) (Page et al. 2021). To capture a broad spectrum of published information, the search included 5 established medical databases: Cochrane (Cochrane Reviews | Cochrane Library), Global Index Medicus (Global Index Medicus – World Health Organization), Web of Science (https://www.webofscience.com), Embase (www.embase.com) and PubMed (https://pubmed.ncbi.nlm.nih.gov/). Search terms included in the study were: “Dup15q syndrome“, „idic15q“, „duplication 15q11.2-q13 syndrome“. The search focused on publications in English language and was conducted on 29. July 2024. An inclusive data retrieval process was used to include relevant publications by cross-references, which would otherwise be missed. Screening and Eligibility Criteria In a first screening process, we excluded duplicated publications which were listed in several databases. One goal of this study was to evaluate the completeness and quality of genetic data reported on Dup15q syndrome in the literature. Subsequently, publications were screened for relevance, particularly on the availability of genetic data. We further aimed to conduct an in-depth analysis of genetic data at the individual case level. For that purpose, publications without any patient-level genetic data were excluded. Only publications fulfilling these criteria were deemed eligible for data extraction. Data Extraction and Variables Patient-level genetic data were extracted from the included publications. Each case received an individual identifier within this study. Individuals which were described in multiple publications were only included once using the same identifier. For each case, we extracted the following variables to enable a comprehensive analysis: authors and the year of publication, reference genome build, breakpoints defined at the nucleotide level, breakpoints defined by the recurrent breakpoint regions (BP1 to BP5), estimated and exact size in kilobases, parental-origin, technology used for genetic testing, patient’s origin and nomenclature used to describe the genetic alteration. It was also extracted whether the gain of 15q material was due to the presence of a supernumerary (i)dic(15) chromosome or to an interstitial CNV. Data Curation As this study was focused on (i)dic(15), we excluded cases involving interstitial CNVs or cases where CNV type information was unavailable. As our study integrates different diagnostic methodologies which were used in the respective publications, we focused on the most relevant technologies in the context of Dup15q syndrome like karyotyping, fluorescence in situ hybridization (FISH), array-based technologies and testing for parental origin (MS-MLPA, microsatellite analysis). We harmonized and summarized terminologies across the different publications. In publications without annotation of proband nationality, the country of the first author was used to determine country annotation. Statistical Analysis Standard procedures of descriptive statistics were applied. Variables were illustrated using counts and percentages of the total cohort of (i)dic(15), unless stated otherwise. Percentages are rounded to whole numbers where appropriate. All analyses were performed using R (version 4.4.0; 24.04.2024) environment for statistical computing and graphics (https://www.r-project.org). Please refer to Suppl. Table 1 for detailed descriptions and software versions of the packages used. Missing data were not imputed. Ethics Because this study is entirely based on the published scientific literature, and no patient or animal studies were conducted for this systematic analysis, an Institutional Review Board approval was not necessary. Result Generation of a Dup15q syndrome cohort utilizing literature-based patient-level genotype data To identify and extract patient-level genetic data from the literature, we conducted a comprehensive and systematic literature search. PRISMA criteria were respected (Page et al. 2021). Cumulatively, 235 publications from PubMed (n=86), Embase (n=60) and Web of Science (n=89) were received, the search within the Cochrane and Global Index Medicus databases yielded no results. In an inclusive data retrieval process, these publications were manually screened for cross-references that might contribute additional relevant publications. With that approach, we identified 17 additional publications (n=4 on 28. September 2024; n=1 on 14. Novembre 2024; n=12 on 15. Novembre 2024). This resulted in a total of 252 publications available for manual review. In a first screening process, we excluded duplicates (n=155). Further, publications without any patient-level genotype data were excluded (n=59). Data extraction was performed on the remaining 38 publications. From these publications, patient-level genotype data were extracted for 421 individual cases. Individuals included in more than one publication were only included once. 108 cases showed an interstitial CN-gain, 3 cases had no CNV type information available. This corresponds to a percentage of 74% (310/418) of cases showing an supernumerary (i)dic(15), in line with current prevalence estimates in the medical literature. As this study was focused on (i)dic(15), we excluded cases involving interstitial CNVs or cases where CNV type information was unavailable (n=111). In summary, this approach identified 310 cases from 38 publications with gain of 15q genetic material with a supernumerary chromosome, primarily in the form of an (i)dic(15) (Figure 1) (Al Ageeli et al. 2014; Baker et al. 2020; Battaglia et al. 1997; Battaglia et al. 2010; Blennow et al. 1995; Bonuccelli et al. 2017; Boronat et al. 2015; Coppola et al. 2013; Crolla et al. 1995; Dangles et al. 2021; Dawson et al. 2015; Dennis et al. 2006; DiStefano et al. 2016; Eggermann et al. 2002; Flejter et al. 1996; Friedman et al. 2016; Frohlich et al. 2022; Frohlich et al. 2016; Han et al. 2021; Hou and Wang 1998; Ingason et al. 2011; Kim et al. 2012; Kleefstra et al. 2010; Maggouta et al. 2003; Mann et al. 2004; Mim et al. 2024; Orrico et al. 2009; Ortiz-Prado et al. 2021; Roberts et al. 2003; Sahoo et al. 2005; Saravanapandian et al. 2020; Saravanapandian et al. 2021; Shehi et al. 2022; Urraca et al. 2013; Wang et al. 2004; Wang et al. 2015; Wegiel et al. 2015; Wegiel et al. 2012). Figure 1 Flow chart illustrating the systematic literature retrieval process according to PRISMA criteria for systematic review and subsequent data extraction process. In total, 310 cases with (i)dic(15) from 38 publications were included in this study. This study therefore has successfully generated the largest literature-based cohort of published patient-level genetic data for Dup15q syndrome to date. Detailed data for each patient is publicly available in Suppl. Table 2. The global distribution of cases from different countries is illustrated in Suppl. Figure 1, comprising mainly countries with high quality diagnostic infrastructure. Systematic analysis of publication patterns Scientific interest in Dup15q syndrome and potential shifts in research focus over time were evaluated, allowing to uncover possible research gaps. We analyzed publication trends of patient-level data over time, spanning nearly three decades (Figure 2A, Suppl. Table 3). The oldest publication included in this study dates back to 1995, the most recent to 2022. Interestingly, there was no clear peak in the number of publications, with a maximum of 3 publications per year in 2016. The highest absolute number of reported Dup15q cases were published in the scientific literature in 2003. As illustrated in the word cloud (Figure 2B) the nomenclature of the (i)dic(15) is highly variable and heterogeneous across different publications (i.e. smc(15), inv dup(15)), underscoring the urgent need to use standardized nomenclature to improve and facilitate research communication. To address this, we reviewed the International System for Human Cytogenomics Nomenclature (ISCN) 2024 to evaluate nomenclature aspects (Suppl. Table 4). We propose to use pseudo (iso) dicentric chromosome 15q with its ISCN conform abbreviation psu (i)dic(15) or simply (i)dic(15) for this particular supernumerary chromosome consisting of duplicated 15p, 15cen and proximal 15q region to streamline and standardize usage in clinical and research contexts. To evaluate the overall quality and completeness of the reported data and to identify possible gaps, the extent of available data was quantified for key parameters (Figure 2C). Information about the genetic test used for diagnostic testing were available in 66% (n=206), data on the parental derivation of the (i)dic(15) in 33% of cases (n=103). The approximate size of the (i)dic(15) was