Phenotypic heterogeneity of Duplication Syndrome 22q11.2: relevance of genomic DNA analysis

Phenotypic heterogeneity of Duplication Syndrome 22q11.2: relevance of genomic DNA analysis | 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 Case Report Phenotypic heterogeneity of Duplication Syndrome 22q11.2: relevance of genomic DNA analysis Maria Carolina Florez Polo, Lina Johanna Moreno Giraldo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7927418/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract The 22q11.2DupS is a rare autosomal dominant disorder characterized by a broad spectrum of clinical manifestations, including intellectual disability, dysmorphic features, and congenital anomalies. The phenotypic heterogeneity of 22q11.2DupS complicates both clinical diagnosis and management. Traditional screening methods, such as fetal ultrasound, often fail to detect these abnormalities early, leading to delayed diagnoses. However, advancements in chromosomal microarray analysis (CMA) hold promise for improving detection, particularly in high-risk pregnancies. This report presents the case of a female patient with dysmorphias, neurodevelopmental delay and behavioral alterations without related family history or consanguinity. A diagnosed patient with 22q11.2DupS through genomic DNA analysis using the Agilent® SurePrint G3 Human CGH + SNP array. A heterozygous interstitial duplication was identified at chromosomal coordinates 22q11.22. This duplication affects the TOP3B gene, which is not currently associated with any known pathology but has been implicated in genomic stability and cellular aging. The 22q11.2DupS is a rare chromosomal disorder characterized by a broad spectrum of phenotypic manifestations, including intellectual disability, dysmorphic features, and congenital anomalies. Despite increasing recognition of this condition, comprehensive descriptions of its full clinical spectrum remain limited. Similar duplications have been classified with varying pathogenicity in public databases. In conclusion, 22q11.2DupS presents a complex clinical challenge due to its broad phenotypic spectrum. Early detection through advanced genetic testing, such as CGH + SNP array, genetic counseling, and therapies like cognitive-behavioral therapy and speech therapy, are essential for the effective management of the condition. As no specific therapies are available, treatment remains symptomatic. 22q11.2 duplication syndrome genetic testing chromosomal microarray interstitial duplication TOP3B gene clinical spectrum precision medicine Figures Figure 1 Introduction Chromosome 22q11.2 contains a region of low-copy number repeats (LCRs) that is particularly susceptible to unequal crossing over during meiosis, leading to the development of 22q11.2 deletion syndrome (22q11.2DS) or 22q11.2 duplication syndrome (22q11.2DupS). (1). Chromosome 22 exhibits a high susceptibility to non-allelic homologous recombination (NAHR) due to the abundance of LCRs, specifically designated as LCR-A through LCR-H within the 22q11.2 region. This recombination mechanism generates copy number variations (CNVs), such as duplications and deletions, characterized by recurrent breakpoints and diverse phenotypic presentations. (2). The 22q11.2 locus contains genes critical for brain development (3). The 22q11.2 duplication syndrome (22q11.2DupS) is an autosomal dominant disorder resulting from an additional copy of a segment of chromosome 22. This duplication, along with deletions in the same region, arises due to unequal crossover events during meiosis I, which occur as a consequence of misalignment of low-copy repeat sequences (LCRs) within the 22q11 band (4). The prevalence of 22q11.2 duplication syndrome (22q11.2DupS) in individuals with intellectual disability is estimated to be 1 in 700. Considering that approximately 6.5 million people in the United States have an intellectual disability, it is projected that there are around 9,285 cases of 22q11.2 duplication syndrome within this population (5). The 22q11.2DupS is a rare chromosomal disorder characterized by a broad spectrum of phenotypic manifestations, including intellectual disability, dysmorphic features, and congenital anomalies. Despite increasing recognition of this condition, comprehensive descriptions of its full clinical spectrum remain limited (1). In addition to structural anomalies, emerging evidence suggests that language development may be significantly affected in individuals with 22q11.2DupS. A study by Jente et al. (2023) found that children with 22q11.2 duplications exhibited notable language impairments when compared to the general population. Although both 22q11.2 deletion syndrome (22q11.2DS) and 22q11.2DupS are associated with language deficits, differences in what are considered natural features of these impairments have been observed. While 22q11.2DS is primarily characterized by word-level difficulties, individuals with 22q11.2DupS demonstrate more pronounced sentence-level impairments (6). These findings underscore the need for further research to elucidate the neurodevelopmental impact of this condition. Prenatal diagnosis of 22q11.2DupS presents significant challenges due to its phenotypic variability and incomplete penetrance (7). Current screening methods rely heavily on fetal ultrasound to identify abnormalities that may prompt further genetic testing. However, factors such as fetal developmental variability, ultrasound technology limitations, and operator experience can lead to missed diagnoses, particularly in the early stages of pregnancy (8). Given the expanding role of chromosomal microarray analysis (CMA) in prenatal diagnostics, there is potential for improved detection rates, particularly in pregnancies identified as high-risk due to advanced maternal age or abnormal first-trimester