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Limb disorders v1.127 SMAD6 Eleanor Williams Classified gene: SMAD6 as Green List (high evidence)
Limb disorders v1.127 SMAD6 Eleanor Williams Added comment: Comment on list classification: Promoting from red to green. Notes from Genomics England clinical team - Sufficient cases, scope of panel includes radial anomalies therefore potentially informative for some patients.

Note reduced penetrance.
Limb disorders v1.127 SMAD6 Eleanor Williams Gene: smad6 has been classified as Green List (High Evidence).
Limb disorders v1.56 SMAD6 Eleanor Williams commented on gene: SMAD6: Added Incomplete penetrance as Yang et al 2019 found only 20% penetrance for LOF variant carriers.
Limb disorders v1.56 SMAD6 Eleanor Williams Penetrance for gene SMAD6 was set from to None
Limb disorders v1.55 SMAD6 Eleanor Williams Publications for gene: SMAD6 were set to
Limb disorders v1.54 SMAD6 Eleanor Williams Phenotypes for gene: SMAD6 were changed from radioulnar synostosis to radioulnar synostosis
Limb disorders v1.54 SMAD6 Eleanor Williams Phenotypes for gene: SMAD6 were changed from to radioulnar synostosis
Limb disorders v1.53 SMAD6 Eleanor Williams changed review comment from: Not associated with radioulnar synostosis in OMIM or Gene2Phenotype, although is associated with susceptibility to craniosynostosis and Aortic valve disease 2.

PMID: 31138930 - Yang et al 2019 - investigated 140 sporadic patients and 11 families with RUS of an unknown cause. Potentially disease causing variants were found in SMAD6 in 30 individuals from 27 families. In 22 individuals the variants were detected by whole exome sequencing and confirmed by Sanger sequencing. In the remaining 8 individuals targetting sequencing of SMAD6 using Sanger sequencing was performed. 27 different variants were identified (19 LOF and 8 missense), in 24 sporadic patients and three families. Parental genomic DNA was available for 11 probands with SMAD6 rare variants. Sanger sequencing validated that four variants were de novo, six were inherited from the probands’ unaffected mother, and one was inherited from the probands’ unaffected father.
Reduced penetrance was found - after excluding the index cases, the found 2/10 SMAD6- LOF carriers have nsRUS. Therefore, the penetrance of RUS in SMAD6-LOF cases is reduced (~20%).
No significant associations were observed between BMP2-Chr20–7106289T-C genotype and nsRUS in cases with SMAD6 rare variants.; to: Not associated with radioulnar synostosis in OMIM or Gene2Phenotype, although is associated with susceptibility to craniosynostosis and Aortic valve disease 2.

PMID: 31138930 - Yang et al 2019 - investigated 140 sporadic patients and 11 families with Radioulnar synostosis (RUS) of an unknown cause. Potentially disease causing variants were found in SMAD6 in 30 individuals from 27 families. In 22 individuals the variants were detected by whole exome sequencing and confirmed by Sanger sequencing. In the remaining 8 individuals targeted Sanger sequencing of SMAD6 was performed. 27 different variants were identified (19 LOF and 8 missense), in 24 sporadic patients and three families. Parental genomic DNA was available for 11 probands with SMAD6 rare variants. Sanger sequencing validated that four variants were de novo, six were inherited from the probands’ unaffected mother, and one was inherited from the probands’ unaffected father.
Reduced penetrance was found - after excluding the index cases, the found 2/10 SMAD6- LOF carriers have nsRUS. Therefore, the penetrance of RUS in SMAD6-LOF cases is reduced (~20%).
No significant associations were observed between BMP2-Chr20–7106289T-C genotype and nsRUS in cases with SMAD6 rare variants.
Limb disorders v1.53 SMAD6 Eleanor Williams commented on gene: SMAD6: Not associated with radioulnar synostosis in OMIM or Gene2Phenotype, although is associated with susceptibility to craniosynostosis and Aortic valve disease 2.

PMID: 31138930 - Yang et al 2019 - investigated 140 sporadic patients and 11 families with RUS of an unknown cause. Potentially disease causing variants were found in SMAD6 in 30 individuals from 27 families. In 22 individuals the variants were detected by whole exome sequencing and confirmed by Sanger sequencing. In the remaining 8 individuals targetting sequencing of SMAD6 using Sanger sequencing was performed. 27 different variants were identified (19 LOF and 8 missense), in 24 sporadic patients and three families. Parental genomic DNA was available for 11 probands with SMAD6 rare variants. Sanger sequencing validated that four variants were de novo, six were inherited from the probands’ unaffected mother, and one was inherited from the probands’ unaffected father.
Reduced penetrance was found - after excluding the index cases, the found 2/10 SMAD6- LOF carriers have nsRUS. Therefore, the penetrance of RUS in SMAD6-LOF cases is reduced (~20%).
No significant associations were observed between BMP2-Chr20–7106289T-C genotype and nsRUS in cases with SMAD6 rare variants.
Limb disorders v1.24 SMAD6 Andrew Wilkie reviewed gene: SMAD6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb disorders v1.22 SMAD6 Eleanor Williams gene: SMAD6 was added
gene: SMAD6 was added to Limb disorders. Sources: Expert list
Mode of inheritance for gene: SMAD6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: SMAD6 was set to AMBER
Added comment: Gene suggested for the panel by Andrew Wilkie, Oxford University Hospitals NHS Foundation Trust
Sources: Expert list