De novo mutations in folate-related genes associated with common developmental disorders

Tengfei Luo; Kuokuo Li; Zhengbao Ling; Guihu Zhao; Bin Li; Zheng Wang; Xiaomeng Wang; Ying Han; Lu Xia; Yi Zhang; Qiao Zhou; Zhenghuan Fang; Yijing Wang; Qian Chen; Xun Zhou; Hongxu Pan; Yuwen Zhao; Yige Wang; Lijie Dong; Yuanfeng Huang; Zhengmao Hu; Qian Pan; Kun Xia; Jinchen Li

doi:10.1016/j.csbj.2021.02.011

De novo mutations in folate-related genes associated with common developmental disorders

Comput Struct Biotechnol J. 2021 Mar 1:19:1414-1422. doi: 10.1016/j.csbj.2021.02.011. eCollection 2021.

Authors

Tengfei Luo¹, Kuokuo Li², Zhengbao Ling¹, Guihu Zhao^{3

4}, Bin Li^{3

4}, Zheng Wang³, Xiaomeng Wang¹, Ying Han¹, Lu Xia¹, Yi Zhang³, Qiao Zhou³, Zhenghuan Fang¹, Yijing Wang¹, Qian Chen³, Xun Zhou³, Hongxu Pan³, Yuwen Zhao³, Yige Wang³, Lijie Dong¹, Yuanfeng Huang¹, Zhengmao Hu¹, Qian Pan¹, Kun Xia^{1

5}, Jinchen Li^{3

4}

Affiliations

¹ Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
² Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.
³ National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
⁵ School of Basic Medical Science, Central South University, Changsha, Hunan, China.

Abstract

Folate deficiency is an environmental risk factor for several developmental disorders. De novo mutations (DNMs) also play important etiological roles in various developmental disorders. However, it remains unclear whether DNMs in folate-related genes (FRGs) contribute to developmental disorders. We obtained a list of 1,821 FRGs from folate metabolism pathways and the Comparative Toxicogenomics Database, along with data concerning DNMs in 15,404 cases and 3,391 controls from the Gene4Denovo database. We used a TADA-Denovo model to prioritize candidate disease-associated FRGs, and characterized these genes in terms of genic intolerance, functional networks, and expression patterns. Compared with the controls, FRGs were significantly enriched in likely damaging DNMs (ldDNMs) in patients with developmental disorders (1.54 ≤ odds ratio ≤ 3.39, P _adj ≤ 0.0075). Furthermore, FRGs with ldDNMs rather than with likely non-damaging DNMs (lndDNMs) overlapped significantly among the five developmental disorders included in the datasets. The TADA-Denovo model prioritized 96 candidate disease-associated FRGs, which were intolerant to genetic variants. Their functional networks mainly involved pathways associated with chromatin modification, organ development, and signal transduction pathways. DNMT3A, KMT2B, KMT2C, and YY1 emerged as hub FRGs from the protein-protein interaction network. These candidate disease-associated FRGs are preferentially expressed in the excitatory neurones during embryonic development, and in the cortex, cerebellum, striatum, and amygdala during foetal development. Overall, these findings show that DNMs in FRGs are associated with the risk of developmental disorders. Further research on these DNMs may facilitate the discovery of developmental disorder biomarkers and therapeutic targets, enabling detailed, personalized, and precise folate treatment plan.

Keywords: ADD, all five developmental disorders; ASD, autism spectrum disorder; CHD, congenital heart disease; Candidate disease-associated genes; DNMs, De novo mutations; De novo mutation; Developmental disorders; Dmis, deleterious missense variants; EE, epileptic encephalopathy; Expression patterns; FRGs, folate-related genes; Folate-related gene; ID, intellectual disability; PPI, Protein–protein interaction; PTV, protein-truncating variants; RVIS, residual variation intolerance scores; SNPs, single nucleotide polymorphisms; TADA, Transmitted And De novo Association; Tmis, tolerant missense variants; UDD, undiagnosed developmental disorder; ldDNMs, likely damaging DNMs; lndDNMs, likely non-damaging DNMs; pLI, probability of loss-of-function intolerance.