screening results (2). Early detection and timely supportive care, including genetic counseling and therapies like cognitive-behavioral therapy and speech therapy, are essential for effective management of this condition. Ongoing research is necessary to deepen understanding and improve the management of 22q11.2 duplication syndrome (22q11.2Dup) (4). Identifying 22q11.2DupS through genetic testing not only confirms the diagnosis but also enables early intervention strategies, including specialized therapies for neurodevelopmental impairments, structured follow-up for congenital anomalies, and multidisciplinary care approaches aimed at improving long-term outcomes (4). Case report It is presented the case of an 11-year-5-month-old female, born to non-consanguineous parents (both 32 years old at the time of conception), with a previous cesarean section. She was born at term with a weight of 2500 g and a height of 50 cm. Without prenatal ultrasound alterations, there were no signs of perinatal complications. On physical examination, she presented dysmorphic features, including a broad forehead, widely spaced eyes, a bulbous nose, retrognathia, irregular dentition, a high-arched palate, and small, low-set ears. Additional findings included a webbed neck, global developmental delay, and mutism. She avoided eye contact and did not engage with the examiner. Her medical history includes mild bilateral conductive hearing loss. She has surgical history, including adenoidectomy, turbinoplasty, tonsillectomy, and tympanostomy with ventilation tube placement on two occasions. She has been diagnosed with mild to moderate cognitive deficit, IQ 40, and primary language development disorder characterized by functional impairment of comprehensive and expressive language by a neuropsychology test report, schooled in third grade, without psychiatry assessment. A chromosomal karyotype analysis performed revealed a 46,XX result. Considering the above and adding the importance of ruling out the presence of genetic syndrome related to phenotypic and neurodevelopmental-behavioral alterations in the patient without related family history and given the need for a precise diagnosis to guide management, provision of appropriate follow-up, determination of prognosis and offering genetic counseling—including an assessment of heritability risk—chromosomal microarray analysis (CMA) or comparative genomic hybridization (CGH) was requested. These molecular cytogenetic techniques allow for detecting copy number variations (CNVs), such as deletions or duplications, which could explain her clinical presentation. Results Genomic DNA extraction was conducted from a peripheral blood sample of the patient, followed by the implementation of corresponding quality controls. Subsequently, labeling of both the patient's DNA and the reference DNA (female control) was carried out followed by hybridization using the Agilent® SurePrint G3 Human CGH + SNP array 4x180K (array number: 252983083582_1_2-430046) , according to previously established protocols of an accredited laboratory for genomic studies. The data were scanned using SureScan®, with subsequent data acquisition, quality analysis, and result interpretation performed using Agilent CytoGenomics v5® software. A heterozygous interstitial duplication of uncertain clinical significance was detected at chromosomal coordinates 22q11.22, with genomic coordinates chr22:21959009_22202339. Similar-sized duplications have been reported in the Database of Genomic Variants (DGV) and Genome Aggregation Database (gnomAD). Similar-sized duplications have been classified as likely pathogenic and were reported in patients with attention deficit hyperactivity disorder (ADHD), mild intellectual disability, obsessive-compulsive behavior, and schizophrenia. This duplication partially overlaps a locus identified by the Clinical Genome Resource as having evidence of triplosensitivity ( https://clinicalgenome.org/ ). (Fig. 1 ) Data reanalysis is performed through applied bioinformatics and by searching for this coordinate in GeneScout Location (from NCBI, GRCh38 (hg38)): CHR22:21,957,025 − 21,982,787, it relates to Chromosome 22q11.2 microduplication syndrome, mechanism of inheritance of AD and case report; MIM Phenotype 608363; the TOP3B DNA topoisomerase III beta gene is located in this coordinate, Gene MIM Number: 603582; Dosage ID:ISCA-14015, ClinGen Curation ID:CCID:008026. A search in the Human Phenotype Ontology (HPO) for the TOP3B gene (NCBIGene:8940), located at 22q11.22, describes that TOP3B encodes a DNA topoisomerase, an enzyme that regulates the topological states of DNA during transcription. This enzyme facilitates the transient cleavage and re-ligation of a single DNA strand, allowing strand passage and relaxation of supercoils, thereby modifying DNA topology. TOP3B interacts with the DNA helicase SGS1 and plays a crucial role in DNA recombination, genomic stability, and cellular aging. Additionally, reduced expression of this gene has been associated with increased survival rates in breast cancer patients. A pseudogene of TOP3B is also present on chromosome 22. A summary of reviewed information includes descriptions of patients with microduplications of 22q11.21–q11.23 with de novo inheritance mechanisms, maternal, and unknown inheritance, including the LCR22D-LCR22E region of chromosome 22, which contains TOP3B. These patients had heterogeneous phenotypes with variable features, including developmental delays, attention deficits, mild intellectual disability, dysmorphic features, and hypotonia. These duplications contained several genes besides TOP3B, and patients with a range of phenotypes were found. Discussion Duplications encompassing the LCR-A to LCR-D interval have been associated with a spectrum of clinical manifestations, ranging from mild