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De Novo Mutations in Inhibitors of Wnt, BMP, and Ras/ERK Signaling

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De Novo Mutations in Inhibitors of Wnt, BMP, and Ras/ERK Signaling De novo mutations in inhibitors of Wnt, BMP, and PNAS PLUS Ras/ERK signaling pathways in non-syndromic midline craniosynostosis Andrew T. Timberlakea,b, Charuta G. Fureya,c,1, Jungmin Choia,1, Carol Nelson-Williamsa,1, Yale Center for Genome Analysis2, Erin Loringa, Amy Galmd, Kristopher T. Kahlec, Derek M. Steinbacherb, Dawid Larysze, John A. Persingb, and Richard P. Liftona,f,3 aDepartment of Genetics, Yale University School of Medicine, New Haven, CT 06510; bSection of Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT 06510; cDepartment of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510; dCraniosynostosis and Positional Plagiocephaly Support, New York, NY 10010; eDepartment of Radiotherapy, The Maria Skłodowska Curie Memorial Cancer Centre and Institute of Oncology, 44-101 Gliwice, Poland; and fLaboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065 Contributed by Richard P. Lifton, July 13, 2017 (sent for review June 6, 2017; reviewed by Yuji Mishina and Jay Shendure) Non-syndromic craniosynostosis (NSC) is a frequent congenital ing pathways being implicated at lower frequency (5). Examples malformation in which one or more cranial sutures fuse pre- include gain-of-function (GOF) mutations in FGF receptors 1–3, maturely. Mutations causing rare syndromic craniosynostoses in which present with craniosynostosis of any or all sutures with humans and engineered mouse models commonly increase signaling variable hypertelorism, proptosis, midface abnormalities, and of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK path- syndactyly, and loss-of-function (LOF) mutations in TGFBR1/2 ways, converging on shared nuclear targets that promote bone that present with craniosynostosis in conjunction with severe formation. In contrast, the genetics of NSC is largely unexplored. cardiac/vascular abnormalities and other extracranial defects. More than 95% of NSC is sporadic, suggesting a role for de novo Whereas most syndromic craniosynostoses demonstrate patent mutations. Exome sequencing of 291 parent–offspring trios with Mendelian inheritance (5), the vast majority of non-syndromic midline NSC revealed 15 probands with heterozygous damaging cases are sporadic, suggesting a possible role for de novo mu- de novo mutations in 12 negative regulators of Wnt, BMP, and tation. To test this possibility, in a prior study of whole-exome MEDICAL SCIENCES −11 Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10 ). SMAD6 sequencing of 191 probands with midline non-syndromic cranio- had 4 de novo and 14 transmitted mutations; no other gene had synostosis (NSC), including 132 case-parent trios, we found a more than 1. Four familial NSC kindreds had mutations in genes significant excess of damaging protein-altering de novo muta- previously implicated in syndromic disease. Collectively, these muta- tions, likely accounting for ∼11% of cases. One gene, SMAD6, tions contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mecha- Significance nism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a Craniosynostosis is a common congenital malformation resulting frequent two-locus pathogenesis. These findings implicate new from premature fusion of the bones that comprise the cranial genes in NSC and demonstrate related pathophysiology of common vault, requiring surgery in infancy to prevent adverse neurologic non-syndromic and rare syndromic craniosynostoses. These findings outcomes. Eighty-five percent of cases are non-syndromic and of have implications for diagnosis, risk of recurrence, and risk of ad- unknown cause. By exome sequencing of families with non- verse neurodevelopmental outcomes. Finally, the use of pathways syndromic midline craniosynostosis, we show that 5% of cases identified in rare syndromic disease to find genes accounting for have de novo damaging mutations in negative regulators of the non-syndromic cases may prove broadly relevant to understanding Wnt, bone morphogenetic protein (BMP), and Ras/ERK signaling other congenital disorders featuring high locus heterogeneity. pathways, developmental cascades that converge on common nuclear targets to promote bone formation. Another 5% have transmitted mutations in these pathways. Common variants near de novo mutation | craniosynostosis | BMP signaling | Wnt signaling | BMP2 Ras/ERK signaling show genetic interaction with these rare mutations. The results provide insight into pathophysiology and have immedi- ate implications for the diagnosis and genetic counseling of raniosynostosis affects 1 in 2,000 live births, constituting the families with craniosynostosis. Csecond most-common craniofacial birth defect following orofacial clefts (1). Premature fusion of any cranial suture is Author contributions: A.T.T., J.A.P., and R.P.L. designed research; A.T.T., C.G.F., C.N.