Clinical characteristics and mutation spectrum in 33 Chinese families with familial exudative vitreoretinopathy

Abstract

Objective To explore the clinical manifestations and search for the variants of six related genes ( LRP5 , FZD4 , TSPAN12 , NDP , KIF11 and ZNF408 ) in Chinese patients with familial exudative vitreoretinopathy (FEVR), and investigate the correlation between the genetic variants and the clinical characteristics. Patients and methods Clinical data, including the retinal artery angle, acquired from wide-field fundus imaging, structural and microvascular features of the retina obtained from optical coherence tomography (OCT) and OCT angiography (OCTA) were collected from 33 pedigrees. Furthermore, mutation screening was performed. Variants filtering, bioinformatics analysis and Sanger sequencing were conducted to verify the variants. Results Twenty-one variants were successfully detected in 16 of 33 families, of which 10 variants were newly identified. The proportion of variants in LRP5 , FZD4 , TSPAN12 , NDP and KIF11 was 38.1% (8/21), 33.3% (7/21), 19.1% (4/21), 4.8% (1/21) and 4.8% (1/21), respectively. Three new variants were considered to be pathogenic or likely pathogenic. The FEVR group tended to exhibit a smaller retinal artery angle, higher incidence of foveal hypoplasia and lower vascular density compared to the control group. Patients who harboured variants of FZD4 exhibited greater severity of FEVR than those with LRP5 variants. However, those who harboured LRP5 variants tended to possess lower foveal vascular density. Conclusions Six known pathogenic genes were screened in 33 pedigrees with FEVR in our study, which revealed 10 novel variants. These findings enrich the clinical features and mutation spectrum in Chinese patients with FEVR, revealing the genotype-phenotype relationship, and contributing to the diagnosis and treatment of the disease. Key messages We identified 21 variants in 5 genes ( LRP5, FZD4, TSPAN12, NDP and KIF11) associated with FEVR, 10 of which are novel (three were pathogenic or likely pathogenic). The proportion of variants was the highest for the LRP5 gene. FZD4 variants may be responsible for greater FEVR severity than LRP5 variants.

Osteoporosis, Fractures, and Blindness Due to a Missense Mutation in the LRP5 Receptor

“…1,3 Most forms of FEVR affect only the eye and may be caused by mutations in LRP5 or in about 14 other genes including FZD4, TSPAN12, NDP, and KIF11. 4 Incomplete loss-of-function mutations in LRP5 can result in a distinct form of FEVR whose phenotype includes osteoporosis and predisposition to fracture in addition to the incomplete or anomalous vascularization of the peripheral retina for which the condition is known. [4][5][6] Because OPPG and LRP5-mutation-induced FEVR arise secondary to similar genetic mechanisms, it has been proposed that the conditions are in fact a continuum and should not be considered separate entities.…”

“…4 Incomplete loss-of-function mutations in LRP5 can result in a distinct form of FEVR whose phenotype includes osteoporosis and predisposition to fracture in addition to the incomplete or anomalous vascularization of the peripheral retina for which the condition is known. [4][5][6] Because OPPG and LRP5-mutation-induced FEVR arise secondary to similar genetic mechanisms, it has been proposed that the conditions are in fact a continuum and should not be considered separate entities. 5,7,8 While the skeletal characteristics of adolescents with OPPG have been described, 9,10 the skeletal phenotypes of patients with LRP5-mutation-induced FEVR have not been explored in depth.…”

LRP5, Bone Mass Polymorphisms and Skeletal Disorders

“…Related to OPPG is LRP5 variant-induced familial exudative vitreoretinopathy (FEVR; OMIM 133780 [40]), a disorder characterized by disorganized retinal blood vessel development leading to incomplete vascularization of the peripheral retina [41,42]. Clinically, FEVR displays genetic heterogeneity, and variants of at least 14 genes have been implicated in its pathogenesis [43]. These include variants in genes related to the WNT signaling pathway, e.g., LRP5, FZD4 (OMIM 604579 [44]), and CTNNB1 (OMIM 617572 [45]), which have been reported to be responsible for FEVR.…”

Optical Coherence Tomography and Optical Coherence Tomography Angiography in Pediatric Retinal Diseases

“…A more recent study by Mao et al also found lower VD of the DCP in the digenic inheritance of FEVR patients. Patients with LRP5 variants had lower foveal VD in SCP and DCP and a higher acirculatory index than TSPAN12 variants [ 75 ]. This finding shows the application of OCTA in different phenotypes and genotypes in the FEVR disease spectrum.…”