neurodevelopmental impairments to severe congenital anomalies, including bladder exstrophy and cardiac malformations. The phenotypic heterogeneity of 22q11.2DupS complicates clinical diagnosis and management ( 2 ). Previous studies, such as that by Mary L. et al. (2021), have contributed insights into the prevalence of various clinical features associated with 22q11.2DupS. Their analysis of 42 patients, supplemented by 20 additional cases from the literature, highlighted a range of congenital anomalies, including congenital heart defects (26.1%), cleft or submucous cleft palate (11.7%), growth failure (27.4%), microcephaly (16.3%), macrocephaly (4.9%), hearing loss (16.2%), vision anomalies (28.1%), intellectual disability (24.3%), learning disabilities (22.4%), developmental delay (58.1%), seizures (11.3%), autism spectrum disorder (13.4%), and Attention deficit disorder (ADD)/Attention deficit hyperactivity disorder (ADHD) (18.5%) ( 2 ). Patients with 22q11.2DupS have also been reported to have a variety of other spectrums of congenital heart disease (CHD), including anomalous pulmonary venous connections, d-transposition of the great arteries, Ebstein's anomaly, and vascular rings ( 9 ). In the study by Barkit L.E. (2021), birth history was available for 37 subjects. Most of the patients described (86%) were born at full term (n = 32), and ultrasound anomalies were reported in four pregnancies. Birth weights and lengths were recorded for 33 and 27 subjects, respectively, with the majority (67%) having birth weights below the 50th percentile (n = 22). Regarding diagnostic methods, CGH or SNP microarray was the most used technique (78.6%, n = 33), followed by FISH (9.5%, n = 4), qPCR (9.5%, n = 4), and prenatal diagnosis via MaterniT® Genome array (2.4%, n = 1). The mean age at diagnosis was 3.5 years (SD 4.2 years), emphasizing the delayed identification of the condition in many cases. Notably, this cohort exhibited a higher prevalence of congenital heart defects, vision anomalies, and growth impairment compared to the general population ( 1 ). The condition encompasses a wide range of congenital anomalies and neurodevelopmental challenges. The high frequency of congenital heart defects, growth failure, and vision anomalies in affected individuals suggests that early and comprehensive medical evaluations are crucial for optimizing patient outcomes. Additionally, given the significant prevalence of neurodevelopmental disorders, including intellectual disability, developmental delay, autism spectrum disorder, and ADHD/ADD, routine neurocognitive assessments should be considered in clinical practice ( 1 ). Prenatal screening and diagnosis of 22q11.2DupS continue to pose significant challenges. ( 8 ). Li et al. (2023) report two prenatal cases of 22q11.2DupS detected by noninvasive prenatal testing (NIPT) and confirmed via SNP array in fetal amniotic fluid. CNV-seq analysis of maternal blood assessed clinical manifestations and identified breakpoints and affected genes. The study highlights the phenotypic variability of 22q11.2 duplication syndrome, emphasizes the importance of prenatal diagnosis, and provides guidance for genetic counseling. ( 10 ). The variability in ultrasound findings, coupled with the limitations of current screening programs, results in many cases being undiagnosed until postnatal genetic testing is performed ( 8 ). Advanced genomic technology integration, such as chromosomal microarrays, into routine prenatal care has enhanced detection rates of fetal chromosomal abnormalities, particularly in high-risk pregnancies ( 2 ). These diagnostic tools allow for a more precise diagnosis, facilitating the implementation of targeted treatment strategies and personalized medical follow-up. Diagnosis of 22q11.2 duplication syndrome only based on clinical features is challenging, as most cases evade detection by routine karyotyping. Chromosomal microarray analysis has improved the identification of chromosome 22 copy number variations, increasing diagnostic accuracy ( 11 ). Patients with 22q11.2DupS often have a wide range of health issues, and many of these symptoms mimic those of other conditions. Currently, no specific therapies are available. Therefore, the treatment of these syndromes is symptomatic. ( 11 ). In summary, 22q11.2DupS represents a complex genetic condition with a broad range of clinical manifestations. Ongoing research should be focused on improving early detection strategies and developing targeted interventions to address the diverse medical and developmental challenges affected individuals face. Conclusion This case report highlights the complexity of the phenotypic variability of the 22q11.2 duplication syndrome (22q11.2DupS), emphasizing the challenges associated with diagnosis and, most importantly, personalized diagnosis and management. The findings underscore the importance of genomic testing, particularly chromosomal microarray analysis, in detecting copy number variations that might go unnoticed with other diagnostic approaches. Given the syndrome's association with neurodevelopmental disorders and previously described congenital anomalies, early detection and timely intervention—including genetic counseling and therapies such as cognitive-behavioral therapy and speech therapy—are essential for an effective and targeted approach that improves prognosis and ensures appropriate follow-up. In conclusion, this case reinforces the importance of integrating genomic medicine and genomic data reanalysis and evaluating patients with neurodevelopmental disorders and congenital anomalies. Enhancing diagnostic accuracy and enabling early intervention may achieve a more personalized and more effective management approach. Declarations Funding The authors declare that they received no financial support for the research, authorship, and/or