stated in only 2% of cases (n=5). Additionally, data on the exact nucleotide-level breakpoint or the involvement of recurrent breakpoints (BP1-BP5) were provided in 2% (n=7) and 51% (n=151) of cases, respectively (Suppl. Table 2). Further, the diagnostic methods and platforms used for testing were categorized and analyzed to track their frequency and evolution over time (Figure 2D). Notably, 33% of the cases lacked any diagnostic method information. The most frequently employed methods were karyotyping and fluorescence in situ hybridization (FISH), used in 55% and 54% of cases, respectively. Interestingly, higher-resolution methods, such as array-based techniques, were applied in only 21% of cases. To our knowledge, cases characterized using whole genome or exome sequencing have not been published yet. Although 33% of the reported cases had specific information on parental derivation, only in 17% of the cases the utilized genetic testing methods had been specified. Of these, (methylation-specific) multiplex ligation-dependent probe amplification (MS-MLPA) (12%) and microsatellite analysis (nearly 5%) were the primarily used methods. This suggests a gap in reporting the methodology of parental origin/derivation testing. Figure 1 Literature-based patient-level data set for Dup15q syndrome. (A) Barplots illustrating the total number of cases (x-axis) reported across different years (y-axis). Years without any case publications were excluded. (B) Wordcloud illustrating the spectrum and frequency of different nomenclature referring to (i)dic(15) used in the initial publications. The size of the text correlates with the number of publications which used the nomenclature. (C) Barplots illustrating the percentage of available data within the (i)dic(15) cohort. The percentage values refer to the total number of patients in the dataset (n=310). Breakpoint information specifies, whether the approximately breakpoint regarding the known recurrent breakpoint sites (BP1-BP5) or the exact breakpoint on nucleotide level was provided (exact breakpoint). (D) Barplots illustrating the percentage of cases which were analyzed with the corresponding diagnostic tools (x-axis). All array-based methods where subsumed under “Array ”. (MS-)MLPA = (methylation-specific) multiplex ligation-dependent probe amplification. MSA = microsatellite analysis. NA = Data not available Molecular architecture of the supernumerary (i)dic(15) The molecular structure and architecture of (i)dic(15) remains poorly characterized. A comprehensive understanding of the structure and its effects on gene expression is essential for improving genotype-phenotype predictions in Dup15q syndrome. To address this gap, we systematically analyzed the available genotype data regarding the molecular architecture of the (i)dic(15). We conducted a detailed analysis of the chromosomal breakpoints, focusing on their genomic distribution and frequency within the specific recurrent breakpoint regions (BP1 to BP5). Cases lacking information about the involved breakpoints were excluded from this analysis. The final analysis comprised 151 (i)dic(15) cases. Our findings revealed two main clusters of (i)dic(15) formations. The most frequent breakpoint combination was BP3:BP3, resulting in a symmetric idic(15) (n = 91; 61%). The second most prevalent combination was BP4:BP5, producing an asymmetric dicentric chromosome (n = 43; 29%). Less common breakpoint combinations included BP5:BP5 (n = 6; 4%), BP2:BP3 (n = 5; 3%), BP2:BP2 (n = 2; 1%), BP3:BP4 (n = 2; 1%) and BP4:BP4 (n = 1; 0.6%) (Figure 3, Suppl. Figure 2, Suppl. Table 5). Statistical analysis by chi square test confirmed the non-random distribution of breakpoint-breakpoint combinations (H 0 = breakpoint-breakpoint combinations are randomly distributed, X 2 = 389.45, df =7, p < 2.2×10 −16 ). Figure 3 Molecular architecture of supernumerary (i)dic(15) Dotplot illustrating the breakpoint combinations involved in the formation of (i)dic(15) chromosomes. Each point illustrates one patient. Colors indicate a specific data cluster, the shown dots where artificially scattered to facilitate visual interpretation. Only cases with available breakpoint information were included (n=151). Additionally, a small number of cases showed complex genomic rearrangements within the corresponding genomic intervals. These included hexasomy with a tricentric supernumerary chromosome and interstitial deletions within the marker chromosome (Suppl. Table 2, Suppl. Figure 2). These findings underscore the structural complexity and variability associated with Dup15q syndrome. Given that the involved 15q11.2q13 locus is rich in imprinted genes, which show differential expression depending on whether the affected chromosome 15 is maternally or paternally derived, we examined the parental-origin of the (i)dic(15) chromosomes. Of the 103 cases analyzed and annotated with parental-origin data, three were paternally derived, while 100 were maternally derived (Suppl. Table 2). Discussion In this study, we generated the largest literature-based cohort consisting of patient-level genotype data for Dup15q syndrome. This is a valuable resource for the scientific community, leveraging primary study identification and data-driven genotype analysis. A systematic analysis of publication patterns gave valuable insight into the historical and current research focus, highlighting the variability in nomenclature, identifying diagnostic trends and uncovering knowledge gaps. Utilizing the available genetic data, our study provides an understanding of the genomic architecture of supernumerary (i)dic(15) chromosomes, emphasizing the need for a deeper characterization of their structural variability. The described publication trends confirmed the ongoing interest in Dup15q syndrome, showing the enduring clinical relevance of Dup15q syndrome and the urgent need to understand its genotypical and phenotypical heterogeneity. Using a literature-based approach allowed us to confirm current estimations from the medical literature giving a frequency of a causative (i)dic(15) in ~ 75% of cases and interstitial CN-gains in ~ 25% (Battaglia 2008 ; Lusk et al. 1993 ; Ortiz-Prado et al. 2021 ). Further, our analysis stresses the need for a reliable nomenclature, to facilitate research communication and to avoid fragmentation of information. Historical genotype descriptions like inv dup(15q) or supernumerary marker chromosome are still frequently used. As the additional chromosomes are dicentric with one centromere being inactivated in most cases and usually resulting from a recombination between two homologues, nomenclature according to the current ISCN is “pseudo-dicentric chromosome 15” in most cases. In the cases where a mechanism based on a single breakpoint and fusion between sister chromatids is proven, it might also be referred to as a “pseudo iso-dicentric chromosome 15”. Besides the usage of correct ISCN nomenclature in genetic reports, the nomenclature within scientific publications should be generalizable, but also concise. Addressing this issue, we propose the nomenclature (i)dic(15), stressing the diverse breakpoints and variable structure of (i)dic(15), like in asymmetric (i)dic(15) chromosomes. We unraveled valuable insight into the architecture of (i)dic(15). Our results show that most (i)dic(15) had breakpoints at BP3:BP3, forming symmetric, isodicentric chromosomes, with BP4:BP5 being the next most common combination, resulting in asymmetric dicentric structures. Other combinations also occur but represent a minority of cases. This distribution suggests that the breakpoints BP3:BP3 and BP4/5:BP4/5 may represent a genomic hotspot prone to (i)dic(15) formation. The reasons why these breakpoints show mainly mutual combination during (i)dic(15) formation remains elusive. This underscores both the complexity of Dup15q syndrome and the challenges in advancing our understanding of its genotype-phenotype correlations. The concentration of breakpoints at BP3 and BP4/5 may be explained by intrinsic genomic features, such as repetitive sequences, chromatin organization, or susceptibility to recombination. Symmetric (BP3:BP3) and asymmetric (BP4:BP5) configurations may arise from distinct mechanisms. There is also evidence that even within the recurrent breakpoint regions, the exact breakpoint on nucleotide level is variable (Roberts et al. 2003 ; Wang et al. 2004 ). Investigating these mechanisms could reveal how specific structural features of the chromosomal region 15q influence the likelihood of rearrangement, and this might help identifying predisposing parental factors. While our data primarily