Limb disordersGene: SMAD6
radio-ulnar synostosis (Yang Genetics in Medicine 2019)
Created: 1 Aug 2019, 5:10 p.m. | Last Modified: 1 Aug 2019, 5:10 p.m.
Panel Version: 1.24
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.
Created: 26 Nov 2019, 1:06 a.m. | Last Modified: 26 Nov 2019, 1:06 a.m.
Panel Version: 1.127
Added Incomplete penetrance as Yang et al 2019 found only 20% penetrance for LOF variant carriers.
Created: 8 Aug 2019, 10:07 a.m. | Last Modified: 8 Aug 2019, 10:07 a.m.
Panel Version: 1.56
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.
Created: 8 Aug 2019, 9:28 a.m. | Last Modified: 8 Aug 2019, 9:31 a.m.
Panel Version: 1.53
Gene suggested for the panel by Andrew Wilkie, Oxford University Hospitals NHS Foundation Trust
Sources: Expert list
Created: 1 Aug 2019, 4:39 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Gene: smad6 has been classified as Green List (High Evidence).
Penetrance for gene SMAD6 was set from to None
Publications for gene: SMAD6 were set to
Phenotypes for gene: SMAD6 were changed from radioulnar synostosis to radioulnar synostosis
Phenotypes for gene: SMAD6 were changed from to radioulnar synostosis
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