publication of this article. Conflicts of Interest The authors declare that they have no conflicts of interest to disclose regarding the content of this manuscript. Ethical Approval This study was reviewed and approved by the Institutional Ethics Committee of Clínica Nueva de Cali , which certified that all procedures complied with internationally recognized ethical standards, including the Declaration of Helsinki, the Council for International Organizations of Medical Sciences (CIOMS) guidelines, and the International Council for Harmonisation (ICH) Good Clinical Practice. Additionally, the research adhered to Resolution 008430/1993 issued by the Ministry of Health of Colombia, which regulates health research at the national level. A copy of the institutional ethics approval letter is attached to this submission. Consent to Participate Written informed consent was obtained from the patient’s legal guardians prior to inclusion in this study. Consent for Publication Written consent for publication of this case report, including clinical and genetic information, was obtained from the patient’s legal guardians. Data and Materials Availability All data generated or analyzed during this study are included in this published article. Additional details are available from the corresponding author upon reasonable request. Code Availability Not applicable Author Contributions All authors contributed equally to the conception, data collection, analysis, and writing of the manuscript. Both authors critically reviewed and approved the final version of the paper. Clinical trial number: not applicable. References Barkit LE, et al. 22q11.2 duplications: Expanding the clinical presentation. Am J Med Genet A. 2022;188(3):779–87. Mary, L., et al. Prenatal phenotype of 22q11 micro-duplications: A systematic review and report on 12 new cases. Eur J Med Genet. 2022;65:104422. Schleifer CH. Effects of gene dosage and development on subcortical nuclei volumes in individuals with 22q11.2 copy number variations. Neuropsychopharmacology. 2024;49(5):1024–32. doi:10.1038/s41386-023-01841-2. Balakrishnan RK, et al. A case of 22q11.2 microduplication syndrome with review of literature. Educ Adm Theory Pract. 2024;30(5):2256–2358. Mikulas C, et al. 22q11.2 duplication syndrome: A rare chromosomal disorder with variable phenotypical and clinical presentations. Scholar Pilot Valid Stud. 2023;4(1):14–7. doi:10.32778/SPVS.71366.2023.37. Verbesselt J, et al. Language profiles of school-aged children with 22q11.2 copy number variants. Genes. 2023;14(4):679. Jiang Y, et al. Prenatal diagnosis and genetic study of 22q11.2 microduplication in Chinese fetuses: A series of 31 cases and literature review. Mol Genet Genomic Med. 2024;12(1):e2498. Wang X, et al. Preliminary study of noninvasive prenatal screening for 22q11.2 deletion/duplication syndrome using multiplex dPCR assay. Orphanet J Rare Dis. 2023;18(1):278. Butensky A. Cardiac evaluation of patients with 22q11.2 duplication syndrome. Am J Med Genet A. 2021;185(3):753–8. doi:10.1002/ajmg.a.62011. Li H, Gong Y, Chen J, Xie L, Li B, Xiang Y, Xie M. Diagnosis of prenatal 22q11.2 duplication syndrome: a two-case study. J Genet. 2023;102(4). Jun KR. Deletion or Duplication Syndromes of Chromosome 22. J Interdiscip Genomics. 2024;6(1):1-5. Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":247678,"visible":true,"origin":"","legend":"\u003cp\u003eGenomic View (https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11993)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7927418/v1/87cfe1fa11424e5e91a5968c.png"},{"id":95315606,"identity":"21c7fd14-0312-4771-ac6b-8e560a818b16","added_by":"auto","created_at":"2025-11-06 15:56:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":595841,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7927418/v1/a778c5c3-606f-46af-8f3c-8edaec96437c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Phenotypic heterogeneity of Duplication Syndrome 22q11.2: relevance of genomic DNA analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChromosome 22q11.2 contains a region of low-copy number repeats (LCRs) that is particularly susceptible to unequal crossing over during meiosis, leading to the development of 22q11.2 deletion syndrome (22q11.2DS) or 22q11.2 duplication syndrome (22q11.2DupS). (1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChromosome 22 exhibits a high susceptibility to non-allelic homologous recombination (NAHR) due to the abundance of LCRs, specifically designated as LCR-A through LCR-H within the 22q11.2 region. This recombination mechanism generates copy number variations (CNVs), such as duplications and deletions, characterized by recurrent breakpoints and diverse phenotypic presentations. (2). The 22q11.2 locus contains genes critical for brain development (3).\u0026nbsp;The 22q11.2 duplication syndrome (22q11.2DupS) is an autosomal dominant disorder resulting from an additional copy of a segment of chromosome 22. This duplication, along with deletions in the same region, arises due to unequal crossover events during meiosis I, which occur as a consequence of misalignment of low-copy repeat sequences (LCRs) within the 22q11 band (4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe prevalence of 22q11.2 duplication syndrome (22q11.2DupS) in individuals with intellectual disability is estimated to be 1 in 700. Considering that approximately 6.5 million people in the United States have an intellectual disability, it is projected that there are around 9,285 cases of 22q11.2 duplication syndrome within this population (5).\u003c/p\u003e\n\u003cp\u003eThe 22q11.2DupS is a rare chromosomal disorder characterized by a broad spectrum of phenotypic manifestations, including intellectual disability, dysmorphic features, and congenital anomalies. Despite increasing recognition of this condition, comprehensive descriptions of its full clinical spectrum remain limited (1).