focused on structural rearrangements, the potential association between specific breakpoint patterns (e.g., symmetric (BP3:BP3) vs. asymmetric (BP4:BP5)) and phenotypic characteristics might be interesting, allowing for genotype-phenotype predictions and to improve the precision of clinical management strategies for affected individuals. By incorporating data on both genotype and phenotype, future research could identify specific structural features that contribute to disease severity. Interestingly, most (i)dic(15) analyzed were maternally derived, aligning with prior evidence that maternal gametogenesis may be more susceptible to (i)dic(15) formation. Additionally, there might be negative reproductive selection against paternal gametes carrying a supernumerary chromosome (Liehr 2006 ; Lusk et al. 1993 ). The underrepresentation of paternally derived cases could also reflect ascertainment bias, as paternal derivation is often associated with milder and more variable phenotypes or even a non-disease phenotype, potentially leading to underdiagnosis or omission from studies. Moreover, the lack of molecular characterization of paternally derived (i)dic(15) highlights a gap in our understanding. Clarifying the differences between maternally and paternally imprinted (i)dic(15) chromosomes and their associated phenotypes could provide valuable insight into the underlying epigenetic disease mechanisms and their phenotypical consequences. Our approach unraveled missing data, especially regarding high resolution genotype data. The predominance of traditional diagnostic methods such as karyotyping and fluorescence in situ hybridization (FISH) in our dataset reflects historical practices, but also highlights the limitations of these techniques in detecting smaller or more complex rearrangements and to specify breakpoints at nucleotide level or to evaluate differentially imprinted regions. The underutilization of high-resolution array-based methods and the absence of whole genome/exome sequencing in reported cases suggest missed opportunities to identify novel cryptic structural variations. However, the repeat-dense structure and large size of supernumerary (i)dic(15) chromosomes challenge even the most sophisticated genetic tools used in routine diagnostics. Emerging long-read sequencing technologies, such as those based on nanopore or single-molecule real-time (SMRT) sequencing, represent a transformative approach to advancing our understanding of the structure and pathomechanisms in the context of (i)dic(15). These methods simultaneously provide detailed structural information, identify epigenetic changes, and allow for better breakpoint definition (Amarasinghe et al. 2020 ; Espinosa et al. 2024 ). Future studies should use these novel innovative approaches to further elucidate the genotype and to close the gaps in the available genetic data underlying Dup15q syndrome. Limitations and directions for future research This study has some limitations which are important to consider for interpretation. First, the analysis relies by design and nature on published information with variable completeness and heterogenous nomenclature. We made substantial efforts to harmonize this. Second, to avoid publication and database biases, we conducted this broad systematic literature review in five authoritative literature databases. As in any systematic review, there is never an absolute guarantee that, despite exhaustive search efforts, some published information may be missed. Third, data in this analysis are mainly from industrialized countries with may not represent the entire global patient community. Restricting the review to publications in specific languages may have led to the exclusion of relevant studies, particularly those from non-industrialized regions. Nevertheless, the size of the present sample set is important, considering that Dup15q syndrome is a rare disorder. Therefore, we consider our study generalizable in the context of the aforementioned important limitations. Conclusion In this study, we generated the largest literature-based cohort consisting of patient-level genotype data for (i)dic(15) associated Dup15q syndrome, allowing for case specific genotype analysis. We identified a significant gap within the molecular characterization of (i)dic(15), especially regarding differentially imprinted regions and nucleotide-level breakpoint and genomic structure information. With our systematic approach, we identified symmetric BP3:BP3 and asymmetric BP4:BP5 (i)dic(15) configurations as the most common (i)dic(15) formations, which may arise from distinct mechanisms and might determine characteristic genotype-phenotype consequences. Declarations Acknowledgements We thank the Eva Mayr-Stihl Stiftung for the support on our efforts to decipher the molecular architecture of Dup15q syndrome. The authors thank the individuals and families with Dup15q syndrome and the Dup15q e.V, for providing overwhelming support for our research program. The authors have no competing interests to declare that are relevant to the content of this article. Author contribution: Conceptualization: S.B., M.R., V.R., K.B., M.H., C.S.; Methodology: S.B., M.R.; Formal analysis and investigation: S.B.; Writing - original draft preparation: S.B; Writing - review and editing: M.R., V.R., K.B., M.H. C.S. Supervision: M.H., C.S. Data availability: The datasets generated during and/or analyzed during the current study are available in the supplementary tables. R code used for analysis is available from the corresponding author on reasonable request. References ISCN 2024: An International System for Human Cytogenomic Nomenclature (2024). S.Karger AG Al Ageeli E, Drunat S, Delanoe C, Perrin L, Baumann C, Capri Y, Fabre-Teste J, Aboura A, Dupont C, Auvin S, El Khattabi L, Chantereau D, Moncla A, Tabet AC, Verloes A (2014) Duplication of the 15q11-q13 region: clinical and genetic study of 30 new cases. 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Korean J Pediatr 55: 487-90. doi: 10.3345/kjp.2012.55.12.487 Kleefstra T, de Leeuw N, Wolf R, Nillesen WM, Schobers G, Mieloo H, Willemsen M, Perrotta CS, Poddighe PJ, Feenstra I, Draaisma J, van Ravenswaaij-Arts CM (2010) Phenotypic spectrum of 20 novel patients with molecularly defined supernumerary marker chromosomes 15 and a review of the literature. Am J Med Genet A 152A: 2221-9. doi: 10.1002/ajmg.a.33529 Liehr T (2006) Familial small supernumerary marker chromosomes are predominantly inherited via the maternal line. Genetics in Medicine 8: 459-462. doi: https://doi.org/10.1097/00125817-200607000-00011 Lusk L, Vogel-Farley V, DiStefano C, Jeste S (1993) Maternal 15q Duplication Syndrome. University of Washington, Seattle, Seattle (WA) Maggouta F, Roberts SE, Dennis NR, Veltman MW, Crolla JA (2003) A supernumerary marker chromosome 15 tetrasomic for the Prader-Willi/Angelman syndrome critical region in a patient with a severe phenotype. J Med Genet 40: e84. doi: 10.1136/jmg.40.7.e84 Mann SM, Wang NJ, Liu DH, Wang L, Schultz RA, Dorrani N, Sigman M, Schanen NC (2004) Supernumerary tricentric derivative chromosome 15 in two boys with intractable epilepsy: another mechanism for partial hexasomy. Hum Genet 115: 104-11. doi: 10.1007/s00439-004-1127-5 Mignon-Ravix C, Depetris D, Luciani JJ, Cuoco C, Krajewska-Walasek M, Missirian C, Collignon P, Delobel B, Croquette M-F, Moncla A, Kroisel PM, Mattei M-G (2007) Recurrent rearrangements in the proximal 15q11–q14 region: a new breakpoint cluster specific to unbalanced translocations. European Journal of Human Genetics 15: 432-440. doi: 10.1038/sj.ejhg.5201775 Mim RA, Soorajkumar A, Kosaji N, Rahman MM, Sarker S, Karuvantevida N, Eshaque TB, Rahaman MA, Islam A, Chowdhury MSJ, Shams N, Uddin KMF, Akter H, Uddin M (2024) Expanding deep phenotypic spectrum associated with atypical pathogenic structural variations overlapping 15q11-q13 imprinting region. Brain Behav 14: e3437. doi: 10.1002/brb3.3437 Orrico A, Zollino M, Galli L, Buoni S, Marangi G, Sorrentino V (2009) Late-onset Lennox-Gastaut syndrome in a patient with 15q11.2-q13.1 duplication. Am J Med Genet A 149A: 1033-5. doi: 10.1002/ajmg.a.32785 Ortiz-Prado E, Iturralde AL, Simbana-Rivera K, Gomez-Barreno L, Hidalgo I, Rubio-Neira M, Espinosa N, Izquierdo-Condoy J, Arteaga-Espinosa ME, Lister A, Lopez-Cortes A, Cabrera-Andrade A (2021) 15q Duplication Syndrome: Report on the First Patient from Ecuador with an Unusual Clinical Presentation. Case Rep Med 2021: 6662054. doi: 10.1155/2021/6662054 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372: n71. doi: 10.1136/bmj.n71 Parijs I, Brison N, Vancoillie L, Baetens M, Blaumeiser