Artificial Cognitive Systems
Alexander J.M. Dingemans
PhD Student - Radboudumc
I am a physician, working partially in the Human Genetics department of the Radboudumc and partially in this lab. As part of my PhD, I am working on applying artificial intelligence in our clinical practice. I hope to improve clinical care for our patients and make the life of doctors easier this way. I will mostly be working on facial recognition and using machine learning and probabilistic programming on phenotypic data, to help assist in diagnosing patients and see if we can predict the outcome of genetic tests.
Castellanos, F., Caufield, J., Chan, L., Chute, C., Cruz-Rojo, J., Dahan-Oliel, N., Davids, J., Dieuleveult, M., Souza, V., Vries, B., Vries, E., DePaulo, J., Derfalvi, B., Dhombres, F., Diaz-Byrd, C., Dingemans, A., Donadille, B., Duyzend, M., Elfeky, R., ..., Nanclares, G. (2024). The Human Phenotype Ontology in 2024: phenotypes around the world.. Nucleic Acids Research, 52(D1)
Abstract taken from Google Scholar:
The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.
Awamleh, Z., Choufani, S., Wu, W., Rots, D., Dingemans, A., Kasri, N., Boronat, S., Ibañez-Mico, S., Herraiz, L., Ferrer, I., Carrascal, A., Pérez-Jurado, L., Lain, G., Ortigoza-Escobar, J., Vries, B., Koolen, D., & Weksberg, R. (2024). A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells. European Journal of Human Genetics, 32(3), 324-332
Abstract taken from Google Scholar:
Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina’s Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We …
Laan, L., Karimi, K., Rooney, K., Lauffer, P., McConkey, H., Caro, P., Relator, R., Levy, M., Bhai, P., Mignot, C., Keren, B., Briuglia, S., Sobering, A., Li, D., Vissers, L., Dingemans, A., Valenzuela, I., Verberne, E., Misra-Isrie, M., ..., Henneman, P. (2024). DNA methylation episignature, extension of the clinical features, and comparative epigenomic profiling of Hao-Fountain syndrome caused by variants in USP7. Genetics in Medicine, 26(3), 101050
Abstract taken from Google Scholar:
Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder caused by pathogenic variants in USP7. HAFOUS is characterized by developmental delay, intellectual disability, speech delay, behavioral abnormalities, autism spectrum disorder, seizures, hypogonadism, and mild dysmorphic features. We investigated the phenotype of 18 participants with HAFOUS and performed DNA methylation (DNAm) analysis, aiming to generate a diagnostic biomarker. Furthermore, we performed comparative analysis with known episignatures to gain more insight into the molecular pathophysiology of HAFOUS.We assessed genomic DNAm profiles of 18 individuals with pathogenic variants and variants of uncertain significance (VUS) in USP7 to map and validate a specific episignature. The comparison between the USP7 cohort and 56 rare genetic disorders with earlier reported DNAm episignatures …
D’Incal, C., Annear, D., Elinck, E., Smagt, J., Alders, M., Dingemans, A., Mateiu, L., Vries, B., Berghe, W., & Kooy, R. (2024). Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel–Van der Aa syndrome. European Journal of Human Genetics, , 1-9
Abstract taken from Google Scholar:
Mutations in ADNP result in Helsmoortel–Van der Aa syndrome. Here, we describe the first de novo intronic deletion, affecting the splice-acceptor site of the first coding ADNP exon in a five-year-old girl with developmental delay and autism. Whereas exome sequencing failed to detect the non-coding deletion, genome-wide CpG methylation analysis revealed an episignature suggestive of a Helsmoortel–Van der Aa syndrome diagnosis. This diagnosis was further supported by PhenoScore, a novel facial recognition software package. Subsequent whole-genome sequencing resolved the three-base pair ADNP deletion c.[-5-1_-4del] with transcriptome sequencing showing this deletion leads to skipping of exon 4. An N-terminal truncated protein could not be detected in transfection experiments with a mutant expression vector in HEK293T cells, strongly suggesting this is a first confirmed diagnosis exclusively due to …
Rots, D., Choufani, S., Faundes, V., Dingemans, A., Vissers, L., Kleefstra, T., Banka, S., & Weksberg, R. (2024). KMT2C pathogenic variants result in a neurodevelopmental disorder with distinct clinical and DNA methylation features. European Journal of Human Genetics, 32, 188-188