\u003c/p\u003e\n\u003cp\u003eIn addition to structural anomalies, emerging evidence suggests that language development may be significantly affected in individuals with 22q11.2DupS. A study by Jente et al. (2023) found that children with 22q11.2 duplications exhibited notable language impairments when compared to the general population. Although both 22q11.2 deletion syndrome (22q11.2DS) and 22q11.2DupS are associated with language deficits, differences in what are considered natural features of these impairments have been observed. While 22q11.2DS is primarily characterized by word-level difficulties, individuals with 22q11.2DupS demonstrate more pronounced sentence-level impairments (6). These findings underscore the need for further research to elucidate the neurodevelopmental impact of this condition.\u003c/p\u003e\n\u003cp\u003ePrenatal diagnosis of 22q11.2DupS presents significant challenges due to its phenotypic variability and incomplete penetrance (7). Current screening methods rely heavily on fetal ultrasound to identify abnormalities that may prompt further genetic testing. However, factors such as fetal developmental variability, ultrasound technology limitations, and operator experience can lead to missed diagnoses, particularly in the early stages of pregnancy (8). Given the expanding role of chromosomal microarray analysis (CMA) in prenatal diagnostics, there is potential for improved detection rates, particularly in pregnancies identified as high-risk due to advanced maternal age or abnormal first-trimester screening results (2).\u003c/p\u003e\n\u003cp\u003eEarly detection and timely supportive care, including genetic counseling and therapies like cognitive-behavioral therapy and speech therapy, are essential for effective management of this condition. Ongoing research is necessary to deepen understanding and improve the management of 22q11.2 duplication syndrome (22q11.2Dup) (4).\u003c/p\u003e\n\u003cp\u003eIdentifying 22q11.2DupS through genetic testing not only confirms the diagnosis but also enables early intervention strategies, including specialized therapies for neurodevelopmental impairments, structured follow-up for congenital anomalies, and multidisciplinary care approaches aimed at improving long-term outcomes (4).\u0026nbsp;\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eIt is presented the case of an 11-year-5-month-old female, born to non-consanguineous parents (both 32 years old at the time of conception), with a previous cesarean section. She was born at term with a weight of 2500 g and a height of 50 cm. Without prenatal ultrasound alterations, there were no signs of perinatal complications.\u003c/p\u003e\u003cp\u003eOn physical examination, she presented dysmorphic features, including a broad forehead, widely spaced eyes, a bulbous nose, retrognathia, irregular dentition, a high-arched palate, and small, low-set ears. Additional findings included a webbed neck, global developmental delay, and mutism. She avoided eye contact and did not engage with the examiner.\u003c/p\u003e\u003cp\u003eHer medical history includes mild bilateral conductive hearing loss. She has surgical history, including adenoidectomy, turbinoplasty, tonsillectomy, and tympanostomy with ventilation tube placement on two occasions. She has been diagnosed with mild to moderate cognitive deficit, IQ 40, and primary language development disorder characterized by functional impairment of comprehensive and expressive language by a neuropsychology test report, schooled in third grade, without psychiatry assessment. A chromosomal karyotype analysis performed revealed a 46,XX result.\u003c/p\u003e\u003cp\u003eConsidering the above and adding the importance of ruling out the presence of genetic syndrome related to phenotypic and neurodevelopmental-behavioral alterations in the patient without related family history and given the need for a precise diagnosis to guide management, provision of appropriate follow-up, determination of prognosis and offering genetic counseling\u0026mdash;including an assessment of heritability risk\u0026mdash;chromosomal microarray analysis (CMA) or comparative genomic hybridization (CGH) was requested. These molecular cytogenetic techniques allow for detecting copy number variations (CNVs), such as deletions or duplications, which could explain her clinical presentation.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eGenomic DNA extraction was conducted from a peripheral blood sample of the patient, followed by the implementation of corresponding quality controls. Subsequently, labeling of both the patient's DNA and the reference DNA (female control) was carried out followed by \u003cb\u003ehybridization using the Agilent\u0026reg; SurePrint G3 Human CGH\u0026thinsp;+\u0026thinsp;SNP array 4x180K (array number: 252983083582_1_2-430046)\u003c/b\u003e, according to previously established protocols of an accredited laboratory for genomic studies. The data were scanned using SureScan\u0026reg;, with subsequent data acquisition, quality analysis, and result interpretation performed using Agilent CytoGenomics v5\u0026reg; software.\u003c/p\u003e\u003cp\u003eA heterozygous interstitial duplication of uncertain clinical significance was detected at chromosomal coordinates 22q11.22, with genomic coordinates chr22:21959009_22202339. Similar-sized duplications have been reported in the Database of Genomic Variants (DGV) and Genome Aggregation Database (gnomAD). Similar-sized duplications have been classified as likely pathogenic and were reported in patients with attention deficit hyperactivity disorder (ADHD), mild intellectual disability, obsessive-compulsive behavior, and schizophrenia. This duplication partially overlaps a locus identified by the Clinical Genome Resource as having evidence of triplosensitivity (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicalgenome.org/\u003c/span\u003e\u003cspan address=\"https://clinicalgenome.