Phenotype and genetic variation analysis of primary congenital lymphedema caused by FLT4 gene mutation in fetus

Shanshan Zhai^*Limin YuanJing LiLing LiuLulu HuYanjie BanXuewen YangJie YangXuezhe OuyangNana HuangYuan TianTing WangXiao Kong

• The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China

The purpose of this retrospective study is to investigate the imaging phenotype and genetic variation of three fetuses with FLT4 gene mutations in three families. Ultrasound images of the three affected fetuses were collected, fetal specimens obtained by amniocentesis, and peripheral blood samples collected from both parents for whole exome sequencing (WES) and copy number variation sequencing (CNV-seq). The primary prenatal imaging phenotype of fetuses from three families showed bilateral lower limb and foot dorsum lymphedema. Genetic testing: There is a paternal c.3122G>A (p.R1041Q) heterozygous variant of FLT4 gene (NM_182925.5) in family 1 fetus, a paternal c.3284G>A (p.S1095N) heterozygous variant of FLT4 gene (NM_182925.5) in family 2 fetus and a maternal c.2560G>A (p.G854S) heterozygous variant of FLT4 gene (NM_182925.5) in family 3 fetus. Postpartum follow-up: the fetus in family 1 mainly presented with bilateral foot dorsum lymphedema at birth, which improved significantly after surgical treatment at one month of age; the fetus in family 2 had mild lymphedema in both feet at birth, which significantly subsided at 18 months of age; the pregnancy was terminated in family 3.. Bilateral lower limb lymphedema is a typical clinical manifestation during fetal stage. Some cases follow a benign course of natural regression while some cases achieve a good prognosis via surgical intervention. The FLT4 c.3284G>A variant identified in this study has not been previously reported, which broadens the mutation spectrum of this gene.This study provides valuable insights for prenatal diagnosis, genetic counseling, and prognosis evaluation of the disease.