Prenatal diagnosis of Fowler syndrome with two novel pathogenic variants of FLVCR2

Proliferative vasculopathy and hydranencephaly-hydrocephaly (PVHH) syndrome, also known as Fowler syndrome, is a rare autosomal recessive disorder characterized by hydrocephaly and glomerular vasculopathy in the central nervous system. Fetal cases with Fowler syndrome usually leaded to severe fetal malformation and intrauterine death. Homozygous or compound heterozygous mutations in FLVCR2 cause Fowler syndrome. In the study, we described a prenatal case of Fowler syndrome from a Chinese family. Trio clinical exome sequencing was performed to detect the suspected genetic variants, and cellular assays were used to investigate the deleterious effects caused by the two novel FLVCR2 variants identified in the proband. The trio clinical exome sequencing identified the proband had compound heterozygous variants in exon 1 of FLVCR2 : c.320 C > T (p.Ser107Phe) and c.345del (p.Tyr116Thrfs*17), which were inherited from the father and the mother, respectively. We examined the cellular effects of the two novel variants. The novel missense variant c.320 C > T resulted in abnormal cellular localization with intracellular accumulation and partial endoplasmic reticulum retention of mutant protein. Together with the undetectable protein expression caused by c.345del variant, the two novel FLVCR2 variants contributed to the severe fetal malformation of the fetus. Furthermore, the study summarized the reported fetal cases with Fowler syndrome to compare various fetal phenotypes caused by different FLVCR2 pathogenic variants. The study made definitive diagnosis for this prenatal case of Fowler syndrome through the integrated strategy of clinical observation, genotyping and functional analysis. Our study also broadened the variant spectrum of FLVCR2 , and summarized prenatal clinical features to promote awareness of Fowler syndrome.