Isabelle Schrauwen

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Journals/Publications

• Abdullah, ., Bharadwaj, T., Javed, S., Khan, H., Acharya, A., Ji, W., Umm-E-Kalsoom, ., Ali, H., Schrauwen, I., Ahmad, W., Lakhani, S. A., & Leal, S. M. (2025). Novel Variants Underlie Nonsyndromic Postaxial Polydactyly. Genes, 16(9).
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  Extra digits on the hands and/or feet are a frequent condition known as polydactyly. Twelve nonsyndromic polydactyly genes have been identified, including .
• Bharadwaj, T., Acharya, A., Manyisa, N. R., Aboagye, E. T., Peigou Wonkam, R., Xhakaza, L., Popel, K., de Kock, C., Schrauwen, I., Wonkam, A., & Leal, S. M. (2025). The Diverse Genetic Landscape of Hearing Impairment in South African Families. Clinical genetics, 108(5), 511-520.
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  To elucidate the genetic etiology of hearing impairment (HI) in South Africa, 45 nonsyndromic HI (NSHI) and syndromic HI (SHI) families with ≥ 2 affected members were analyzed. Exome and sanger sequencing were used to identify causal genes. For NSHI, 14 of 24 families segregated variants in NSHI genes, that is, CDH23, GJB2, MITF, MYO7A, MYO15A, PCDH15, POU3F4, REST, SLC26A4, TMPRSS3, and WFS1. For the 21 SHI families, 14 have Waardenburg syndrome, two Branchio-Oto-Renal syndromes, and one each with Bartter, Chudley-McCullough, Deafness-Albinism, MYH9-related disorder, and Pendred syndromes. The cause of SHI was determined for 14 families, with EDN3, EDNRB, GPSM2, MITF, MYH9, SLC12A1, and SLC26A4 underlying the syndrome in a single family, EYA1 in two families, and PAX3 in five families. For the NSHI and SHI genes, 52.9% and 35.7% of the variants, respectively, have not been reported in disease etiology. Additionally, two Waardenburg families segregated variants in NSHI genes, BDP1 and MYO6, but these findings need to be validated. This study enhances the understanding of the genetic landscape of HI in South Africa, revealing a high level of locus and allelic heterogeneity. Studying diverse populations provides new insights into HI etiology that, in turn, can improve genetic diagnosis and personalized management.
• Cornejo-Sanchez, D. M., Bharadwaj, T., Dong, R., Wang, G. T., Schrauwen, I., DeWan, A. T., & Leal, S. M. (2025). Mendelian non-syndromic and syndromic hearing loss genes contribute to presbycusis. European journal of human genetics : EJHG, 33(6), 758-767.
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  Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants in well-established Mendelian HL genes play an important role in ARHL etiology. In all we identified 32 Mendelian HL genes which are associated with ARHL. We performed single and rare-variant aggregate association analyses using exome data obtained from white-Europeans with self-reported hearing phenotypes from the UK Biobank. Our analysis revealed previously unreported associations between ARHL and rare-variants in Mendelian non-syndromic and syndromic HL genes, including MYO15A, and WFS1. Additionally, rare-variant aggregate association analyses identified associations with Mendelian HL genes i.e., ACTG1, GRHL2, KCNQ4, MYO7A, PLS1, TMPRSS3, and TNRC6B. Four novel ARHL genes were also detected: FBXO2 and PALM3, implicated in HL in mice, TWF1, associated with HL in Dalmatian dogs, and TXNDC17. In-silico analyses provided further evidence of inner ear expression of these genes in both murine and human models, supporting their relevance to ARHL. Analysis of variants with minor allele frequency >0.005 revealed additional ARHL associations with known e.g., ILDR1 and novel i.e., ABHD12, COA8, KANSL1, SERAC1, and UBE3B Mendelian non-syndromic and syndromic HL genes as well as ARHL associations with genes that have not been previously reported to be involved in HL e.g., VCL. Rare-variants in Mendelian HL genes typically exhibited higher effect sizes for ARHL compared to those in other associated genes. In conclusion, this study highlights the critical role Mendelian non-syndromic and syndromic HL genes play in the etiology of ARHL.
• Planas-Serra, L., Rodríguez-Ruiz, M., Anderson, E. N., Rodríguez-Palmero, A., Vélez-Santamaria, V., Schlüter, A., Verdura, E., Gereñu, G., Jiménez-Zúñiga, A., Iñañez, A., Casas, J., Bech, J. J., De La Torre, C., Martínez, . J., Ruiz, M., Fourcade, S., Iascone, M., Tenconi, R., Meier, K., , Diegmann, S., et al. (2025). Bi-allelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder. American journal of human genetics, 112(11), 2643-2664.
