Abstract
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.
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Acknowledgements
The Comprehensive Therapy Program for Craniofacial Anomalies (RPWP.07.02.02-30-0037/16) was supported by European Social Fund and Wielkopolska Voivodeship (Regional Operational Programme for Wielkopolskie Voivodeship 2014-2020).
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The Comprehensive Therapy Program for Craniofacial Anomalies (RPWP.07.02.02-30-0037/16) was supported by European Social Fund and Wielkopolska Voivodeship (Regional Operational Programme for Wielkopolskie Voivodeship 2014-2020).
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All authors read and approved the final manuscript. JD contributed to designing the study, conducting molecular analyses, and interpreting results. BB contributed to designing the study, recruiting patients and controls, and collecting clinical data. MB and ASŻ contributed to the clinical evaluation of patients. PJ contributed to the discussion about NGS results. RP contributed to NGS data analysis and interpretation of results. AM was responsible for designing the study, analysing the clinical and NGS data, interpreting results, writing the manuscript, and preparing all tables.
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The research design and experimental protocols were approved by the Institutional Review Board of Poznan University of Medical Sciences, Poland (no 1115/18). Informed consent was obtained from all study participants or their legal guardians.
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Dąbrowska, J., Biedziak, B., Szponar-Żurowska, A. et al. Identification of novel susceptibility genes for non-syndromic cleft lip with or without cleft palate using NGS-based multigene panel testing. Mol Genet Genomics 297, 1315–1327 (2022). https://doi.org/10.1007/s00438-022-01919-w
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DOI: https://doi.org/10.1007/s00438-022-01919-w