Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles

Timberlake, Andrew T.; Choi, Jungmin; Zaidi, Samir; Lu, Qiongshi; Nelson‐Williams, Carol; Brooks, Eric D.; Bilgüvar, Kaya; Tikhonova, Irina; Mane, Shrikant; Yang, Jenny; Sawh-Martinez, Rajendra; Persing, Sarah; Zellner, Elizabeth; Loring, Erin; Chuang, Carolyn; Galm, Amy; Hashim, Peter W.; Steinbacher, Derek M.; DiLuna, Michael L.; Duncan, Charles C.; Pelphrey, Kevin A.; Zhao, Hongyu; Persing, John A.; Lifton, Richard P.

doi:10.7554/elife.20125

Cited by 172 publications

(217 citation statements)

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“…These SMAD6 mutations showed striking incomplete penetrance, which was explained by epistatic interaction with a previously identified (11) common risk allele near the BMP signaling ligand, BMP2 (10). No other gene had more than one damaging de novo mutation.…”

Section: Significancementioning

confidence: 84%

“…Statistical analysis of the burden of de novo mutations in craniosynostosis cases and autism controls were performed in R using the denovolyzeR package, as previously described (10,46). The expected number of de novo mutations in case and control cohorts across variant classes was calculated, and this value was compared with the observed number in each cohort using Poisson statistics (13).…”

Section: Methodsmentioning

confidence: 99%

“…surpassed genome-wide thresholds for significance, with three damaging de novo mutations and 10 rare independent transmitted LOF or damaging missense (D-mis) mutations (10). These SMAD6 mutations showed striking incomplete penetrance, which was explained by epistatic interaction with a previously identified (11) common risk allele near the BMP signaling ligand, BMP2 (10).…”

Section: Significancementioning

confidence: 96%

“…We previously demonstrated incomplete penetrance of SMAD6 mutations, and showed epistasis between these rare mutations and common risk alleles near BMP2 that were the strongest signal in a prior genome-wide association study (GWAS) of sagittal NSC (10,11). Following addition herein of five new kindreds with a de novo or rare transmitted SMAD6 mutation, we reevaluated penetrance and interaction of SMAD6 and BMP2 alleles by association and parametric analysis of linkage under a two-locus model considering rare damaging alleles of SMAD6 and the common risk allele of SNP rs1884302.…”

Section: Transmitted Mutations In Smad6 and Epistasis With A Common Riskmentioning

confidence: 99%

“…There was also highly significant linkage of rare SMAD6 mutations and common BMP2 risk alleles under a parametric two-locus model [logarithm of the odds (LOD) score 8.2, odds >100 million:1 in favor of linkage], which is >1,400× more likely than the best single-locus model (Fig. S2 and Tables S8 and S9) (10).…”

Section: Transmitted Mutations In Smad6 and Epistasis With A Common Riskmentioning

confidence: 99%

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De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. 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 × 10 −11 ). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. 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 frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

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Section: Significancementioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Section: Significancementioning

confidence: 96%

Section: Transmitted Mutations In Smad6 and Epistasis With A Common Riskmentioning

confidence: 99%

Section: Transmitted Mutations In Smad6 and Epistasis With A Common Riskmentioning

confidence: 99%

See 3 more Smart Citations

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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100

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DIAPH1 Variants in Non–East Asian Patients With Sporadic Moyamoya Disease

et al. 2021

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IMPORTANCE Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals. OBJECTIVE To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. DESIGN, SETTING, AND PARTICIPANTSA genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016)(2017)(2018)(2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.MAIN OUTCOMES AND MEASURES Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. RESULTSOf the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10 −6 ) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.CONCLUSIONS AND RELEVANCE These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk...

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Genetic advances in craniosynostosis

Lattanzi

Barba

Pietro

et al. 2017

American J of Med Genetics Pt A

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Craniosynostosis, the premature ossification of one or more skull sutures, is a clinically and genetically heterogeneous congenital anomaly affecting approximately 1 in 2,500 live births. In most cases, it occurs as an isolated congenital anomaly, i.e. nonsyndromic craniosynostosis (NCS), the genetic and environmental causes of which remain largely unknown. Recent data suggest that at least some of the midline NCS cases may be explained by two loci inheritance. In approximately 25–30% of patients craniosynostosis presents as a feature of a genetic syndrome due to chromosomal defects or mutations in genes within interconnected signaling pathways. The aim of this review is to provide a detailed and comprehensive update on the genetic and environmental factors associated with NCS, integrating the scientific findings achieved during the last decade. Focus on the neurodevelopmental, imaging and treatment aspects of NCS is also provided.

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Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles

Cited by 172 publications

References 46 publications

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

DIAPH1 Variants in Non–East Asian Patients With Sporadic Moyamoya Disease

Genetic advances in craniosynostosis

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