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eData reanalysis is performed through applied bioinformatics and by searching for this coordinate in GeneScout Location (from NCBI, GRCh38 (hg38)): CHR22:21,957,025\u0026thinsp;\u0026minus;\u0026thinsp;21,982,787, it relates to Chromosome 22q11.2 microduplication syndrome, mechanism of inheritance of AD and case report; MIM Phenotype 608363; the TOP3B DNA topoisomerase III beta gene is located in this coordinate, Gene MIM Number: 603582; Dosage ID:ISCA-14015, ClinGen Curation ID:CCID:008026.\u003c/p\u003e\u003cp\u003eA search in the Human Phenotype Ontology (HPO) for the TOP3B gene (NCBIGene:8940), located at 22q11.22, describes that TOP3B encodes a DNA topoisomerase, an enzyme that regulates the topological states of DNA during transcription. This enzyme facilitates the transient cleavage and re-ligation of a single DNA strand, allowing strand passage and relaxation of supercoils, thereby modifying DNA topology. TOP3B interacts with the DNA helicase SGS1 and plays a crucial role in DNA recombination, genomic stability, and cellular aging. Additionally, reduced expression of this gene has been associated with increased survival rates in breast cancer patients. A pseudogene of TOP3B is also present on chromosome 22.\u003c/p\u003e\u003cp\u003eA summary of reviewed information includes descriptions of patients with microduplications of 22q11.21\u0026ndash;q11.23 with \u003cem\u003ede novo\u003c/em\u003e inheritance mechanisms, maternal, and unknown inheritance, including the LCR22D-LCR22E region of chromosome 22, which contains TOP3B. These patients had heterogeneous phenotypes with variable features, including developmental delays, attention deficits, mild intellectual disability, dysmorphic features, and hypotonia. These duplications contained several genes besides TOP3B, and patients with a range of phenotypes were found.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDuplications encompassing the LCR-A to LCR-D interval have been associated with a spectrum of clinical manifestations, ranging from mild neurodevelopmental impairments to severe congenital anomalies, including bladder exstrophy and cardiac malformations. The phenotypic heterogeneity of 22q11.2DupS complicates clinical diagnosis and management (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePrevious studies, such as that by Mary L. et al. (2021), have contributed insights into the prevalence of various clinical features associated with 22q11.2DupS. Their analysis of 42 patients, supplemented by 20 additional cases from the literature, highlighted a range of congenital anomalies, including congenital heart defects (26.1%), cleft or submucous cleft palate (11.7%), growth failure (27.4%), microcephaly (16.3%), macrocephaly (4.9%), hearing loss (16.2%), vision anomalies (28.1%), intellectual disability (24.3%), learning disabilities (22.4%), developmental delay (58.1%), seizures (11.3%), autism spectrum disorder (13.4%), and Attention deficit disorder (ADD)/Attention deficit hyperactivity disorder (ADHD) (18.5%) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Patients with 22q11.2DupS have also been reported to have a variety of other spectrums of congenital heart disease (CHD), including anomalous pulmonary venous connections, d-transposition of the great arteries, Ebstein's anomaly, and vascular rings (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn the study by Barkit L.E. (2021), birth history was available for 37 subjects. Most of the patients described (86%) were born at full term (n\u0026thinsp;=\u0026thinsp;32), and ultrasound anomalies were reported in four pregnancies. Birth weights and lengths were recorded for 33 and 27 subjects, respectively, with the majority (67%) having birth weights below the 50th percentile (n\u0026thinsp;=\u0026thinsp;22). Regarding diagnostic methods, CGH or SNP microarray was the most used technique (78.6%, n\u0026thinsp;=\u0026thinsp;33), followed by FISH (9.5%, n\u0026thinsp;=\u0026thinsp;4), qPCR (9.5%, n\u0026thinsp;=\u0026thinsp;4), and prenatal diagnosis via MaterniT\u0026reg; Genome array (2.4%, n\u0026thinsp;=\u0026thinsp;1). The mean age at diagnosis was 3.5 years (SD 4.2 years), emphasizing the delayed identification of the condition in many cases. Notably, this cohort exhibited a higher prevalence of congenital heart defects, vision anomalies, and growth impairment compared to the general population (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe condition encompasses a wide range of congenital anomalies and neurodevelopmental challenges. The high frequency of congenital heart defects, growth failure, and vision anomalies in affected individuals suggests that early and comprehensive medical evaluations are crucial for optimizing patient outcomes. Additionally, given the significant prevalence of neurodevelopmental disorders, including intellectual disability, developmental delay, autism spectrum disorder, and ADHD/ADD, routine neurocognitive assessments should be considered in clinical practice (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePrenatal screening and diagnosis of 22q11.2DupS continue to pose significant challenges. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Li et al. (2023) report two prenatal cases of 22q11.2DupS detected by noninvasive prenatal testing (NIPT) and confirmed via SNP array in fetal amniotic fluid. CNV-seq analysis of maternal blood assessed clinical manifestations and identified breakpoints and affected genes. The study highlights the phenotypic variability of 22q11.2 duplication syndrome, emphasizes the importance of prenatal diagnosis, and provides guidance for genetic counseling. