Universität zu Köln

Stefanski, Arthur, Perez-Palma, Eduardo, Mrdjen, Marko, McHugh, Megan, Leu, Costin and Lal, Dennis (2022). BRIEF REPORT Identification and quantification of oligogenic loss-of-function disorders. Genet. Med., 24 (3). S. 729 - 736. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1530-0366

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Abstract

Purpose: Monogenic disorders can present clinically heterogeneous symptoms. We hypothesized that in patients with a monogenic disorder caused by a large deletion, frequently additional loss-of-function (LOF)-intolerant genes are affected, potentially contributing to the phenotype. Methods: We investigated the LOF-intolerant gene distribution across the genome and its association with benign population and pathogenic classified deletions from individuals with presumably monogenic disorders. For people with presumably monogenic epilepsy, we compared Human Phenotype Ontology terms in people with large and small deletions. Results: We identified LOF-intolerant gene dense regions that were enriched for ClinVar and depleted for population copy number variants. Analysis of data from 143,000 individuals with a suspected monogenic disorder showed that 2.5% of haploinsufficiency disorder???associated deletions can affect at least 1 other LOF-intolerant gene. Focusing on epilepsy, we observed that 13.1% of pathogenic and likely pathogenic ClinVar deletions <3 megabase pair, covering the diagnostically most relevant genes, affected at least 1 additional LOF-intolerant gene. Those patients have potentially more complex phenotypes with increasing deletion size. Conclusion: We could systematically show that large deletions frequently affected admditional LOF-intolerant genes in addition to the established disease gene. Further research is needed to understand how additional potential disease-relevant genes influence monogenic disorders to improve clinical care and the efficacy of targeted therapies. ?? 2021 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stefanski, Arthur UNSPECIFIED UNSPECIFIED UNSPECIFIED Perez-Palma, Eduardo UNSPECIFIED UNSPECIFIED UNSPECIFIED Mrdjen, Marko UNSPECIFIED UNSPECIFIED UNSPECIFIED McHugh, Megan UNSPECIFIED UNSPECIFIED UNSPECIFIED Leu, Costin UNSPECIFIED UNSPECIFIED UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-684547
DOI:	10.1016/j.gim.2021.10.026
Journal or Publication Title:	Genet. Med.
Volume:	24
Number:	3
Page Range:	S. 729 - 736
Date:	2022
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1530-0366
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COPY NUMBER VARIANTS Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68454