Isabelle Schrauwen

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Scholarly Contributions

Journals/Publications

• 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.
• 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.

Presentations

• 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. (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.