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The variability in ultrasound findings, coupled with the limitations of current screening programs, results in many cases being undiagnosed until postnatal genetic testing is performed (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Advanced genomic technology integration, such as chromosomal microarrays, into routine prenatal care has enhanced detection rates of fetal chromosomal abnormalities, particularly in high-risk pregnancies (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). These diagnostic tools allow for a more precise diagnosis, facilitating the implementation of targeted treatment strategies and personalized medical follow-up.\u003c/p\u003e\u003cp\u003eDiagnosis of 22q11.2 duplication syndrome only based on clinical features is challenging, as most cases evade detection by routine karyotyping. Chromosomal microarray analysis has improved the identification of chromosome 22 copy number variations, increasing diagnostic accuracy (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePatients with 22q11.2DupS often have a wide range of health issues, and many of these symptoms mimic those of other conditions. Currently, no specific therapies are available. Therefore, the treatment of these syndromes is symptomatic. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn summary, 22q11.2DupS represents a complex genetic condition with a broad range of clinical manifestations. Ongoing research should be focused on improving early detection strategies and developing targeted interventions to address the diverse medical and developmental challenges affected individuals face.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case report highlights the complexity of the phenotypic variability of the 22q11.2 duplication syndrome (22q11.2DupS), emphasizing the challenges associated with diagnosis and, most importantly, personalized diagnosis and management. The findings underscore the importance of genomic testing, particularly chromosomal microarray analysis, in detecting copy number variations that might go unnoticed with other diagnostic approaches. Given the syndrome's association with neurodevelopmental disorders and previously described congenital anomalies, early detection and timely intervention\u0026mdash;including genetic counseling and therapies such as cognitive-behavioral therapy and speech therapy\u0026mdash;are essential for an effective and targeted approach that improves prognosis and ensures appropriate follow-up.\u003c/p\u003e\u003cp\u003eIn conclusion, this case reinforces the importance of integrating genomic medicine and genomic data reanalysis and evaluating patients with neurodevelopmental disorders and congenital anomalies. Enhancing diagnostic accuracy and enabling early intervention may achieve a more personalized and more effective management approach.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe authors declare that they received no financial support for the research, authorship, and/or publication of this article.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe authors declare that they have no conflicts of interest to disclose regarding the content of this manuscript.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThis study was reviewed and approved by the Institutional Ethics Committee of \u003cstrong\u003eClínica Nueva de Cali\u003c/strong\u003e, which certified that all procedures complied with internationally recognized ethical standards, including the Declaration of Helsinki, the Council for International Organizations of Medical Sciences (CIOMS) guidelines, and the International Council for Harmonisation (ICH) Good Clinical Practice. Additionally, the research adhered to Resolution 008430/1993 issued by the Ministry of Health of Colombia, which regulates health research at the national level.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eA copy of the institutional ethics approval letter is attached to this submission.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWritten informed consent was obtained from the patient’s legal guardians prior to inclusion in this study.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for Publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWritten consent for publication of this case report, including clinical and genetic information, was obtained from the patient’s legal guardians.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData and Materials Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll data generated or analyzed during this study are included in this published article. Additional details are available from the corresponding author upon reasonable request.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNot applicable\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll authors contributed equally to the conception, data collection, analysis, and writing of the manuscript. Both authors critically reviewed and approved the final version of the paper.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical trial number: not applicable.\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBarkit LE, et al. 22q11.2 duplications: Expanding the clinical presentation. Am J Med Genet A. 2022;188(3):779\u0026ndash;87.\u003c/li\u003e\n\u003cli\u003eMary, L., et al. Prenatal phenotype of 22q11 micro-duplications: A systematic review and report on 12 new cases. Eur J Med Genet. 2022;65:104422.\u003c/li\u003e\n\u003cli\u003eSchleifer CH. Effects of gene dosage and development on subcortical nuclei volumes in individuals with 22q11.2 copy number variations. \u003cem\u003eNeuropsychopharmacology.\u003c/em\u003e 2024;49(5):1024\u0026ndash;32. doi:10.1038/s41386-023-01841-2.