PT  - JOURNAL ARTICLE
AU  - Luyckx, Ilse
AU  - Walton, Isaac Scott
AU  - Boeckx, Nele
AU  - Van Schil, Kristof
AU  - Pang, Chingyiu
AU  - De Praeter, Mania
AU  - Lord, Helen
AU  - Watson, Christopher Mark
AU  - Bonthron, David T
AU  - Van Laer, Lut
AU  - Wilkie, Andrew O M
AU  - Loeys, Bart
TI  - Homozygous <em>SMAD6</em> variants in two unrelated patients with craniosynostosis and radioulnar synostosis
AID  - 10.1136/jmg-2023-109151
DP  - 2024 Apr 01
TA  - Journal of Medical Genetics
PG  - 363--368
VI  - 61
IP  - 4
4099  - http://jmg.bmj.com/content/61/4/363.short
4100  - http://jmg.bmj.com/content/61/4/363.full
SO  - J Med Genet2024 Apr 01; 61
AB  - Background SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6 were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic SMAD6 variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described.Cases Here, we present the first two patients with craniosynostosis harbouring homozygous SMAD6 variants. The male probands, both born to healthy consanguineous parents, were diagnosed with metopic synostosis and bilateral or unilateral radioulnar synostosis. Additionally, one proband had global developmental delay. Echocardiographic evaluation did not reveal cardiac or outflow tract abnormalities.Molecular analyses The novel missense (c.[584T>G];[584T>G], p.[(Val195Gly)];[(Val195Gly)]) and missense/splice-site variant (c.[817G>A];[817G>A], r.[(817g>a,817delins[a;817+2_817+228])];[(817g>a,817delins[a;817+2_817+228])], p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72)]) both locate in the functional MH1 domain of the protein and have not been reported in gnomAD database. Functional analyses of the variants showed reduced inhibition of BMP signalling or abnormal splicing, respectively, consistent with a hypomorphic mechanism of action.Conclusion Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6 to include craniosynostosis.