B, Boulanger S, Désir J, Dimitrov B, Fieremans N, Janssens K, Janssens S, Marichal A, Menten B, Meunier C, Van Berkel K, Van Den Bogaert A, Devriendt K, Van Den Bogaert K, Vermeesch JR (2024) Population screening for 15q11-q13 duplications: corroboration of the difference in impact between maternally and paternally inherited alleles. Eur J Hum Genet 32: 31-36. doi: 10.1038/s41431-023-01336-6 Pujana MA, Nadal M, Guitart M, Armengol L, Gratacòs M, Estivill X (2002) Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons. European Journal of Human Genetics 10: 26-35. doi: 10.1038/sj.ejhg.5200760 Punt AM, Judson MC, Sidorov MS, Williams BN, Johnson NS, Belder S, den Hertog D, Davis CR, Feygin MS, Lang PF, Jolfaei MA, Curran PJ, van IWF, Elgersma Y, Philpot BD (2022) Molecular and behavioral consequences of Ube3a gene overdosage in mice. JCI Insight 7. doi: 10.1172/jci.insight.158953 Roberts SE, Maggouta F, Thomas NS, Jacobs PA, Crolla JA (2003) Molecular and fluorescence in situ hybridization characterization of the breakpoints in 46 large supernumerary marker 15 chromosomes reveals an unexpected level of complexity. Am J Hum Genet 73: 1061-72. doi: 10.1086/379155 Sahoo T, Shaw CA, Young AS, Whitehouse NL, Schroer RJ, Stevenson RE, Beaudet AL (2005) Array-based comparative genomic hybridization analysis of recurrent chromosome 15q rearrangements. Am J Med Genet A 139A: 106-13. doi: 10.1002/ajmg.a.31000 Saravanapandian V, Frohlich J, Hipp JF, Hyde C, Scheffler AW, Golshani P, Cook EH, Reiter LT, Senturk D, Jeste SS (2020) Properties of beta oscillations in Dup15q syndrome. J Neurodev Disord 12: 22. doi: 10.1186/s11689-020-09326-1 Saravanapandian V, Nadkarni D, Hsu SH, Hussain SA, Maski K, Golshani P, Colwell CS, Balasubramanian S, Dixon A, Geschwind DH, Jeste SS (2021) Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome. Mol Autism 12: 54. doi: 10.1186/s13229-021-00460-8 Shehi E, Shah H, Singh A, Pampana VS, Kaur G (2022) The Linkage Between Autism Spectrum Disorder and Dup15q Syndrome: A Case Report. Cureus 14: e24205. doi: 10.7759/cureus.24205 Urraca N, Cleary J, Brewer V, Pivnick EK, McVicar K, Thibert RL, Schanen NC, Esmer C, Lamport D, Reiter LT (2013) The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature. Autism Res 6: 268-79. doi: 10.1002/aur.1284 Wang NJ, Liu D, Parokonny AS, Schanen NC (2004) High-resolution molecular characterization of 15q11-q13 rearrangements by array comparative genomic hybridization (array CGH) with detection of gene dosage. Am J Hum Genet 75: 267-81. doi: 10.1086/422854 Wang Q, Wu W, Xu Z, Luo F, Zhou Q, Li P, Xie J (2015) Copy number changes and methylation patterns in an isodicentric and a ring chromosome of 15q11-q13: report of two cases and review of literature. Mol Cytogenet 8: 97. doi: 10.1186/s13039-015-0198-4 Wegiel J, Flory M, Schanen NC, Cook EH, Nowicki K, Kuchna I, Imaki H, Ma SY, Wegiel J, London E, Casanova MF, Wisniewski T, Brown WT (2015) Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications. Acta Neuropathol Commun 3: 63. doi: 10.1186/s40478-015-0241-z Wegiel J, Schanen NC, Cook EH, Sigman M, Brown WT, Kuchna I, Nowicki K, Wegiel J, Imaki H, Ma SY, Marchi E, Wierzba-Bobrowicz T, Chauhan A, Chauhan V, Cohen IL, London E, Flory M, Lach B, Wisniewski T (2012) Differences between the pattern of developmental abnormalities in autism associated with duplications 15q11.2-q13 and idiopathic autism. J Neuropathol Exp Neurol 71: 382-97. doi: 10.1097/NEN.0b013e318251f537 Additional Declarations No competing interests reported. Supplementary Files Suppl.Tables.xlsx Suppl.Figure.pptx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5833554","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":407260879,"identity":"628a6a14-56ed-4236-9f12-e67b54751015","order_by":0,"name":"Sebastian Burkart","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":true,"prefix":"","firstName":"Sebastian","middleName":"","lastName":"Burkart","suffix":""},{"id":407260880,"identity":"8e560bc3-4a5d-4250-bfec-d46a12c42377","order_by":1,"name":"Markus Ries","email":"","orcid":"","institution":"Heidelberg University, University Hospital Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Markus","middleName":"","lastName":"Ries","suffix":""},{"id":407260881,"identity":"bb930c1c-9d38-42e0-be85-af4d788eb9f6","order_by":2,"name":"Verena Romero","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Verena","middleName":"","lastName":"Romero","suffix":""},{"id":407260882,"identity":"d9837fed-173f-4150-87ca-9eaa2762dc14","order_by":3,"name":"Karin Burau","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Karin","middleName":"","lastName":"Burau","suffix":""},{"id":407260883,"identity":"64f1a460-867d-4be1-b1e7-d06470bc75ce","order_by":4,"name":"Christian P. Schaaf","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"P.","lastName":"Schaaf","suffix":""},{"id":407260884,"identity":"8d116f80-d51a-4e49-8614-f40f44722276","order_by":5,"name":"Maja Hempel","email":"","orcid":"","institution":"University Hospital Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Maja","middleName":"","lastName":"Hempel","suffix":""}],"badges":[],"createdAt":"2025-01-15 10:23:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5833554/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5833554/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":74944403,"identity":"f098a36e-3156-417e-bcbb-234225adda10","added_by":"auto","created_at":"2025-01-28 15:12:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":104294,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart illustrating the systematic literature retrieval process according to PRISMA criteria for systematic review and subsequent data extraction process. In total, 310 cases with (i)dic(15) from 38 publications were included in this study.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5833554/v1/e00351e4cdd509a9d5e74423.png"},{"id":74944673,"identity":"ebb2a33c-8b66-4bc7-b117-05750d5e4efd","added_by":"auto","created_at":"2025-01-28 15:20:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":127105,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLiterature-based patient-level data set for Dup15q syndrome.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eBarplots illustrating the total number of cases (x-axis) reported across different years (y-axis). Years without any case publications were excluded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(B) \u003c/strong\u003eWordcloud illustrating the spectrum and frequency of different nomenclature referring to (i)dic(15) used in the initial publications. The size of the text correlates with the number of publications which used the nomenclature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(C) \u003c/strong\u003eBarplots illustrating the percentage of available data within the (i)dic(15) cohort. The percentage values refer to the total number of patients in the dataset (n=310). Breakpoint information specifies, whether the approximately breakpoint regarding the known recurrent breakpoint sites (BP1-BP5) or the exact breakpoint on nucleotide level was provided (exact breakpoint).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(D) \u003c/strong\u003eBarplots illustrating the percentage of cases which were analyzed with the corresponding diagnostic tools (x-axis). All array-based methods where subsumed under “Array\u003cem\u003e”. \u003c/em\u003e(MS-)MLPA = (methylation-specific) multiplex ligation-dependent probe amplification. MSA = microsatellite analysis. NA = Data not available\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5833554/v1/3f61f2b916b9905cb1445d1e.png"},{"id":74944407,"identity":"1e00b69b-603b-4426-81c3-bf6c5ee12a5c","added_by":"auto","created_at":"2025-01-28 15:12:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":16460,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMolecular architecture of supernumerary (i)dic(15)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDotplot illustrating the breakpoint combinations involved in the formation of (i)dic(15) chromosomes. Each point illustrates one patient. Colors indicate a specific data cluster, the shown dots where artificially scattered to facilitate visual interpretation. Only cases with available breakpoint information were included (n=151).