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  The ribosomal protein S6 kinase family members play essential biological functions in disease, from cancer to intellectual disability. Little is known about ribosomal proteins S6 kinase C1 (RPS6KC1), aside from its lack of phosphorylation capacity and its roles in sphingosine-1-phosphate signaling and peroxiredoxin-3 (PRDX3) transport to mitochondria. Through whole-exome sequencing, we identified bi-allelic RPS6KC1 variants in 13 individuals from 8 independent families. Phenotypic manifestations included neurodevelopmental delay, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome caused by RPS6KA3 mutations. Functional studies on peripheral blood mononuclear cells (PBMCs) from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and sphingosine kinase 1 (SPHK1), accompanied by marked repression of the mammalian target of rapamycin (mTOR)/phosphatidylinositol 3-kinase (PI3K) pathway. We detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Further studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan. These findings underscore the crucial roles of RPS6KC1 in neurodevelopment by controlling ribosomal protein synthesis, lipid signaling, and the mTOR pathway.
• Sattar, S., Bharadwaj, T., Kalsoom, U. E., Acharya, A., Khan, S., Leal, S. M., & Schrauwen, I. (2025). A pathogenic COL7A1 variant highlights semi-dominant inheritance in dystrophic epidermolysis bullosa. BMC medical genomics, 18(1), 26.
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  Dystrophic epidermolysis bullosa is a rare subtype of inherited epidermolysis bullosa, caused by variants in the collagen type VII alpha 1 chain (COL7A1) gene (MIM120120). Both autosomal dominant and recessive inheritance has been reported with variable phenotype. We investigated a Pakistani family with dystrophic epidermolysis bullosa via exome sequencing and identified a pathogenic nonsense variant in COL7A1 NM_000094 c.1573 C > T:p.(Arg525*). The inheritance pattern observed was consistent with a semi-dominant model, where heterozygous parents exhibited a mild phenotype, and homozygous children were more severely affected. For dystrophic epidermolysis bullosa, loss-of-function variants are typically associated with the autosomal recessive form, while missense variants are linked to the autosomal dominant form. A review of the literature suggests a semi-dominance pattern for some missense variants, particularly glycine substitutions, but this concept had not been formally recognized. This study highlights the importance of considering semi-dominant inheritance models for dystrophic epidermolysis bullosa and other Mendelian diseases with an autosomal recessive mode of inheritance, as it can significantly impact diagnosis and genetic counseling.
• Thomas, H. B., Demain, L. A., Cabrera-Orefice, A., Schrauwen, I., Shamseldin, H. E., Rea, A., Bharadwaj, T., Smith, T. B., Oláhová, M., Thompson, K., He, L., Kaur, N., Shukla, A., Abukhalid, M., Ansar, M., Rehman, S., Riazuddin, S., Abdulwahab, F., Smith, J. M., , Stark, Z., et al. (2025). Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency. American journal of human genetics, 112(4), 952-962.
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  Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.
• Tshering, K. C., DiStefano, M. T., Oza, A. M., Ajuyah, P., Webb, R., Edoh, E., Broeren, E., Ratliff, J., Gitau, V., Paris, K., Aburyyan, A., Alexander, J., Albano, V., Bai, D., Booth, K. T., Buonfiglio, P. I., Charfeddine, C., Dalamón, V., Castillo, I. D., , Moreno-Pelayo, M. A., et al. (2025). ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time. Genetics in medicine : official journal of the American College of Medical Genetics, 27(10), 101500.
• Twumasi Aboagye, E., Adadey, S. M., Alves de Souza Rios, L., Esoh, K. K., Wonkam-Tingang, E., Xhakaza, L., De Kock, C., Schrauwen, I., Amenga-Etego, L., Lang, D., Awandare, G. A., Leal, S. M., Mowla, S., & Wonkam, A. (2025). Bi-Allelic Variant Identified with Exome Sequencing in a Consanguineous Multiplex Ghanaian Family Segregating Non-Syndromic Hearing Loss. International journal of molecular sciences, 26(7).
