A novel splice-site mutation in the LRP5 gene causing Familial Exudative Vitreoretinopathy

Abstract

Familial Exudative Vitreoretinopathy (FEVR) is an inherited heterogeneous eye disorder in children that can be caused by mutations in the LRP5 gene with autosomal dominant or recessive mode of inheritance. Patients might show variable clinical features ranging from few or no visual problems to early-onset blindness. Mutations which lead to loss or gain of function in the LRP5 gene, can affect vascularization, bone density or both. In this investigation we report two children (8-year-old girl and 6-year-old boy) with severe type of FEVR from unrelated families. Both patients presented with bilateral blindness and reduced Bone Mineral Density. Next generation sequencing was used to identify the causative mutation, which revealed a novel homozygous splice-site mutation (NM_002335.4: c.686+1G>T) in the LRP5 gene in our patients. Sanger sequencing was carried out to validate the NGS result in our patients and their families that confirmed the autosomal recessive inheritance pattern in these families. Moreover, q-Real Time PCR was conducted to quantify the mRNA expression level of LRP5 gene in patients and their family members, which revealed nearly the full decrease in the LRP5 expression level in patients and around 50% decrease in the carriers of mutation compared to controls that strongly suggesting the pathogenicity of the identified mutation. Current study identified a novel pathogenic homozygous splice-site mutation in the LRP5 gene and confirms this gene's involvement in an autosomal recessive FEVR (severe form), therefore it can help to conduct an accurate genetic counseling and prenatal diagnosis for high risk families.