Abstract
Craniosynostosis is one of the most common congenital craniofacial birth defects. The genetic etiology is complex, involving syndromic developmental diseases, chromosomal abnormalities, and monogenic non-syndromic diseases. Herein, we presented a proband of craniosynostosis, who firstly displayed structural abnormalities. This research conducted dynamic ultrasound monitoring a fetus with gradually developing intrauterine growth retardation (IUGR). A novel de novo variant c.41G > A: p.W14* in SMAD6 was identified by pedigree analysis and genetic examination approaches. Recombinant plasmid carrying wild-type sequence and mutant that carries c.41G > A in SMAD6 were constructed and transfected into HEK293T cells. mRNA and protein expression of SMAD6 were reduced in SMAD6 mutants compared to the wild type. Cycloheximide (CHX) treatment and si-UPF1 transfection rescued the SMAD6 mRNA expression in the mutant construct, indicating that c.41G > A: p.W14* in SMAD6 triggered nonsense-mediated mRNA degradation (NMD) process and thus led to haploinsufficiency of the protein product. Our study demonstrated that whole-exome sequencing (WES) was a powerful tool for further diagnosis and etiological identification once fetal malformation was detected by ultrasound. Novel de novo c.41G > A: p.W14* in SMAD6 is pathogenic and potentially leads to craniosynostosis via NMD process.