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  Genetic studies and phenotypic expansion of hearing loss (HL) for people living in Africa are greatly needed. We evaluated the clinical phenotypes of three affected siblings presenting non-syndromic (NS) HL and five unaffected members of a consanguineous Ghanaian family. Analysis of exome sequence data was performed for all affected and one unaffected family members. In-depth genetic and cellular characterization studies were performed to investigate biological significance of the implicated variant using bioinformatic tools and cell-based experimentation. Audiological examinations showed severe-to-profound, bilateral, symmetrical, and post-lingual onset. The whole-exome sequencing (WES) identified a homozygous frameshift variant: MARVEL domain containing 2 ():c.1058dup;p.(Val354Serfs*5) in all affected siblings. This frameshift variant leads to an early stop codon insertion and predicted to be targeted by nonsense medicated decay (mutant protein predicted to lack conserved C-terminal domain if translated). Cell immunofluorescence and immunocytochemistry studies exposed the functional impact of the mutant protein's expression, stability, localization, protein-protein binding, barrier function, and actin cytoskeleton architecture. The identified variant segregates with NSHL in the index Ghanaian family. The data support this nonsense variant as pathogenic, likely to impact the homeostasis of ions, solutes, and other molecules, compromising membrane barrier and signaling in the inner ear spaces.
• Uwibambe, E., Yalcouyé, A., Aboagye, E. T., Xhakaza, L., Popel, K., Dukuze, N., Bharadwaj, T., de Kock, C., Schrauwen, I., Leal, S. M., Mutesa, L., & Wonkam, A. (2025). Exome sequencing revealed a novel homozygous variant in TRMT61 A in a multiplex family with atypical Cornelia de Lange Syndrome from Rwanda. BMC medical genomics, 18(1), 85.
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  In 30% of patients who exhibit the clinical profile of Cornelia de Lange Syndrome (CdLS), the genetic cause remains undetermined. This proportion tends to be higher in low-resource settings including Africa. We performed a molecular characterization of CdLS in a multiplex Rwandan family.
• Yalcouyé, A., Schrauwen, I., Traoré, O., Bamba, S., Aboagye, E. T., Acharya, A., Bharadwaj, T., Latanich, R., Esoh, K., Fortes-Lima, C. A., de Kock, C., Jonas, M., Maiga, A. D., Cissé, C. A., Sangaré, M. A., Guinto, C. O., Landouré, G., Leal, S. M., & Wonkam, A. (2025). Whole-exome sequencing reveals known and candidate genes for hearing impairment in Mali. HGG advances, 6(1), 100391.
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  Hearing impairment (HI) is the most common neurosensory disorder globally and is reported to be more prevalent in low-income countries. In high-income countries, up to 50% of congenital childhood HI is of genetic origin. However, there are limited genetic data on HI from sub-Saharan African populations. In this study, we investigated the genetic causes of HI in the Malian populations, using whole-exome sequencing. Furthermore, cDNA was transfected into HEK293T cells for localization and expression analysis in a candidate gene. Twenty-four multiplex families were enrolled, 50% (12/24) of which are consanguineous. Clustering methods showed patterns of admixture from non-African sources in some Malian populations. Variants were found in six known nonsyndromic HI (NSHI) genes, four genes that can underlie either syndromic HI (SHI) or NSHI, one SHI gene, and one novel candidate HI gene. Overall, 75% of families (18/24) were solved, and 94.4% (17/18) had variants in known HI genes including MYO15A, CDH23, MYO7A, GJB2, SLC26A4, PJVK, OTOGL, TMC1, CIB2, GAS2, PDCH15, and EYA1. A digenic inheritance (CDH23 and PDCH15) was found in one family. Most variants (59.1%, 13/22) in known HI genes were not previously reported or associated with HI. The UBFD1 candidate HI gene, which was identified in one consanguineous family, is expressed in human inner ear organoids. Cell-based experiments in HEK293T showed that mutants UBFD1 had a lower expression, compared to wild type. We report the profile of known genes and the UBFD1 candidate gene for HI in Mali and emphasize the potential of gene discovery in African populations.
• Bharadwaj, T., Acharya, A., Khan, F. U., Khan, S., Ullah, I., Schrauwen, I., Ahmad, W., & Leal, S. M. (2024). THBS1 is a new autosomal recessive non-syndromic hearing impairment gene. BMC medical genomics, 17(1), 291.
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  Prelingual hearing impairment (HI) is genetically highly heterogenous. Early diagnosis and intervention are essential for psychosocial development. In this study we investigated a consanguineous family from Pakistan with autosomal recessive (AR) non-syndromic sensorineural HI (NSHI).
• Lessel, I., Baresic, A., Chinn, I. K., May, J., Goenka, A., Chandler, K. E., Posey, J. E., Afenjar, A., Averdunk, L., Bedeschi, M. F., Besnard, T., Brager, R., Brick, L., Brugger, M., Brunet, T., Byrne, S., Calle-Martín, O. d., Capra, V., Cardenas, P., , Chappé, C., et al. (2025). DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders. American journal of human genetics.
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  BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.