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5833554/v1/816a7d1c795197ab9e43d97c.png"},{"id":74945824,"identity":"bd212f4d-6e08-4335-9275-dd3386640229","added_by":"auto","created_at":"2025-01-28 15:28:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":870227,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5833554/v1/ea1c742d-3ca1-4b3f-9247-0c7691e60828.pdf"},{"id":74944406,"identity":"d5768d04-9c00-4281-9c97-25c79046d7ef","added_by":"auto","created_at":"2025-01-28 15:12:30","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":45345,"visible":true,"origin":"","legend":"","description":"","filename":"Suppl.Tables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5833554/v1/3335e836eb036b0250635550.xlsx"},{"id":74944419,"identity":"7a613450-a024-4868-b11b-a395c1266b37","added_by":"auto","created_at":"2025-01-28 15:12:31","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19953264,"visible":true,"origin":"","legend":"","description":"","filename":"Suppl.Figure.pptx","url":"https://assets-eu.researchsquare.com/files/rs-5833554/v1/13c45f513be7ea4e81ca8e1a.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Unraveling the genomic architecture of supernumerary (iso-) dicentric chromosomes in Dup15q syndrome: Insight from a systematic literature-based study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChromosomal aberrations, particularly copy-number variations (CNVs), are frequent genetic alterations in neurodevelopmental disorders (NDDs), yet the comprehensive study of their structure and impact on genome-wide gene expression remains underexplored. Copy-number gains within the chromosomal 15q11.2-q13.1 region are among the most common chromosomal aberrations in NDD, closely linked to Dup15q syndrome, an infantile-onset neurodevelopmental disorder (Battaglia 2008; Depienne et al. 2009; Lusk et al. 1993; Wang et al. 2004). In approximately 75% of the cases, Dup15q syndrome is caused by a supernumerary pseudo (iso-)dicentric chromosome 15 [ (i)dic(15) ], while interstitial tandem CN gains account for the remaining 25%. Dup15q syndrome encompasses a wide spectrum of clinical manifestations, including hypotonia, developmental delay ranging from mild to severe, behavioral abnormalities, sleep disturbances, and epilepsy. The phenotypic severity of Dup15q syndrome seems to be determined by CNV number (triplications or tetraplications of the 15q11.2-q13.1 region) and localization of the additional genetic material (interstitial copy number gain or (i)dic(15)). However, dosage effects of this region alone do not fully explain the clinical variability observed in Dup15q syndrome (Urraca et al. 2013).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis suggests that additional pathomechanisms like size, structural variations, parental derivation, and epigenetic modifications (e.g., DNA methylation profiles) play significant roles in disease manifestation and expression\u0026nbsp;(Elamin et al. 2023; Parijs et al. 2024; Punt et al. 2022).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe 15q11.2-q13.1 region is unique within the human genome, containing abundant repetitive sequences and imprinted genes that exhibit parent-of-origin-specific expression (Cook et al. 1997; Hogart et al. 2010; Parijs et al. 2024). CNVs within this region are largely driven by low-copy repeat (LCR)-mediated recombination events, facilitated by recurrent breakpoint regions (BP1–BP5) located proximally on 15q. The distinct syndromic outcomes of CN-gains in this region are influenced by parent-of-origin effects, with maternally imprinted CN-gains being associated with significantly higher disease burden (Christian et al. 1999; Cox and Butler 2015; Mignon-Ravix et al. 2007; Pujana et al. 2002; Roberts et al. 2003).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere is a high medical need for a comprehensive understanding of the molecular structure of (i)dic(15), which is essential for an in-depth insight to the complex pathomechanisms and advancing clinical predictions in Dup15q syndrome, however, this remains\u0026nbsp;considerably underexplored. To close this gap, we conducted a comprehensive literature-based analysis of the supernumerary (i)dic(15) chromosome in Dup15q syndrome, with the following objectives:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eTo create an accessible set of genotype data from (i)dic(15) cases derived from the existing literature.\u003c/li\u003e\n \u003cli\u003eTo assess the quality and completeness of available genetic data and to identify gaps for future research.\u003c/li\u003e\n \u003cli\u003eTo elucidate the current knowledge of the molecular architecture of (i)dic(15) by mapping the distribution and frequency of chromosomal breakpoints within recurrent regions (BP1–BP5).\u003c/li\u003e\n \u003cli\u003eTo analyze the current knowledge of the parental origin of (i)dic(15).\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThis systematic literature-based case-level analysis allows novel data-driven insight into Dup15q syndrome, such as the molecular architecture of (i)dic(15), and helps \u0026nbsp;identifying and closing further gaps in the current knowledge. \u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eSelection Process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA comprehensive and systematic literature review in compliance with PRISMA criteria was conducted to identify publications reporting patient-level genetic data for (i)dic(15) (Page et al. 2021). To capture a broad spectrum of published information, the search included 5 established medical databases: Cochrane (Cochrane Reviews | Cochrane Library), Global Index Medicus (Global Index Medicus – World Health Organization), Web of Science (https://www.webofscience.com), Embase (www.embase.com) and PubMed (https://pubmed.ncbi.nlm.nih.gov/). Search terms included in the study were: “Dup15q syndrome“, „idic15q“, „duplication 15q11.2-q13 syndrome“. The search focused on publications in English language and was conducted on 29. July 2024. An inclusive data retrieval process was used to include relevant publications by cross-references, which would otherwise be missed. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eScreening and Eligibility Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn a first screening process, we excluded duplicated publications which were listed in several databases. One goal of this study was to evaluate the completeness and quality of genetic data reported on Dup15q syndrome in the literature. Subsequently, publications were screened for relevance, particularly on the availability of genetic data. We further aimed to conduct an in-depth analysis of genetic data at the individual case level. For that purpose, publications without any patient-level genetic data were excluded. Only publications fulfilling these criteria were deemed eligible for data extraction. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Extraction and Variables\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient-level genetic data were extracted from the included publications. Each case received an individual identifier within this study. Individuals which were described in multiple publications were only included once using the same identifier. For each case, we extracted the following variables to enable a comprehensive analysis: authors and the year of publication, reference genome build, breakpoints defined at the nucleotide level, breakpoints defined by the recurrent breakpoint regions (BP1 to BP5), estimated and exact size in kilobases, parental-origin, technology used for genetic testing, patient’s origin and nomenclature used to describe the genetic alteration. It was also extracted whether the gain of 15q material was due to the presence of a supernumerary (i)dic(15) chromosome or to an interstitial CNV. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Curation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs this study was focused on (i)dic(15), we excluded cases involving interstitial CNVs or cases where CNV type information was unavailable. As our study integrates different diagnostic methodologies which were used in the respective publications, we focused on the most relevant technologies in the context of Dup15q syndrome like karyotyping, fluorescence \u003cem\u003ein situ\u003c/em\u003e hybridization (FISH), array-based technologies and testing for parental origin (MS-MLPA, microsatellite analysis). We harmonized and summarized terminologies across the different publications. In publications without annotation of proband nationality, the country of the first author was used to determine country annotation. