Detection of FZD4, LRP5 and TSPAN12 genes variants in Malay premature babies with retinopathy of prematurity

Abstract

Purpose: To determine the mutational analyses of familial exudative vitreoretinopathy (FEVR)-causing genes in Malay patients with retinopathy of prematurity (ROP) to obtain preliminary data for gene alterations in the Malay community. Methods: A comparative cross-sectional study involving 86 Malay premature babies (ROP = 41 and non-ROP = 45) was performed from September 2012 to December 2014. Mutation analyses in (FEVR)-causing genes ( NDP , FZD4 , LRP5 , and TSPAN12 ) were performed using DNA from premature babies using polymerase chain reaction (PCR) and direct sequencing. Sequencing results were confirmed with PCR-Restriction Fragment Length Polymorphism (RFLP). Results: We found variants of FZD4, LRP5 , and TSPAN12 in this study. One patient from each group showed a non-synonymous alteration in FZD4 , c.502C>T (p.P168S). A synonymous variant of LRP5 [c.3357G>A (p.V1119V)] was found in 30 ROP and 28 non-ROP patients. Two variants of TSPAN12 , c.765G>T (p.P255P) and c.*39C>T (3′UTR), were also recorded (29 and 21 in ROP, 33 and 26 in non-ROP, respectively). Gestational age and birth weight were found to be significantly associated with ROP ( P value < 0.001 and 0.001, respectively). Conclusion: Analysis of data obtained from the ROP Malay population will enhance our understanding of these FEVR-causing gene variants. The c.3357G>A (p.V1119V) variant of LRP5 , and c.765G>T (p.P255P) and c.*39C>T variants of TSPAN12 could be common polymorphisms in the Malay ethnic group; however, this requires further elucidation. Future studies using larger groups and higher numbers of advanced cases are necessary to evaluate the relationship between FEVR-causing gene variants and the risk of ROP susceptibility in Malaysian infants.

Mechanisms Underlying Rare Inherited Pediatric Retinal Vascular Diseases: FEVR, Norrie Disease, Persistent Fetal Vascular Syndrome

“…Additional features included microaneurysms, impaired hyaloid vessel regression, focal hemorrhages, retinal TSPAN12 variants can cause autosomal-dominant FEVR [57]. Variants of human TSPAN-12 have also been linked with ROP, specific types of cancer via regulation of progression, viral infections using TSPAN-12, and mental retardation [58][59][60]. Many variants identified in probands diagnosed with FEVR are predicted to result in a truncated protein, though studies were unable to perceive a difference in clinical presentation between patients with shortened proteins and those with missense mutations [57].…”

Mechanisms Underlying Rare Inherited Pediatric Retinal Vascular Diseases: FEVR, Norrie Disease, Persistent Fetal Vascular Syndrome

“…TSPAN12 variants can cause autosomal dominant FEVR [51]. Variants of human TSPAN-12 have also been linked with ROP, specific types of cancer via regulation of progression, viral infections using TSPAN-12, and mental retardation [52][53][54]. Many variants identified in probands diagnosed with FEVR are predicted to result in a truncated protein, though studies were unable to perceive a difference in clinical presentation between patients with shortened proteins and those with missense mutations [51].…”

Exploration of Hub Genes in Retinopathy of Prematurity Based on Bioinformatics Analysis of the Oxygen-Induced Retinopathy Model

“…Oxygen-induced retinopathy (OIR) phenotypes in rodent models also revealed proof of genetic effects, with discrepancies in retinal avascular areas and VEGF expression found between different rat strains [ 6 – 8 ]. An increasing number of researchers have reported that multiple genes are involved in predisposition to ROP in animal models and humans, and numerous candidate gene-related studies have been performed [ 9 – 13 ]. However, which genes are crucially and closely correlated with ROP is still unclear.…”

“…Recently, some studies have used microarray data profiles to illustrate the pathogenesis of ROP [ 9 – 14 ], but these studies were based on only a single cohort or single genetic event. To overcome this inadequacy, a comprehensive combination of gene expression profiling techniques and integrative bioinformatics approaches should be performed.…”