Presentations

• Schrauwen, I. (2025, 05/06/2025).

  Omics-Driven Insights into the Pathophysiology of Neurological and Sensorineural Disorders

  . Keynote Neuroscience speaker, Biomedical Research Day. University of Arizona College of Medicine-Phoenix, Phoenix, AZ.
• Schrauwen, I. (2025, 01/27/2025).

  Exploring the genomic dark matter of neurodevelopmental disorders. 

  . Barrow at Phoenix Children’s Pediatric Neuroscience Grand Rounds, Phoenix Children Hospital. virtual.
• Schrauwen, I. (2025, 01/31/2025).

  Decoding the Genomic Dark Matter of Rare Neurological Disorders. 

  . BMI & Data Science (BIDS) Seminar ASU. Health Futures Center Arizona State University.
• Schrauwen, I. (2025, 03/12/2025).

  Unraveling Neurological Diseases: A Journey Through the Genomic Dark Matter

  . UACOMP MD/PhD Colloquium, University of Arizona College of Medicine-Phoenix. University of Arizona College of Medicine-Phoenix.
• Schrauwen, I. (2025, 05/07/2025).

  The Genetics of Hearing loss

  . Grand Rounds, Department of Otolaryngology. University of Arizona, Banner – University Medical Center Tucson and Banner – University Medical Center South.
• Schrauwen, I. (2025, 09/03/2025).

  Exploring the genomic dark matter of neurodevelopmental disorders. 

  . Genetics Graduate Interdisciplinary Program. University of Arizona, Tuscon.
• Schrauwen, I. (2025, 11/22/2025).

  Harnessing Transcriptomics for Precision Medicine: From Diagnosis to Therapeutic discovery. 

  . BMS Department seminar series. University of Arizona, Phoenix.
• Schrauwen, I. (2024). Omics-Driven Approaches in Nervous and Sensory System Disorders. Colloquium, Graduate Interdisciplinary Program in Neuroscience & Department of Neuroscience School of Mind, Brain & Behavior. University of Arizona,.
• Schrauwen, I. (2024). The Genetic Etiology of Pediatric Hearing loss. Department of Audiology, Phoenix Children’s Hospital.
• Schrauwen, I. (2024). The Genetic Etiology of Pediatric Hearing loss. Department of Otolaryngology, Phoenix Children’s Hospital.
• Schrauwen, I. (2024). The genomic dark matter of neurodevelopmental disorders. Department of Genetics & Metabolism, Phoenix Children’s Hospital.

Poster Presentations

• Schrauwen, I. (2025, 03/18-22/25).

  Genetics of Perrault syndrome in a family with ten affected individuals.