Abstract taken from Google Scholar:
KMT2C pathogenic variants result in a neurodevelopmental disorder with distinct clinical and DNA methylation features — Research Explorer The University of Manchester Skip to main navigation Skip to search Skip to main content Research Explorer The University of Manchester Home Research Explorer The University of Manchester Logo Home Research Profiles Research units Research output Projects Impacts Activities Press/Media Prizes Equipment and Facilities Datasets Student theses Search by expertise, name or affiliation KMT2C pathogenic variants result in a neurodevelopmental disorder with distinct clinical and DNA methylation features D Rots, S Choufani, V Faundes, A Dingemans, L Vissers, T Kleefstra, S Banka, R Weksberg Division of Evolution, Infection and Genomics Research output: Contribution to journal › Meeting Abstract › peer-review Overview Original language English Pages (from-to) 188-…
Dingemans, A., Hinne, M., Truijen, K., Goltstein, L., Reeuwijk, J., Leeuw, N., Schuurs-Hoeijmakers, J., Pfundt, R., Diets, I., Hoed, J., Boer, E., Spek, J., Jansen, S., Bon, B., Jonis, N., Ockeloen, C., Silfhout, A., Kleefstra, T., Koolen, D., ..., Vries, B. (2023). PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework. Nature Genetics, 55(9), 1598-1607
Abstract taken from Google Scholar:
Several molecular and phenotypic algorithms exist that establish genotype–phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore’s ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype–phenotype studies by …
Spek, J., Relator, R., Kerkhof, J., McConkey, H., Levy, M., Tedder, M., Louie, R., Fletcher, R., Moore, H., Childers, A., Farrelly, E., Champaigne, N., Lyons, M., Everman, D., Rogers, R., Skinner, S., Renck, A., Matalon, D., Dills, S., ..., Butler, K. (2023). DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency. Genetics in Medicine, 25(1), 63-75
Abstract taken from Google Scholar:
Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency.We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model …
Harms, F., Dingemans, A., Hempel, M., Pfundt, R., Bierhals, T., Casar, C., Müller, C., Niermeijer, J., Fischer, J., Jahn, A., Hübner, C., Majore, S., Agolini, E., Novelli, A., Smagt, J., Ernst, R., Binsbergen, E., Mancini, G., Slegtenhorst, M., ..., Kutsche, K. (2023). de novo PHF5A variants are associated with craniofacial abnormalities, developmental delay, and hypospadias. Genetics in Medicine, 25(10), 100927
Abstract taken from Google Scholar:
The SF3B splicing complex is composed of SF3B1-6 and PHF5A. We report a developmental disorder caused by de novo variants in PHF5A.Clinical, genomic, and functional studies using subject-derived fibroblasts and a heterologous cellular system were performed.We studied 9 subjects with congenital malformations, including preauricular tags and hypospadias, growth abnormalities, and developmental delay who had de novo heterozygous PHF5A variants, including 4 loss-of-function (LOF), 3 missense, 1 splice, and 1 start-loss variant. In subject-derived fibroblasts with PHF5A LOF variants, wild-type and variant PHF5A mRNAs had a 1:1 ratio, and PHF5A mRNA levels were normal. Transcriptome sequencing revealed alternative promoter use and downregulated genes involved in cell-cycle regulation. Subject and control fibroblasts had similar amounts of PHF5A with the predicted …
Dingemans, A., Jansen, S., Reeuwijk, J., Leeuw, N., Pfundt, R., Schuurs-Hoeijmakers, J., Bon, B., Marcelis, C., Ockeloen, C., Willemsen, M., Sluijs, P., Santen, G., Kooy, R., Silfhout, A., Kleefstra, T., Koolen, D., Vissers, L., & Vries, B. (2023). PhenomAD-NDD: the Phenomics Aggregation Database of comorbidities in 51,227 pediatric individuals with NeuroDevelopmental Disorders. medRxiv, , 2023.11. 29.23299167
Abstract taken from Google Scholar:
Dingemans, A., Truijen, K., Kim, J., Alaçam, Z., Faivre, L., Collins, K., Gerkes, E., Haelst, M., Laar, I., Lindstrom, K., Nizon, M., Pauling, J., Heropolitańska-Pliszka, E., Plomp, A., Racine, C., Sachdev, R., Sinnema, M., Skranes, J., Veenstra-Knol, H., ..., Vissers, L. (2022). Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON. European Journal of Human Genetics, 30(3), 271-281
Abstract taken from Google Scholar:
Zhu–Tokita–Takenouchi–Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter …