Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Marbach, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Rustad, Cecilie F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Riess, Angelika UNSPECIFIED UNSPECIFIED UNSPECIFIED Dukic, Dejan UNSPECIFIED UNSPECIFIED UNSPECIFIED Hsieh, Tzung-Chien UNSPECIFIED orcid.org/0000-0003-3828-4419 UNSPECIFIED Jobani, Itamar UNSPECIFIED UNSPECIFIED UNSPECIFIED Prescott, Trine UNSPECIFIED UNSPECIFIED UNSPECIFIED Bevot, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Erger, Florian UNSPECIFIED orcid.org/0000-0002-2768-1702 UNSPECIFIED Houge, Gunnar UNSPECIFIED UNSPECIFIED UNSPECIFIED Redfors, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Stokowy, Tomasz UNSPECIFIED orcid.org/0000-0003-0017-8338 UNSPECIFIED Gilissen, Christian UNSPECIFIED orcid.org/0000-0003-1693-9699 UNSPECIFIED Kubisch, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Scarano, Emanuela UNSPECIFIED UNSPECIFIED UNSPECIFIED Mazzanti, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Fiskerstrand, Torunn UNSPECIFIED UNSPECIFIED UNSPECIFIED Krawitz, Peter M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lessel, Davor UNSPECIFIED orcid.org/0000-0003-4496-244X UNSPECIFIED Netzer, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language MEMBRANE PROTEIN LEM2; MUTATIONS; LOCALIZATION Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15100