The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping
| العنوان: | The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping |
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| المؤلفون: | Emanuela Scarano, Tomasz Stokowy, Tzung-Chien Hsieh, Florian Erger, Janine Altmueller, Christian Gilissen, Gunnar Houge, Trine Prescott, Christian Kubisch, Andrea Bevot, Maria Redfors, Davor Lessel, Laura Mazzanti, Torunn Fiskerstrand, Angelika Riess, Dejan Đukić, Peter Krawitz, Cecilie F. Rustad, Christian Netzer, Itamar Jobani, Felix Marbach |
| المصدر: | American Journal of Human Genetics, 104, 4, pp. 749-757 American Journal of Human Genetics, 104, 749-757 |
| بيانات النشر: | Elsevier BV, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Adolescent, Computational biology, Biology, 03 medical and health sciences, Progeria, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Artificial Intelligence, Report, Cell Line, Tumor, Genetics, medicine, Humans, Mass Screening, Supernumerary, Diagnosis, Computer-Assisted, Child, Gene, Genetics (clinical), Cell Nucleus, Genetic disorder, Membrane Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Geneticist, Fibroblasts, Prognosis, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, Face, Mutation, Nuclear lamina, Intention tremor, medicine.symptom, Medical Informatics, 030217 neurology & neurosurgery |
| الوصف: | Over a relatively short period of time, the clinical geneticist’s “toolbox” has been expanded by machine-learning algorithms for image analysis, which can be applied to the task of syndrome identification on the basis of facial photographs, but these technologies harbor potential beyond the recognition of established phenotypes. Here, we comprehensively characterized two individuals with a hitherto unknown genetic disorder caused by the same de novo mutation in LEMD2 (c.1436C>T;p.Ser479Phe), the gene which encodes the nuclear envelope protein LEM domain-containing protein 2 (LEMD2). Despite different ages and ethnic backgrounds, both individuals share a progeria-like facial phenotype and a distinct combination of physical and neurologic anomalies, such as growth retardation; hypoplastic jaws crowded with multiple supernumerary, yet unerupted, teeth; and cerebellar intention tremor. Immunofluorescence analyses of patient fibroblasts revealed mutation-induced disturbance of nuclear architecture, recapitulating previously published data in LEMD2-deficient cell lines, and additional experiments suggested mislocalization of mutant LEMD2 protein within the nuclear lamina. Computational analysis of facial features with two different deep neural networks showed phenotypic proximity to other nuclear envelopathies. One of the algorithms, when trained to recognize syndromic similarity (rather than specific syndromes) in an unsupervised approach, clustered both individuals closely together, providing hypothesis-free hints for a common genetic etiology. We show that a recurrent de novo mutation in LEMD2 causes a nuclear envelopathy whose prognosis in adolescence is relatively good in comparison to that of classical Hutchinson-Gilford progeria syndrome, and we suggest that the application of artificial intelligence to the analysis of patient images can facilitate the discovery of new genetic disorders. |
| وصف الملف: | application/pdf |
| تدمد: | 0002-9297 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6e979612262a8a27f16eb75d61eabdf7 https://doi.org/10.1016/j.ajhg.2019.02.021 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....6e979612262a8a27f16eb75d61eabdf7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00029297 |
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