Abstract
PurposeEnrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism near BMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype.MethodsWe performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants.ResultsWe found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10−7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype.ConclusionPathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.
Highlights
Craniosynostosis (CRS), the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ∼1 in 2000
What is the contribution of SMAD6 variants in all presentations of CRS? Second, can it be assumed that all rare SMAD6 missense variants affect protein function? Third, can the two-locus (SMAD6/rs1884302) model be confirmed in an independent cohort? Here, we address these questions
Patients The clinical studies were approved by respective Institutional Review Boards (IRB): Oxfordshire Research Ethics Committee (REC) B (C02.143), London–Riverside REC (09/H0706/20), East of England–Cambridge South REC (14/EE/1112 for 100,000 Genomes Project [100kGP]), the Medical Ethical Committee of the Erasmus University Medical Center Rotterdam (MEC-2012–140), and the IRB of the University of California–Davis (International Craniosynostosis Consortium [ICC]; protocol 215635–23)
Summary
Craniosynostosis (CRS), the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ∼1 in 2000. Environmental factors, polygenic inheritance and singlegene or chromosomal abnormalities all contribute to its complex manifestations. Variants in >60 genes have been identified as recurrently associated with CRS, with an underlying genetic cause being found in ∼24% of patients overall.[1,2,3]. The proportion in whom a cause can be determined varies widely depending on clinical diagnosis: from 88% for bicoronal synostosis down to 8% for sagittal synostosis (SS).[2] Until recently, success in identifying a genetic diagnosis has been low in nonsyndromic midline CRS, under 1% for both sagittal and metopic suture fusions.[2].
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