Plastic Surgery Research Council

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De novo Mutation Burden Reveals Novel Molecular Subtypes of Non-syndromic Craniosynostosis
Andrew T. Timberlake, PhD1, Charuta G. Furey, BS1, Jungmin Choi, PhD2, Carol Nelson-Williams, BS2, Derek M. Steinbacher, DMD MD1, Dawid Larysz, MD3, John A. Persing, MD1, Richard P. Lifton, MD PhD4.
1Yale University School of Medicine, New Haven, CT, USA, 2Yale University Dept of Genetics, New Haven, CT, USA, 3The Maria Skłodowska Curie Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland, 4The Rockefeller University, New York, NY, USA.

Purpose: Craniosynostosis is one of the most frequent congenital malformations encountered by the craniofacial surgeon. 15% of cases are syndromic and with well-characterized genetic etiologies, however non-syndromic cases account for 85% of the burden of disease. Despite this prevalence, the genetic etiology of non-syndromic craniosynsotosis (NSC) is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. By comparing the burden of de novo mutations in NSC cases and controls, we sought to identify those sporadic mutations causing craniosynostosis.
Methods: We performed whole exome sequencing on a cohort of 384 probands with NSC affecting the sagittal (n = 237), metopic (n = 136), combined sagittal and metopic (n = 10), or combined sagittal and coronal (n = 1) sutures. These included 291 complete parent– offspring trios, and 50 probands from kindreds with multiple NSC-affected family members. Of the targeted bases, 96.6% had 8 or more independent reads, and 88.6% had 20 or more. In parallel, we analyzed de novo variants in parents and healthy siblings of 1,789 autism probands from the Simons simplex collection sequenced on the same platform.
Results: Exome sequencing of 291 parent–offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10−11). SMAD6 had 4 de novo and 14 transmitted mutations (P < 10-21), strongly replicating our previous association of SMAD6 to midline NSC. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease, including TWIST1, TCF12, ERF and MSX2. Collectively, these mutations explain 10% of cases studied. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism of disease pathogenesis.
Conclusions: These findings implicate several new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. The results continue to support substantial genetic heterogeneity in NSC, and identify novel molecular subtypes of disease. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes.


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