Identification of novel susceptibility genes for non-syndromic cleft lip with or without cleft palate using NGS-based multigene panel testing

• Published in: Molecular genetics and genomics : MGG 2022-09, Vol.297 (5), p.1315-1327
• Main Authors: Dąbrowska, Justyna, Biedziak, Barbara, Szponar-Żurowska, Anna, Budner, Margareta, Jagodziński, Paweł P., Płoski, Rafał, Mostowska, Adrianna
• Format: Article
• Language: English
• Subjects: Animal Genetics and Genomics; Biochemistry; Biomedical and Life Sciences; Birth defects; Cleft lip/palate; Fibroblast growth factor 4; Fibroblast growth factor 8; Genome-wide association studies; Genomes; Heritability; Human Genetics; Life Sciences; Microbial Genetics and Genomics; Next-generation sequencing; Original Article; Orofacial clefts; Plant Genetics and Genomics; Wnt protein
• ISSN: 1617-4615; 1617-4623
• DOI: 10.1007/s00438-022-01919-w

For non-syndromic cleft lip with or without cleft palate (ns-CL/P), the proportion of heritability explained by the known risk loci is estimated to be about 30% and is captured mainly by common variants identified in genome-wide association studies. To contribute to the explanation of the “missing heritability” problem for orofacial clefts, a candidate gene approach was taken to investigate the potential role of rare and private variants in the ns-CL/P risk. Using the next-generation sequencing technology, the coding sequence of a set of 423 candidate genes was analysed in 135 patients from the Polish population. After stringent multistage filtering, 37 rare coding and splicing variants of 28 genes were identified. 35% of these genetic alternations that may play a role of genetic modifiers influencing an individual's risk were detected in genes not previously associated with the ns-CL/P susceptibility, including COL11A1, COL17A1, DLX1 , EFTUD2 , FGF4, FGF8 , FLNB , JAG1 , NOTCH2 , SHH , WNT5A and WNT9A . Significant enrichment of rare alleles in ns-CL/P patients compared with controls was also demonstrated for ARHGAP29, CHD7, COL17A1, FGF12, GAD1 and SATB2 . In addition, analysis of panoramic radiographs of patients with identified predisposing variants may support the hypothesis of a common genetic link between orofacial clefts and dental abnormalities. In conclusion, our study has confirmed that rare coding variants might contribute to the genetic architecture of ns-CL/P. Since only single predisposing variants were identified in novel cleft susceptibility genes, future research will be required to confirm and fully understand their role in the aetiology of ns-CL/P.