\u003c/li\u003e\n\u003cli\u003eBalakrishnan RK, et al. A case of 22q11.2 microduplication syndrome with review of literature. Educ Adm Theory Pract. 2024;30(5):2256\u0026ndash;2358.\u003c/li\u003e\n\u003cli\u003eMikulas C, et al. 22q11.2 duplication syndrome: A rare chromosomal disorder with variable phenotypical and clinical presentations. Scholar Pilot Valid Stud. 2023;4(1):14\u0026ndash;7. doi:10.32778/SPVS.71366.2023.37.\u003c/li\u003e\n\u003cli\u003eVerbesselt J, et al. Language profiles of school-aged children with 22q11.2 copy number variants. Genes. 2023;14(4):679.\u003c/li\u003e\n\u003cli\u003eJiang Y, et al. Prenatal diagnosis and genetic study of 22q11.2 microduplication in Chinese fetuses: A series of 31 cases and literature review. Mol Genet Genomic Med. 2024;12(1):e2498.\u003c/li\u003e\n\u003cli\u003eWang X, et al. Preliminary study of noninvasive prenatal screening for 22q11.2 deletion/duplication syndrome using multiplex dPCR assay. Orphanet J Rare Dis. 2023;18(1):278.\u003c/li\u003e\n\u003cli\u003eButensky A. Cardiac evaluation of patients with 22q11.2 duplication syndrome. \u003cem\u003eAm J Med Genet A.\u003c/em\u003e 2021;185(3):753\u0026ndash;8. doi:10.1002/ajmg.a.62011.\u003c/li\u003e\n\u003cli\u003eLi H, Gong Y, Chen J, Xie L, Li B, Xiang Y, Xie M. Diagnosis of prenatal 22q11.2 duplication syndrome: a two-case study. \u003cem\u003eJ Genet.\u003c/em\u003e 2023;102(4).\u003c/li\u003e\n\u003cli\u003eJun KR. Deletion or Duplication Syndromes of Chromosome 22. \u003cem\u003eJ Interdiscip Genomics.\u003c/em\u003e 2024;6(1):1-5.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"molecular-cytogenetics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mocy","sideBox":"Learn more about [Molecular Cytogenetics](http://molecularcytogenetics.biomedcentral.com/)","snPcode":"13039","submissionUrl":"https://submission.nature.com/new-submission/13039/3","title":"Molecular Cytogenetics","twitterHandle":"@OAgenetics","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"22q11.2 duplication syndrome, genetic testing, chromosomal microarray, interstitial duplication, TOP3B gene, clinical spectrum, precision medicine","lastPublishedDoi":"10.21203/rs.3.rs-7927418/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7927418/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe 22q11.2DupS is a rare autosomal dominant disorder characterized by a broad spectrum of clinical manifestations, including intellectual disability, dysmorphic features, and congenital anomalies. The phenotypic heterogeneity of 22q11.2DupS complicates both clinical diagnosis and management. Traditional screening methods, such as fetal ultrasound, often fail to detect these abnormalities early, leading to delayed diagnoses. However, advancements in chromosomal microarray analysis (CMA) hold promise for improving detection, particularly in high-risk pregnancies.\u003c/p\u003e\u003cp\u003eThis report presents the case of a female patient with dysmorphias, neurodevelopmental delay and behavioral alterations without related family history or consanguinity. A diagnosed patient with 22q11.2DupS through genomic DNA analysis using the Agilent\u0026reg; SurePrint G3 Human CGH\u0026thinsp;+\u0026thinsp;SNP array. A heterozygous interstitial duplication was identified at chromosomal coordinates 22q11.22. This duplication affects the TOP3B gene, which is not currently associated with any known pathology but has been implicated in genomic stability and cellular aging. The 22q11.2DupS is a rare chromosomal disorder characterized by a broad spectrum of phenotypic manifestations, including intellectual disability, dysmorphic features, and congenital anomalies. Despite increasing recognition of this condition, comprehensive descriptions of its full clinical spectrum remain limited. Similar duplications have been classified with varying pathogenicity in public databases.\u003c/p\u003e\u003cp\u003eIn conclusion, 22q11.2DupS presents a complex clinical challenge due to its broad phenotypic spectrum. Early detection through advanced genetic testing, such as CGH\u0026thinsp;+\u0026thinsp;SNP array, genetic counseling, and therapies like cognitive-behavioral therapy and speech therapy, are essential for the effective management of the condition. As no specific therapies are available, treatment remains symptomatic.\u003c/p\u003e","manuscriptTitle":"Phenotypic heterogeneity of Duplication Syndrome 22q11.2: relevance of genomic DNA analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-06 04:14:35","doi":"10.21203/rs.3.rs-7927418/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-09T18:34:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"86617756171432472541458822918803644548","date":"2026-02-17T19:31:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-23T18:30:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-23T18:19:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-23T04:03:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Cytogenetics","date":"2025-10-23T02:02:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-cytogenetics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mocy","sideBox":"Learn more about [Molecular Cytogenetics](http://molecularcytogenetics.biomedcentral.com/)","snPcode":"13039","submissionUrl":"https://submission.nature.com/new-submission/13039/3","title":"Molecular Cytogenetics","twitterHandle":"@OAgenetics","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"04851a3c-5d65-425f-85d4-91e79ced1f7b","owner":[],"postedDate":"November 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-06T04:14:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-06 04:14:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7927418","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7927418","identity":"rs-7927418","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}