A case of Fraser Syndrome 2 in Chinese fetus caused by novel compound heterozygous variants in the FREM2 gene

Weidong Wei^1,2Yinan Fan³Jiaqi song³Yedan Lou³Tao Zhang^1,2Hua Yuan^1,2Jie-Yuan Jin³Sinan Zhang⁴Xin Jin^3*

• ¹Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China
• ²Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
• ³Shaoxing University, Shaoxing, China
• ⁴Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Naval Military Medical University, ShangHai, China

Background: Fraser syndrome (FS) is an autosomal recessive inherited malformation disorder, characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tracts. Variants in the FREM2 gene are the major genetic cause. However, clinical diagnosis remains challenging due to phenotypic heterogeneity. Methods: A 24-week pregnant woman came to our hospital for genetic diagnosis. The ultrasound showed bilateral renal agenesis or dysplasia, absence of the bladder, and almost no amniotic fluid. Trio-whole exome sequencing (Trio-WES) identified two novel compound heterozygous variants in the fetal FREM2 gene: a maternal, frameshift variant, c.5908_5909del, p.Leu1970ValfsTer33, and a paternal, nonsense variant; c.7881C>G,p.Tyr2627Ter. Conclusion: We report a rare case of Fraser syndrome 2 caused by compound heterozygous mutations in the FREM2 gene. Our findings expanded the FREM2 genotypic spectrum and demonstrated the significance of Trio-WES for prenatal diagnosis of recessive disorders.