PT  - JOURNAL ARTICLE
AU  - Dennis Lal
AU  - Patrick May
AU  - Kaitlin E. Samocha
AU  - Jack A. Kosmicki
AU  - Elise B. Robinson
AU  - Rikke S. Møller
AU  - Roland Krause
AU  - Peter Nüernberg
AU  - Sarah Weckhuysen
AU  - Peter De Jonghe
AU  - Renzo Guerrini
AU  - Lisa M. Neupert
AU  - Juliana Du
AU  - Eduardo Perez-Palma
AU  - Carla Marini
AU  - EuroEpinomics-RES Consortium
AU  - James S. Ware
AU  - Mitja Kurki
AU  - Padhraig Gormley
AU  - Sha Tang
AU  - Sitao Wu
AU  - Saskia Biskup
AU  - Annapura Poduri
AU  - Bernd A. Neubauer
AU  - Bobby P. Koeleman
AU  - Katherine L. Helbig
AU  - Yvonne G. Weber
AU  - Ingo Helbig
AU  - Amit R. Majithia
AU  - Aarno Palotie
AU  - Mark J. Daly
TI  - Gene family information facilitates variant interpretation and identification of disease-associated genes
AID  - 10.1101/159780
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 159780
4099  - http://biorxiv.org/content/early/2017/07/05/159780.short
4100  - http://biorxiv.org/content/early/2017/07/05/159780.full
AB  - Differentiating risk-conferring from benign missense variants, and therefore optimal calculation of gene-variant burden, represent a major challenge in particular for rare and genetic heterogeneous disorders. While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes are paralogs and belong to gene families. It has not been thoroughly investigated how gene family information can be utilized for disease gene discovery and variant interpretation. We developed a paralog conservation score to empirically evaluate whether paralog conserved or nonconserved sites of in-human paralogs are important for protein function. Using this score, we demonstrate that disease-associated missense variants are significantly enriched at paralog conserved sites across all disease groups and disease inheritance models tested. Next, we assessed whether gene family information could assist in discovering novel disease-associated genes. We subsequently developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in more than 10k neurodevelopmental disorder patients. 33 gene family enriched genes represent novel candidate genes which are brain expressed and variant constrained in neurodevelopmental disorders.