SMAD6 – Congenital Radioulnar Synostosis

SMAD6 encodes an intracellular inhibitor of bone morphogenetic protein (BMP) signalling and is robustly associated with autosomal dominant congenital radioulnar synostosis (MONDO:0017985). Variants in SMAD6 have been identified in multiple cohorts of nonsyndromic and familial radioulnar synostosis (RUS), demonstrating a recurrent role in aberrant skeletogenesis.

In a study of 140 nonsyndromic RUS patients and 11 families, exome and Sanger sequencing revealed 22/117 sporadic cases and 16/38 pedigrees harboured SMAD6 loss-of-function (LOF) or rare missense variants (OR = 430 for LOF; 95% CI: 238–7 × 10⁻⁶) with four de novo and three transmitted in an autosomal dominant pattern (PMID:31138930).

A larger cohort analysis of 251 sporadic patients and 27 RUS pedigrees confirmed 93 SMAD6-mutant individuals, including 13 pedigrees with co-segregation and 61 sporadic cases. SMAD6 variants were found in 16/38 pedigrees and 61/393 sporadic patients, with variable expressivity and non-full penetrance (left:right = 20:9) and a female protective effect where only 6.90% of carrier mothers were affected (PMID:34953066).

Inheritance is autosomal dominant with incomplete penetrance. The variant spectrum comprises heterozygous LOF frameshift and nonsense mutations as well as missense substitutions. A representative variant is c.3G>T (p.Met1Ile), observed among RUS probands.

Functional evidence supports a haploinsufficiency mechanism: SMAD6 is a negative BMP antagonist, and BMP-2–Runx2–Smad6 promoter assays showed that SMAD6 loss enhances BMP signalling in osteogenic cells (PMID:17215250). Smad6-deficient mice exhibit skeletal anomalies overlapping human RUS, reinforcing the pathogenic mechanism.

No studies have refuted this association. The convergence of strong genetic segregation, a high mutation burden in both familial and sporadic cases, and consistent functional data confirms a definitive role for SMAD6 haploinsufficiency in congenital radioulnar synostosis.

Key take-home: Heterozygous SMAD6 variants cause autosomal dominant congenital radioulnar synostosis with incomplete penetrance and variable expressivity; SMAD6 should be included in genetic testing panels for RUS.

References

• Molecular genetics & genomic medicine • 2022 • A genotype and phenotype analysis of SMAD6 mutant patients with radioulnar synostosis. PMID:34953066
• Genetics in medicine • 2019 • SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis. PMID:31138930
• The Journal of biological chemistry • 2007 • Bone morphogenetic protein 2 activates Smad6 gene transcription through bone-specific transcription factor Runx2. PMID:17215250

Evidence Based Scoring (AI generated)