Lal, Dennis, May, Patrick ORCID: 0000-0001-8698-3770, Perez-Palma, Eduardo ORCID: 0000-0003-0546-5141, Samocha, Kaitlin E., Kosmicki, Jack A., Robinson, Elise B., Moller, Rikke S., Krause, Roland, Nuernberg, Peter, Weckhuysen, Sarah ORCID: 0000-0003-2878-1147, De Jonghe, Peter, Guerrini, Renzo ORCID: 0000-0002-7272-7079, Niestroj, Lisa M., Du, Juliana, Marini, Carla, Ware, James S., Kurki, Mitja, Gormley, Padhraig, Tang, Sha, Wu, Sitao, Biskup, Saskia, Poduri, Annapurna, Neubauer, Bernd A., Koeleman, Bobby P. C., Helbig, Katherine L., Weber, Yvonne G., Helbig, Ingo, Majithia, Amit R., Palotie, Aarno and Daly, Mark J. (2020). Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders. Genome Med., 12 (1). LONDON: BMC. ISSN 1756-994X

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Abstract

Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, PatrickUNSPECIFIEDorcid.org/0000-0001-8698-3770UNSPECIFIED
Perez-Palma, EduardoUNSPECIFIEDorcid.org/0000-0003-0546-5141UNSPECIFIED
Samocha, Kaitlin E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kosmicki, Jack A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robinson, Elise B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krause, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weckhuysen, SarahUNSPECIFIEDorcid.org/0000-0003-2878-1147UNSPECIFIED
De Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerrini, RenzoUNSPECIFIEDorcid.org/0000-0002-7272-7079UNSPECIFIED
Niestroj, Lisa M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Du, JulianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marini, CarlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ware, James S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kurki, MitjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gormley, PadhraigUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tang, ShaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, SitaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biskup, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poduri, AnnapurnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neubauer, Bernd A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koeleman, Bobby P. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, Katherine L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, Yvonne G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, IngoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Majithia, Amit R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palotie, AarnoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daly, Mark J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-340698
DOI: 10.1186/s13073-020-00725-6
Journal or Publication Title: Genome Med.
Volume: 12
Number: 1
Date: 2020
Publisher: BMC
Place of Publication: LONDON
ISSN: 1756-994X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DE-NOVO MUTATIONS; MULTIPLE SEQUENCE ALIGNMENT; PHYLOGENETIC TREES; ORTHOLOGSMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34069

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