Marbach, Felix, Rustad, Cecilie F., Riess, Angelika, Dukic, Dejan, Hsieh, Tzung-Chien ORCID: 0000-0003-3828-4419, Jobani, Itamar, Prescott, Trine, Bevot, Andrea, Erger, Florian ORCID: 0000-0002-2768-1702, Houge, Gunnar, Redfors, Maria, Altmueller, Janine, Stokowy, Tomasz ORCID: 0000-0003-0017-8338, Gilissen, Christian ORCID: 0000-0003-1693-9699, Kubisch, Christian, Scarano, Emanuela, Mazzanti, Laura, Fiskerstrand, Torunn, Krawitz, Peter M., Lessel, Davor ORCID: 0000-0003-4496-244X and Netzer, Christian (2019). The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping. Am. J. Hum. Genet., 104 (4). S. 749 - 758. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Marbach, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rustad, Cecilie F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riess, AngelikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dukic, DejanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hsieh, Tzung-ChienUNSPECIFIEDorcid.org/0000-0003-3828-4419UNSPECIFIED
Jobani, ItamarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prescott, TrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bevot, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erger, FlorianUNSPECIFIEDorcid.org/0000-0002-2768-1702UNSPECIFIED
Houge, GunnarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Redfors, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stokowy, TomaszUNSPECIFIEDorcid.org/0000-0003-0017-8338UNSPECIFIED
Gilissen, ChristianUNSPECIFIEDorcid.org/0000-0003-1693-9699UNSPECIFIED
Kubisch, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scarano, EmanuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mazzanti, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fiskerstrand, TorunnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krawitz, Peter M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lessel, DavorUNSPECIFIEDorcid.org/0000-0003-4496-244XUNSPECIFIED
Netzer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-151006
DOI: 10.1016/j.ajhg.2019.02.021
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 104
Number: 4
Page Range: S. 749 - 758
Date: 2019
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MEMBRANE PROTEIN LEM2; MUTATIONS; LOCALIZATIONMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15100

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