Next, we have Dr. Ferrer speaking about de novo mutations and signaling pathways related to craniosynostosis. There we go. So, good afternoon. My name is Charita Furey, and I'm a graduating medical student at Yale. And in a few short weeks, I'll be one of the incoming neurosurgical interns at the Barrow. So, thank you all for your time and for this opportunity to present some of the work we're doing at Yale to better understand the genetics of craniosynostosis. So, normally, our cranial growth responds to an increase in brain volume. Our brain size roughly triples by age one, quadruples as a toddler, and approximates 85 percent of adult size by age three. So, the cranial sutures are modified ball and socket joints that allow for parallel and perpendicular growth as our brain develops. Now, in craniosynostosis, however, there's premature fusion of these cranial sutures, and so subsequently, the skull is only able to grow parallel to the fused suture, leading to very characteristic skull shapes. And with an estimated prevalence of one in 2,300 births, craniosynostosis constitutes the second most common craniofacial birth defect behind orophacial clefts. And whereas syndromic craniosynostosis is well characterized, the vast majority of these cases are actually nonsyndromic, approximately 85 percent. And prior to this genetic study, we're of unknown genetic ideology. So, genetics are particularly valuable in craniosynostosis, where we have debate about everything, from when to intervene to how to intervene, with some people arguing for minimally invasive endoscopic approaches, while others maintaining that open approaches are better for neurocognitive outcomes. And even that's rather controversial. Are neurocognitive outcomes really a function of what surgical intervention you pursued, or is resultant developmental delay something that's endogenous to the biology of that patient's particular subtype of craniosynostosis? So, as you can imagine, it would be incredibly powerful to be able to know a patient's particular craniosynostotic genotype in order to answer some of these questions and inform our operative management and surgical planning. So, in order to identify critical genetic determinants of craniosynostosis, we exome sequenced about 966 individuals from all over the country, comprised of 291 patient-parent trios and 93 singleton cases. And so, this in total genetic cohort is one of the first and largest craniosynostosis cohorts of midline nonsyndromic sporadic craniosynostosis. So, interestingly, our results explained about 10% of nonsyndromic cases to novel de novo, as well as transmitted mutations. Here you can actually see that 5% of all cases in this cohort were explained by damaging de novo mutations in RAS-ERK signaling, bone morphogenic pathway, or BMP signaling, as well as Wnt signaling pathways. So, all developmental cascades that converge on common nuclear targets that are important for bone formation. And in this particular figure, you can see significant enrichment of de novo mutations in our craniosynostosis cohort relative to our controls, which are healthy controls from the Simon Simplex autism cohort. Now, additionally, what was incredibly striking was the shared genetic mutations between both nonsyndromic and syndromic craniosynostosis cases. So, in these figures, the italicized and starred genes, as well as red genes, are all genes that are shared between syndromic forms of craniosynostosis as well as nonsyndromic forms. And so, this indicates some shared biology between syndromic craniosynostosis and sporadic nonsyndromic craniosynostosis. And it really highlights the importance of studying these rare extreme syndromic forms of craniosynostosis, because they can identify pathways that underline more common manifestations of this disease. So, in conclusion, this study demonstrates and explains about 10% of sporadic nonsyndromic craniosynostosis cases to be attributable to novel de novo mutations and transmitted mutations in inhibitors of Wnt signaling, BMP signaling, and Ras-ERK signaling pathways. And this, first of all, provides us some insight into the pathophysiology of sporadic nonsyndromic craniosynostosis. And it hopefully allows us to maybe stratify nonsyndromic cases in order to have optimal treatment that's more targeted. And finally, in the more short term, it's allowed us to have better genetic counseling for patients who have nonsyndromic craniosynostosis affecting their family so that they can have, you know, the appropriate information they need as they decide for family planning in the future. And so this work would not have been possible without my close friend and lab mate, Andrew Timberlake, as well as my principal investigator, Christopher Colley, and the scientific guidance of Drs. Murat Ganel and Michael DeLuna and Dr. Richard Lifton. And I just want to thank members of the Colley Lab that are also here, our collaborators, and most importantly, hundreds of families affected by craniosynostosis that participated in our study and make research to better understand this disorder exceptionally fulfilling. So thank you all for your time. Thank you.

Dr. Charita Furey

genetics

craniosynostosis

de novo mutations

signaling pathways