Exploring the association between de novo mutations and non-syndromic cleft lip with or without palate based on whole exome sequencing of case-parent trios.
- Author:
Xi CHEN
1
;
Si Yue WANG
1
;
En Ci XUE
1
;
Xue Heng WANG
1
;
He Xiang PENG
1
;
Meng FAN
1
;
Meng Ying WANG
1
;
Yi Qun WU
1
;
Xue Ying QIN
1
;
Jing LI
1
;
Tao WU
1
;
Hong Ping ZHU
2
;
Jing LI
3
;
Zhi Bo ZHOU
2
;
Da Fang CHEN
1
;
Yong Hua HU
1
Author Information
1. Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China.
2. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Research Center of Engineering and Technology for Computerized Dentistry & NMPA Key Laboratory for Dental Materials, Beijing 100081, China.
3. Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Research Center of Engineering and Technology for Computerized Dentistry & NMPA Key Laboratory for Dental Materials, Beijing 100081, China.
- Publication Type:Journal Article
- Keywords:
De novo mutations;
Enrichment analysis;
Non-syndromic cleft lip with or without palate;
Protein-protein interactions
- MeSH:
Asians;
Case-Control Studies;
Cleft Lip/genetics*;
Cleft Palate/genetics*;
Genetic Predisposition to Disease;
Genome-Wide Association Study;
Genotype;
Humans;
Mutation;
Parents;
Polymorphism, Single Nucleotide;
Whole Exome Sequencing
- From:
Journal of Peking University(Health Sciences)
2022;54(3):387-393
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design.
METHODS:Whole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database.
RESULTS:A total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes.
CONCLUSION:Our study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.