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStandard procedures of descriptive statistics were applied. Variables were illustrated using counts and percentages of the total cohort of (i)dic(15), unless stated otherwise. Percentages are rounded to whole numbers where appropriate. All analyses were performed using R (version 4.4.0; 24.04.2024) environment for statistical computing and graphics (https://www.r-project.org). Please refer to Suppl. Table 1 for detailed descriptions and software versions of the packages used. Missing data were not imputed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBecause this study is entirely based on the published scientific literature, and no patient or animal studies were conducted for this systematic analysis, an Institutional Review Board approval was not necessary.\u003cbr\u003e \u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003e\u003cstrong\u003eGeneration of a Dup15q syndrome cohort utilizing literature-based patient-level genotype data\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo identify and extract patient-level genetic data from the literature, we conducted a comprehensive and systematic literature search. PRISMA criteria were respected (Page et al. 2021). Cumulatively, 235 publications from PubMed (n=86), Embase (n=60) and Web of Science (n=89) were received, the search within the Cochrane and Global Index Medicus databases yielded no results. In an inclusive data retrieval process, these publications were manually screened for cross-references that might contribute additional relevant publications. With that approach, we identified 17 additional publications (n=4 on 28. September 2024; n=1 on 14. Novembre 2024; n=12 on 15. Novembre 2024). This resulted in a total of 252 publications available for manual review. In a first screening process, we excluded duplicates (n=155). Further, publications without any patient-level genotype data were excluded (n=59). Data extraction was performed on the remaining 38 publications. From these publications, patient-level genotype data were extracted for 421 individual cases. Individuals included in more than one publication were only included once. 108 cases showed an interstitial CN-gain, 3 cases had no CNV type information available. This corresponds to a percentage of 74% (310/418) of cases showing an supernumerary (i)dic(15), in line with current prevalence estimates in the medical literature. As this study was focused on (i)dic(15), we excluded cases involving interstitial CNVs or cases where CNV type information was unavailable (n=111).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn summary, this approach identified 310 cases from 38 publications with gain of 15q genetic material with a supernumerary chromosome, primarily in the form of an (i)dic(15) (Figure 1) (Al Ageeli et al. 2014; Baker et al. 2020; Battaglia et al. 1997; Battaglia et al. 2010; Blennow et al. 1995; Bonuccelli et al. 2017; Boronat et al. 2015; Coppola et al. 2013; Crolla et al. 1995; Dangles et al. 2021; Dawson et al. 2015; Dennis et al. 2006; DiStefano et al. 2016; Eggermann et al. 2002; Flejter et al. 1996; Friedman et al. 2016; Frohlich et al. 2022; Frohlich et al. 2016; Han et al. 2021; Hou and Wang 1998; Ingason et al. 2011; Kim et al. 2012; Kleefstra et al. 2010; Maggouta et al. 2003; Mann et al. 2004; Mim et al. 2024; Orrico et al. 2009; Ortiz-Prado et al. 2021; Roberts et al. 2003; Sahoo et al. 2005; Saravanapandian et al. 2020; Saravanapandian et al. 2021; Shehi et al. 2022; Urraca et al. 2013; Wang et al. 2004; Wang et al. 2015; Wegiel et al. 2015; Wegiel et al. 2012).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFlow chart illustrating the systematic literature retrieval process according to PRISMA criteria for systematic review and subsequent data extraction process. In total, 310 cases with (i)dic(15) from 38 publications were included in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study therefore has successfully generated the largest literature-based cohort of published patient-level genetic data for Dup15q syndrome to date. Detailed data for each patient is publicly available in Suppl. Table 2. The global distribution of cases from different countries is illustrated in Suppl. Figure 1, comprising mainly countries with high quality diagnostic infrastructure.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSystematic analysis of publication patterns\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eScientific interest in Dup15q syndrome and potential shifts in research focus over time were evaluated, allowing to uncover possible research gaps. We analyzed publication trends of patient-level data over time, spanning nearly three decades (Figure 2A, Suppl. Table 3). The oldest publication included in this study dates back to 1995, the most recent to 2022. Interestingly, there was no clear peak in the number of publications, with a maximum of 3 publications per year in 2016. The highest absolute number of reported Dup15q cases were published in the scientific literature in 2003. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs illustrated in the word cloud (Figure 2B) the nomenclature of the (i)dic(15) is highly variable and heterogeneous across different publications (i.e. smc(15), inv dup(15)), underscoring the urgent need to use standardized nomenclature to improve and facilitate research communication. To address this, we reviewed the International System for Human Cytogenomics Nomenclature (ISCN) 2024 to evaluate nomenclature aspects (Suppl. Table 4). We propose to use pseudo (iso) dicentric chromosome 15q with its ISCN conform abbreviation psu (i)dic(15) or simply (i)dic(15) for this particular supernumerary chromosome consisting of duplicated 15p, 15cen and proximal 15q region to streamline and standardize usage in clinical and research contexts.\u003c/p\u003e\n\u003cp\u003eTo evaluate the overall quality and completeness of the reported data and to identify possible gaps, the extent of available data was quantified for key parameters (Figure 2C). Information about the genetic test used for diagnostic testing were available in 66% (n=206), data on the parental derivation of the (i)dic(15) in 33% of cases (n=103). The approximate size of the (i)dic(15) was stated in only 2% of cases (n=5). Additionally, data on the exact nucleotide-level breakpoint or the involvement of recurrent breakpoints (BP1-BP5) were provided in 2% (n=7) and 51% (n=151) of cases, respectively (Suppl. Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurther, the diagnostic methods and platforms used for testing were categorized and analyzed to track their frequency and evolution over time (Figure 2D). Notably, 33% of the cases lacked any diagnostic method information. The most frequently employed methods were karyotyping and fluorescence in situ hybridization (FISH), used in 55% and 54% of cases, respectively. Interestingly, higher-resolution methods, such as array-based techniques, were applied in only 21% of cases. To our knowledge, cases characterized using whole genome or exome sequencing have not been published yet. Although 33% of the reported cases had specific information on parental derivation, only in 17% of the cases the utilized genetic testing methods had been specified. Of these, (methylation-specific) multiplex ligation-dependent probe amplification (MS-MLPA) (12%) and microsatellite analysis (nearly 5%) were the primarily used methods. This suggests a gap in reporting the methodology of parental origin/derivation testing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1 Literature-based patient-level data set for Dup15q syndrome.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u0026nbsp;\u003c/strong\u003eBarplots illustrating the total number of cases (x-axis) reported across different years (y-axis). Years without any case publications were excluded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(B)\u0026nbsp;\u003c/strong\u003eWordcloud illustrating the spectrum and frequency of different nomenclature referring to (i)dic(15) used in the initial publications. The size of the text correlates with the number of publications which used the nomenclature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(C)\u0026nbsp;\u003c/strong\u003eBarplots illustrating the percentage of available data within the (i)dic(15) cohort. The percentage values refer to the total number of patients in the dataset (n=310). Breakpoint information specifies, whether the approximately breakpoint regarding the known recurrent breakpoint sites (BP1-BP5) or the exact breakpoint on nucleotide level was provided (exact breakpoint).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(D)\u0026nbsp;\u003c/strong\u003eBarplots illustrating the percentage of cases which were analyzed with the corresponding diagnostic tools (x-axis). All array-based methods where subsumed under \u0026ldquo;Array\u003cem\u003e\u0026rdquo;.