Cross-Disorder Analysis of De Novo Variants Increases the Power of Prioritising Candidate Genes.

Kuokuo Li,Kun Xia,Xiaomeng Wang,Jinchen Li,Qiao Zhou,Bin Li,Guihu Zhao,Zhengbao Ling,Tengfei Luo

doi:10.3390/life11030233

Abstract

De novo variants (DNVs) are critical to the treatment of neurodevelopmental disorders (NDDs). However, effectively identifying candidate genes in small cohorts is challenging in most NDDs because of high genetic heterogeneity. We hypothesised that integrating DNVs from multiple NDDs with genetic similarity can significantly increase the possibility of prioritising the candidate gene. We catalogued 66,186 coding DNVs in 50,028 individuals with nine types of NDDs in cohorts with sizes spanning from 118 to 31,260 from Gene4Denovo database to validate this hypothesis. Interestingly, we found that integrated DNVs can effectively increase the number of prioritised candidate genes for each disorder. We identified 654 candidate genes including 481 shared candidate genes carrying putative functional variants in at least two disorders. Notably, 13.51% (65/481) of shared candidate genes were prioritised only via integrated analysis including 44.62% (29/65) genes validated in recent large cohort studies. Moreover, we estimated that more novel candidate genes will be prioritised with the increase in cohort size, in particular for some disorders with high putative functional DNVs per individual. In conclusion, integrated DNVs may increase the power of prioritising candidate genes, which is important for NDDs with small cohort size.

Highlights

Neurodevelopmental disorders (NDDs) are disorders with high clinical heterogeneity, leading to considerable personal suffering, morbidity, and disability, which increase the burden of global healthcare [1]
Due to strong functional effects of de novo variants (DNVs), CHD8 [13] was found to be associated with autism spectrum disorder (ASD), ID, sleeping problems, macrocephaly, and gastrointestinal symptoms, while DYRK1A [14] is associated with ID, microcephaly, and febrile seizures infancy
We focused on LoF, deleterious missense (Dmis), and putative functional (Pfun), which increase the genetic risk of NDDs

Summary

Introduction

Neurodevelopmental disorders (NDDs) are disorders with high clinical heterogeneity, leading to considerable personal suffering, morbidity, and disability, which increase the burden of global healthcare [1]. With the development of next-generation sequencing technologies, genetic disruptions have been identified as the major reasons for NDDs, especially for de novo variants (DNVs) with important functional effects contributing to early NDDs. Candidate genes in ASD [7], CHD [8], DD [9], EE [10], ID [11], and SCZ [12] were detected and prioritised successfully using whole-exome sequencing (WES) or whole-genome sequencing (WGS) in recent studies. For most NDDs, only several candidate genes have been identified based on DNVs due to genetic heterogeneity, rarity DNVs, limited cohort size, and small gene-level relative risks. This genotype-phenotype association method was validated in our studies based on GeneMatcher [15,16,17].

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