Exome sequencing in orofacial clefts and associated syndromes : PDGFC and PDGFRA as novel contributors
(2025)
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- Authors
- Supervisors
- VIKKULA, Miikka
- Abstract
- The primary objective of this doctoral work was to enhance our understanding of the genetic basis of cleft lip and palate by leveraging the power of exome sequencing. Through four research studies, we sought to uncover both novel genes behind orofacial clefts by identification of high‐impact variants and, in general, to broaden the genetic landscape that contributes to orofacial clefting. In the first study, we interrogated the PDGFC-PDGFRA signalling axis, a pathway previously underexplored in human cleft cohorts despite strong murine evidence that loss of Pdgfc or Pdgfra produces CL/P. By using exome sequencing in a large multi-ethnic cohort, we identified four rare coding variants in PDGFC and six in PDGFRA. Subsequent in vitro assays revealed that a truncating PDGFRA variant impaired receptor-mediated MAPK activation, whereas a PDGFC nonsense transcript partially escaped nonsense-mediated decay, suggesting a possible dominant negative mechanism though not functionally proven. These human data bridge prior animal studies and implicate compromised PDGFC-PDGFRα signalling, possibly in combination with other confounding genetic or environmental factors, as a mechanistic basis for a subset of cleft lip and/or palate patients. The second investigation expanded the known spectrum of ARHGAP29 variants by characterizing four novel loss-of-function variants, including a start-codon loss, two protein-truncating variants, and a frameshift variant, reinforcing ARHGAP29’s significant role in CL/P. The third study applied exome sequencing to a cohort of patients with OC-MAC (Orofacial Cleft and Microphthalmia/Anophthalmia/Coloboma spectrum) yielding a diagnostic rate of 35 percent. (Likely) pathogenic variants were identified in CHD7, TFAP2A, PTPN11, and TP63, while additional variants of uncertain significance highlighted a potential involvement of ciliopathy-associated genes in OC-MAC. Finally, the fourth study delineated the adult manifestations of SATB2-Associated Syndrome, a syndrome where cleft palate is a common feature, by profiling an adult carrier of the recurrent SATB2 p.(Arg239*) variant. Detailed phenotyping across neurocognitive, skeletal, craniofacial, and dental domains revealed the natural history of this syndrome, providing insight into prognosis and management strategies for affected adults. Findings were compared with those of other reported individuals carrying the same recurrent variant. In summary, this thesis enriches our understanding of orofacial cleft genetics by highlighting the value of exome sequencing, revealing a novel human PDGFC-PDGFRA signalling pathway in CL/P, expanding the variant spectrum of ARHGAP29, and defining the adult phenotype associated with a recurrent SATB2 variant. Future research is essential to bridge the remaining heritability gaps and to translate these insights into targeted interventions and personalized counselling for individuals and families affected by cleft lip and palate.
- Affiliations
Citations
Pairet, E. (2025). Exome sequencing in orofacial clefts and associated syndromes : PDGFC and PDGFRA as novel contributors. https://hdl.handle.net/2078.5/260596