Dataset Information

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation.

ABSTRACT:

Purpose

Enrichment 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 nearBMP2 (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.

Methods

We 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.

Results

We 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.

Conclusion

Pathogenic 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.

SUBMITTER: Calpena E

PROVIDER: S-EPMC7462747 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation.

Calpena Eduardo E Cuellar Araceli A Bala Krithi K Swagemakers Sigrid M A SMA Koelling Nils N McGowan Simon J SJ Phipps Julie M JM Balasubramanian Meena M Cunningham Michael L ML Douzgou Sofia S Lattanzi Wanda W Morton Jenny E V JEV Shears Deborah D Weber Astrid A Wilson Louise C LC Lord Helen H Lester Tracy T Johnson David D Wall Steven A SA Twigg Stephen R F SRF Mathijssen Irene M J IMJ Boardman-Pretty Freya F Boyadjiev Simeon A SA Wilkie Andrew O M AOM

Genetics in medicine : official journal of the American College of Medical Genetics 20200605 9

<h4>Purpose</h4>Enrichment 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 nearBMP2 (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 sign ...[more]

PMID: 32499606

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Project description:Objective, the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes in the context of developmental processes and physiology. Patients and Methods, a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition. Results, two co-occurring heterozygous truncating variants in CNOT3 and SMAD6 were identified. Heterozygous loss-of-function variants in CNOT3, encoding a subunit of the CCR4-NOT protein complex, have recently been reported to cause a syndromic condition known as intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF). Enrichment of rare/private variants in the SMAD6 gene, encoding a protein negatively controlling transforming growth factor β/bone morphogenetic protein (TGFB/BMP) signaling, has been described in association with a wide spectrum of congenital heart defects. We dissected the contribution of individual variants to the complex clinical manifestations and profiled a previously unappreciated set of facial features and signs characterizing IDDSADF. Conclusions, two concomitant truncating variants in CNOT3 and SMAD6 are the cause of the combination of features documented in the patient resulting in the unique multisystem neurodevelopmental condition. These findings provide evidence for a functional link between the CCR4-NOT complex and TGFB/BMP signaling in processes controlling cardiac development. Finally, the present revision provides evidence that IDDSADF is characterized by a distinctive facial gestalt.

Dataset Information

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation.

Purpose

Methods

Results

Conclusion

Publications

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation.

Similar Datasets

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