\u0026nbsp;\u003c/em\u003e(MS-)MLPA = (methylation-specific) multiplex ligation-dependent probe amplification. MSA = microsatellite analysis. NA = Data not available\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMolecular architecture of the supernumerary (i)dic(15)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe molecular structure and architecture of (i)dic(15) remains poorly characterized. A comprehensive understanding of the structure and its effects on gene expression is essential for improving genotype-phenotype predictions in Dup15q syndrome. To address this gap, we systematically analyzed the available genotype data regarding the molecular architecture of the (i)dic(15).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe conducted a detailed analysis of the chromosomal breakpoints, focusing on their genomic distribution and frequency within the specific recurrent breakpoint regions (BP1 to BP5). Cases lacking information about the involved breakpoints were excluded from this analysis. The final analysis comprised 151 (i)dic(15) cases. Our findings revealed two main clusters of (i)dic(15) formations. The most frequent breakpoint combination was BP3:BP3, resulting in a symmetric idic(15) (n = 91; 61%). The second most prevalent combination was BP4:BP5, producing an asymmetric dicentric chromosome (n = 43; 29%). Less common breakpoint combinations included BP5:BP5 (n = 6; 4%), BP2:BP3 (n = 5; 3%), BP2:BP2 (n = 2; 1%), BP3:BP4 (n = 2; 1%) and BP4:BP4 (n = 1; 0.6%) (Figure 3, Suppl. Figure 2, Suppl. Table 5). Statistical analysis by chi square test confirmed the non-random distribution of breakpoint-breakpoint combinations (H\u003csub\u003e0\u0026nbsp;\u003c/sub\u003e= breakpoint-breakpoint combinations are randomly distributed, X\u003csup\u003e2\u003c/sup\u003e = 389.45, df =7, p \u0026lt; 2.2\u0026times;10\u003csup\u003e\u0026minus;16\u003c/sup\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3 Molecular architecture of supernumerary (i)dic(15)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDotplot illustrating the breakpoint combinations involved in the formation of (i)dic(15) chromosomes. Each point illustrates one patient. Colors indicate a specific data cluster, the shown dots where artificially scattered to facilitate visual interpretation. Only cases with available breakpoint information were included (n=151).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditionally, a small number of cases showed complex genomic rearrangements within the corresponding genomic intervals. These included hexasomy with a tricentric supernumerary chromosome and interstitial deletions within the marker chromosome (Suppl. Table 2, Suppl. Figure 2). These findings underscore the structural complexity and variability associated with Dup15q syndrome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven that the involved 15q11.2q13 locus is rich in imprinted genes, which show differential expression depending on whether the affected chromosome 15 is maternally or paternally derived, we examined the parental-origin of the (i)dic(15) chromosomes. Of the 103 cases analyzed and annotated with parental-origin data, three were paternally derived, while 100 were maternally derived (Suppl. Table 2). \u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we generated the largest literature-based cohort consisting of patient-level genotype data for Dup15q syndrome. This is a valuable resource for the scientific community, leveraging primary study identification and data-driven genotype analysis. A systematic analysis of publication patterns gave valuable insight into the historical and current research focus, highlighting the variability in nomenclature, identifying diagnostic trends and uncovering knowledge gaps. Utilizing the available genetic data, our study provides an understanding of the genomic architecture of supernumerary (i)dic(15) chromosomes, emphasizing the need for a deeper characterization of their structural variability.\u003c/p\u003e \u003cp\u003eThe described publication trends confirmed the ongoing interest in Dup15q syndrome, showing the enduring clinical relevance of Dup15q syndrome and the urgent need to understand its genotypical and phenotypical heterogeneity. Using a literature-based approach allowed us to confirm current estimations from the medical literature giving a frequency of a causative (i)dic(15) in ~\u0026thinsp;75% of cases and interstitial CN-gains in ~\u0026thinsp;25% (Battaglia \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Lusk et al. \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; Ortiz-Prado et al. \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFurther, our analysis stresses the need for a reliable nomenclature, to facilitate research communication and to avoid fragmentation of information. Historical genotype descriptions like inv dup(15q) or supernumerary marker chromosome are still frequently used. As the additional chromosomes are dicentric with one centromere being inactivated in most cases and usually resulting from a recombination between two homologues, nomenclature according to the current ISCN is \u0026ldquo;pseudo-dicentric chromosome 15\u0026rdquo; in most cases. In the cases where a mechanism based on a single breakpoint and fusion between sister chromatids is proven, it might also be referred to as a \u0026ldquo;pseudo iso-dicentric chromosome 15\u0026rdquo;. Besides the usage of correct ISCN nomenclature in genetic reports, the nomenclature within scientific publications should be generalizable, but also concise. Addressing this issue, we propose the nomenclature (i)dic(15), stressing the diverse breakpoints and variable structure of (i)dic(15), like in asymmetric (i)dic(15) chromosomes.\u003c/p\u003e \u003cp\u003eWe unraveled valuable insight into the architecture of (i)dic(15). Our results show that most (i)dic(15) had breakpoints at BP3:BP3, forming symmetric, isodicentric chromosomes, with BP4:BP5 being the next most common combination, resulting in asymmetric dicentric structures. Other combinations also occur but represent a minority of cases. This distribution suggests that the breakpoints BP3:BP3 and BP4/5:BP4/5 may represent a genomic hotspot prone to (i)dic(15) formation. The reasons why these breakpoints show mainly mutual combination during (i)dic(15) formation remains elusive. This underscores both the complexity of Dup15q syndrome and the challenges in advancing our understanding of its genotype-phenotype correlations. The concentration of breakpoints at BP3 and BP4/5 may be explained by intrinsic genomic features, such as repetitive sequences, chromatin organization, or susceptibility to recombination. Symmetric (BP3:BP3) and asymmetric (BP4:BP5) configurations may arise from distinct mechanisms. There is also evidence that even within the recurrent breakpoint regions, the exact breakpoint on nucleotide level is variable (Roberts et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Wang et al. \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Investigating these mechanisms could reveal how specific structural features of the chromosomal region 15q influence the likelihood of rearrangement, and this might help identifying predisposing parental factors.\u003c/p\u003e \u003cp\u003eWhile our data primarily focused on structural rearrangements, the potential association between specific breakpoint patterns (e.g., symmetric (BP3:BP3) vs. asymmetric (BP4:BP5)) and phenotypic characteristics might be interesting, allowing for genotype-phenotype predictions and to improve the precision of clinical management strategies for affected individuals. By incorporating data on both genotype and phenotype, future research could identify specific structural features that contribute to disease severity.\u003c/p\u003e \u003cp\u003eInterestingly, most (i)dic(15) analyzed were maternally derived, aligning with prior evidence that maternal gametogenesis may be more susceptible to (i)dic(15) formation. Additionally, there might be negative reproductive selection against paternal gametes carrying a supernumerary chromosome (Liehr \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Lusk et al. \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e1993\u003c/span\u003e). The underrepresentation of paternally derived cases could also reflect ascertainment bias, as paternal derivation is often associated with milder and more variable phenotypes or even a non-disease phenotype, potentially leading to underdiagnosis or omission from studies. Moreover, the lack of molecular characterization of paternally derived (i)dic(15) highlights a gap in our understanding. Clarifying the differences between maternally and paternally imprinted (i)dic(15) chromosomes and their associated phenotypes could provide valuable insight into the underlying epigenetic disease mechanisms and their phenotypical consequences.