  . 2025 ACMG Annual Clinical Genetics Meeting. Los Angeles, CA.
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  Faridi R, Smith TB, Demain LAM, Ishibashi Y, Inagaki S, Thomas HB, Rea A, Maqbool A, Schrauwen I, Liaqat K, Ahmed Z, Ghedia S, Green A, Sheffer R, Mor-Shaked H, Wilding M, Hay R, Riazuddin S, He L, Beaman GM, Ahmed W, Leal SM, Taylor RW, O'Keefe RT, Morell R, Schaffer A, Newman WG, Belyantseva IA, Riazuddin S, Friedman TB.
• Schrauwen, I. (2025, 05/06/2025).

  Rare AGAP2 Variants Underlie a Previously Undescribed Neurodevelopmental Syndrome.

  . Biomedical Research Day. University of Arizona College of Medicine-Phoenix, Phoenix, AZ.
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  Acharya A, Verhoeven V, Wilke M, Richardson K, Northrup H, Fernandez-Perrone AL, Fernandez-Jaen A, Patterson WG, Butler KM, Scala M, Striano P, Zara F, Gray C, Perez Flores DC, Woltz RL, Ansar M, Leal SM, Schrauwen I.
• Schrauwen, I. (2025, 05/06/2025).

  A Scalable Bioinformatics Framework For Interrogating RNA Editing. 

  . Biomedical Research Day. University of Arizona College of Medicine-Phoenix, Phoenix, AZ.
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  Rajendran Y, Acharya A, Shinn H, Nasiri H, Bharadwaj T, Leal SM, Richard EM, Schrauwen I.
• Schrauwen, I. (2025, 10/13-85/2025).

  Rare AGAP2 Variants Underlie a Novel Neurodevelopmental Syndrome. 

  . American Society of Human Genetics meeting (ASHG). Boston, MA, USA.
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  Acharya A, Verhoeven V, Wilke M, Richardson K, Northrup H, Fernandez-Perrone AL, Fernandez-Jaen A, Patterson WG, Butler KM, Scala M, Striano P, Zara F, Gray C, Perez Flores DC, Woltz RL, Ansar M, Schrauwen I, Leal SM.
• Schrauwen, I. (2025, 10/13-85/2025).

  Bi-Allelic MARVELD2 Variant Identified with Exome Sequencing in a Consanguineous Multiplex Ghanaian Family Segregating Non-Syndromic Hearing Loss.

  . American Society of Human Genetics meeting (ASHG). Boston, MA, USA.
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  Twumasi Aboagye E, Adadey SM, Alves de Souza Rios L, Esoh KK, Wonkam-Tingang E, Xhakaza L, De Kock C, Schrauwen I, Amenga-Etego L, Lang D, Awandare GA, Leal SM, Mowla S, Wonkam A.
• Schrauwen, I. (2025, 10/13-85/2025).

  Comprehensive analysis of long-read sequencing data reveals hidden variants in unsolved neurodevelopmental disorders.

  . American Society of Human Genetics meeting (ASHG). Boston, MA, USA.
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  Mendoza D, Järvelä I, Acharya A, Rajendran Y, Lim A, Sangare M, Bharadwaj T, Leppälä J, Leal SM, Schrauwen I.
• Schrauwen, I. (2025, 10/14/25).

  RNA Signature-Matching for Therapeutic Discovery in Neurological Disorders.

  . AZ Center for Drug Discovery & Development Summit.. Scottsdale, AZ.
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  Byrne B, Mendoza D, Schrauwen I.
• Schrauwen, I. (2025, 11/14/25).

  Heterozygous CECR2 Variants Support a Distinct Neurodevelopmental Syndrome with Features Overlapping Cat Eye Syndrome.

  . Phoenix Children’s Research Symposium 2025.. Phoenix, AZ.
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  Acharya A, Järvelä I, Hernandez A, Rajendran Y, Bharadwaj T, Goodloe DH, Hiatt SM, Morrison J, Wheeler PG, Hunter JM, Supinger R, Hickey SE, Petersen AK, Magnussen K, Scala M, Striano P, Zara F, Leppälä J, Leal SM, Schrauwen I.
• Schrauwen, I. (2024). Exploring the Genomic Dark Matter of Neurodevelopmental Disorders. . Phoenix Children’s Research Symposium 2024.
• Schrauwen, I. (2024). Uncovering a Balanced Genomic Inversion in a Case with Polymicrogyria via Optical Genome Mapping. . Phoenix Children’s Research Symposium 2024.