2. Academic Validation
  3. Prenatal diagnostic approaches diagnosed craniosynostosis and identified a novel nonsense variant in SMAD6 in a Chinese fetus

Prenatal diagnostic approaches diagnosed craniosynostosis and identified a novel nonsense variant in SMAD6 in a Chinese fetus

  • Gene. 2023 Nov 15:147994. doi: 10.1016/j.gene.2023.147994.
Zhidan Hong 1,  Xuanyi He 1,  Jie Duan 2,  Fang Yu 3,  Huanyu Liu 1,  Dan Lu 4,  Mei Wang 1,  Yuanzhen Zhang 5
Affiliations

Affiliations

  • 1 Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R.China; Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei, P.R. China; Wuhan Clinical Research Center for Reproductive Health and Optimal Birth, Wuhan, Hubei, P.R.China.
  • 2 Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei, P.R. China; Wuhan Clinical Research Center for Reproductive Health and Optimal Birth, Wuhan, Hubei, P.R.China; Department of Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R.China.
  • 3 Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei, P.R. China; Wuhan Clinical Research Center for Reproductive Health and Optimal Birth, Wuhan, Hubei, P.R.China; Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R.China.
  • 4 Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei, P.R. China; Wuhan Clinical Research Center for Reproductive Health and Optimal Birth, Wuhan, Hubei, P.R.China; Department of Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R.China.
  • 5 Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R.China; Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei, P.R. China; Wuhan Clinical Research Center for Reproductive Health and Optimal Birth, Wuhan, Hubei, P.R.China. Electronic address: zhangyuanzhen@whu.edu.cn.
PMID: 37977316 DOI: 10.1016/j.gene.2023.147994
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.

Keywords

SMAD6; craniosynostosis; genetics; novel variant; prenatal diagnosis; whole-exome sequencing.

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