Whole exome sequencing revealed novel pathogenic variants in Vietnamese patients with FEVR.

Background: Familial exudative vitreoretinopathy (FEVR) is a rare inherited disorder marked by incomplete retinal vascularization associated with exudation, neovascularization, and tractional retinal detachment. FEVR is genetically heterogeneous and is caused by variants in six genes: FZD4, LRP5, NDP, TSPAN12, ZNF408, and CTNNB1. In addition, the phenotypic overlap between FEVR and other disorders has been reported in patients harboring variants in other genes, such as KIF11, ATOH7, and RCBTB1.

Purpose: To identify pathogenic variants in Vietnamese pediatric patients diagnosed with FEVR and to investigate the clinical findings in correlation with each causative gene.

Methods: A total of 20 probands underwent ocular examinations with fundoscopy (ophthalmoscopy) or fluorescein angiography. Genomic DNA was extracted from the peripheral blood of the probands and their family members. Multiplex ligation-dependent probe amplification (MLPA) was employed to detect copy number variants of FEVR-causing genes. Short variants were screened by whole-exome sequencing (WES) and then validated by Sanger sequencing.

Results: Fluorescein angiography showed retinal vascular anomalies in all patients. Other ocular abnormalities commonly found were strabismus, nystagmus, exudation, and retinal detachment. Genetic analysis identified 12 different variants in the FZD4, NDP, KIF11, and ATOH7 genes among 20 probands. Four variants were novel, including FZD4 c.169G>C, p.(G57R); NDP c.175-3A>G, splicing; KIF11 c.2146C>T, p.(Q716*) and c.2511_2515del, p.(N838Kfs*17). All patients with the KIF11 variant showed signs of microcephaly and intellectual disability. The patient with Norrie syndrome and their family members were found to have a deletion of exon 2 in the NDP gene.

Conclusions: This study sheds light on the genetic causes of ocular disorders with the clinical expression of FEVR in Vietnamese patients. WES was applied as a comprehensive tool to identify pathogenic variants in complex diseases, such as FEVR, and the detection rate of pathogenic mutations was up to 60%.