-W., treated surgically in infancy to prevent neurological impairment, and Y.C.G.A. performed research; E.L., A.G., K.T.K., D.M.S., D.L., and J.A.P. conducted with cases affecting the midline (sagittal and metopic) sutures patient recruitment; A.T.T., J.C., and R.P.L. analyzed data; and A.T.T. and R.P.L. wrote accounting for more than half of all disease (2, 3). Fifteen per- the paper. cent of cases are syndromic, with extracranial malformations, Reviewers: Y.M., University of Michigan; and J.S., University of Washington. while the remaining 85% are non-syndromic with isolated cra- Conflict of interest statement: J.S. and R.P.L. were among 42 coauthors on a 2015 review niosynostosis (4). article. Many genes have been implicated in human syndromic cra- Freely available online through the PNAS open access option. niosynostoses, with at least 40 showing significant statistical Data deposition: The sequences for case-parent trios reported in this paper have been deposited in the NCBI database of Genotypes and Phenotypes (dbGaP) (accession no. support or having been identified in more than one study (5). phs000744). Many genes have also been implicated by studies of mouse ge- 1C.G.F., J.C., and C.N.-W. contributed equally to this work. netics (4, 6–9). These genes are involved in signaling pathways 2Members of the Yale Center for Genome Analysis: Kaya Bilguvar, Shrikant Mane, Irina that converge on promotion of osteoblast differentiation and Tikhonova, Christopher Castaldi, and James Knight. bone formation. The most prominent of these are the Ras/ERK, 3To whom correspondence should be addressed. Email: [email protected]. bone morphogenetic protein (BMP), and Wnt pathways, with This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ephrin, smoothened/hedgehog, STAT, and retinoic acid signal- 1073/pnas.1709255114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1709255114 PNAS | Published online August 14, 2017 | E7341–E7347 Downloaded by guest on September 24, 2021 surpassed genome-wide thresholds for significance, with three each base in the coding region and flanking splice sites (13). damaging de novo mutations and 10 rare independent trans- Probands showed no significant enrichment of synonymous or mitted LOF or damaging missense (D-mis) mutations (10). missense mutations predicted to be tolerated; however, there was These SMAD6 mutations showed striking incomplete pene- significant enrichment of inferred damaging missense (D-mis) and trance, which was explained by epistatic interaction with a pre- LOF mutations (Table 1). In contrast, no enrichment was ob- viously identified (11) common risk allele near the BMP served in any class of coding region mutation in control subjects. signaling ligand, BMP2 (10). No other gene had more than one From the observed excess of damaging de novo mutations in damaging de novo mutation. In this prior study, the power to probands compared with expectation in this set, we infer that determine which other de novo mutations were pathogenic was damaging protein-altering de novo mutations contribute to ∼8% limited by the study size and the apparent high degree of locus of cases. SMAD6, with three different LOF and one D-mis de heterogeneity. We now report results of whole-exome sequenc- novo mutation, was the only gene with more than one damaging ing of a much larger cohort of NSC families. de novo mutation (probability of three or more de novo LOF − mutations in SMAD6 by chance = 4.0 × 10 10)(Dataset S1). Results Exome Sequencing of Midline NSC. We studied a cohort of Enrichment of Mutations in Negative Regulators of Wnt, BMP, and 384 probands with NSC affecting the sagittal (n = 237), metopic Ras/ERK Signaling. As discussed above, mutations that cause (n = 136), combined sagittal and metopic (n = 10), or combined rare syndromic forms of craniosynostosis in humans and in sagittal and coronal (n = 1) sutures. These included 291 parent– mouse cluster in developmental signaling pathways that converge offspring trios, 132 of which were previously reported (10). on promotion of osteoblast differentiation and bone formation Whole-exome sequencing was performed as described in Meth- (5). These are encompassed by the Ras/ERK, Wnt, BMP, ods. Of the targeted bases, 96.6% had 8 or more independent hedgehog, ephrin, STAT, and retinoic acid signaling pathways reads, and 88.6% had 20 or more (Table S1). In parallel, we (5). We considered whether de novo mutations in these pathways
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