\u003c/p\u003e \u003cp\u003eOur approach unraveled missing data, especially regarding high resolution genotype data. The predominance of traditional diagnostic methods such as karyotyping and fluorescence in situ hybridization (FISH) in our dataset reflects historical practices, but also highlights the limitations of these techniques in detecting smaller or more complex rearrangements and to specify breakpoints at nucleotide level or to evaluate differentially imprinted regions. The underutilization of high-resolution array-based methods and the absence of whole genome/exome sequencing in reported cases suggest missed opportunities to identify novel cryptic structural variations. However, the repeat-dense structure and large size of supernumerary (i)dic(15) chromosomes challenge even the most sophisticated genetic tools used in routine diagnostics. Emerging long-read sequencing technologies, such as those based on nanopore or single-molecule real-time (SMRT) sequencing, represent a transformative approach to advancing our understanding of the structure and pathomechanisms in the context of (i)dic(15). These methods simultaneously provide detailed structural information, identify epigenetic changes, and allow for better breakpoint definition (Amarasinghe et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Espinosa et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Future studies should use these novel innovative approaches to further elucidate the genotype and to close the gaps in the available genetic data underlying Dup15q syndrome.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLimitations and directions for future research\u003c/h2\u003e \u003cp\u003eThis study has some limitations which are important to consider for interpretation. First, the analysis relies by design and nature on published information with variable completeness and heterogenous nomenclature. We made substantial efforts to harmonize this. Second, to avoid publication and database biases, we conducted this broad systematic literature review in five authoritative literature databases. As in any systematic review, there is never an absolute guarantee that, despite exhaustive search efforts, some published information may be missed. Third, data in this analysis are mainly from industrialized countries with may not represent the entire global patient community. Restricting the review to publications in specific languages may have led to the exclusion of relevant studies, particularly those from non-industrialized regions. Nevertheless, the size of the present sample set is important, considering that Dup15q syndrome is a rare disorder. Therefore, we consider our study generalizable in the context of the aforementioned important limitations.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this study, we generated the largest literature-based cohort consisting of patient-level genotype data for (i)dic(15) associated Dup15q syndrome, allowing for case specific genotype analysis. We identified a significant gap within the molecular characterization of (i)dic(15), especially regarding differentially imprinted regions and nucleotide-level breakpoint and genomic structure information. With our systematic approach, we identified symmetric BP3:BP3 and asymmetric BP4:BP5 (i)dic(15) configurations as the most common (i)dic(15) formations, which may arise from distinct mechanisms and might determine characteristic genotype-phenotype consequences.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the Eva Mayr-Stihl Stiftung for the support on our efforts to decipher the molecular architecture of Dup15q syndrome. The authors thank the individuals and families with Dup15q syndrome and the Dup15q e.V, for providing overwhelming support for our research program.\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eAuthor contribution:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: S.B., M.R., V.R., K.B., M.H., C.S.; Methodology: S.B., M.R.; Formal analysis and investigation: S.B.; Writing - original draft preparation: S.B; Writing - review and editing: M.R., V.R., K.B., M.H. C.S. Supervision: M.H., C.S.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe datasets generated during and/or analyzed during the current study are available in the supplementary tables. R code used for analysis is available from the corresponding author on reasonable request.\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eISCN 2024: An International System for Human Cytogenomic Nomenclature (2024). S.Karger AG\u003c/li\u003e\n \u003cli\u003eAl Ageeli E, Drunat S, Delanoe C, Perrin L, Baumann C, Capri Y, Fabre-Teste J, Aboura A, Dupont C, Auvin S, El Khattabi L, Chantereau D, Moncla A, Tabet AC, Verloes A (2014) Duplication of the 15q11-q13 region: clinical and genetic study of 30 new cases. Eur J Med Genet 57: 5-14. doi: 10.1016/j.ejmg.2013.10.008\u003c/li\u003e\n \u003cli\u003eAmarasinghe SL, Su S, Dong X, Zappia L, Ritchie ME, Gouil Q (2020) Opportunities and challenges in long-read sequencing data analysis. 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Acta Neuropathol Commun 3: 63. doi: 10.1186/s40478-015-0241-z\u003c/li\u003e\n \u003cli\u003eWegiel J, Schanen NC, Cook EH, Sigman M, Brown WT, Kuchna I, Nowicki K, Wegiel J, Imaki H, Ma SY, Marchi E, Wierzba-Bobrowicz T, Chauhan A, Chauhan V, Cohen IL, London E, Flory M, Lach B, Wisniewski T (2012) Differences between the pattern of developmental abnormalities in autism associated with duplications 15q11.2-q13 and idiopathic autism. J Neuropathol Exp Neurol 71: 382-97. doi: 10.1097/NEN.0b013e318251f537\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dup15q syndrome, pseudo (iso-)dicentric chromosome 15 [ (i)dic(15) ], literature-based genotype data curation","lastPublishedDoi":"10.21203/rs.3.rs-5833554/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5833554/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChromosomal aberrations, particularly copy-number variations (CNVs), are prevalent in neurodevelopmental disorders (NDD) and significantly contribute to their pathogenesis. Copy-number gains (CN gains) in 15q11-q13, primarily consisting of a pseudo (iso-)dicentric chromosome 15 [ (i)dic(15) ] or an interstitial duplication, are among the most frequent CNVs in NDD. The associated Dup15q syndrome is an early onset neurodevelopmental disorder characterized by global developmental delay, behavioral issues, and seizures with a variable onset and expression of symptoms. While a correlation between number of 15q11-q13 CN gain and symptom severity has been proposed, it fails to fully explain the wide phenotypic variability observed.\u003c/p\u003e \u003cp\u003eWe conducted a comprehensive systematic literature-based analysis of the supernumerary (i)dic(15), generating the largest literature-based cohort consisting of patient-level genotype data for Dup15q syndrome to date. Our findings identified symmetric BP3:BP3 and asymmetric BP4:BP5 (i)dic(15) configurations as the most common (i)dic(15) formations, likely arising from distinct mechanisms and potentially driving characteristic genotype-phenotype outcomes. Additionally, we identified a significant gap within the molecular characterization of (i)dic(15), particularly regarding information on nucleotide-level breakpoint, genomic structure, and differentially imprinted genes, being important aspects for genotype-phenotype predictions.\u003c/p\u003e \u003cp\u003eOur findings provide critical insight into the molecular architecture of (i)dic(15), offering valuable implications for understanding pathomechanisms and guidance for future research into the molecular and clinical aspects of Dup15q syndrome.\u003c/p\u003e","manuscriptTitle":"Unraveling the genomic architecture of supernumerary (iso-) dicentric chromosomes in Dup15q syndrome: Insight from a systematic literature-based study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-28 15:12:25","doi":"10.21203/rs.3.rs-5833554/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"90cfbb47-a0cd-41d2-a351-3c3383ff7fc1","owner":[],"postedDate":"January 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-28T15:12:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-28 15:12:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5833554","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5833554","identity":"rs-5833554","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}