Genetic Analysis Of A Family With Familial Exudative Vitreoretinopathy And Incontinentia Pigmenti

Abstract

Purpose: : Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterised by the incomplete development of the retinal vasculature. Incontinentia pigmenti (IP) is a rare X-linked neuroectodermal disorder characterised by a distinctive skin rash often found in conjunction with abnormalities of the central nervous system, musculoskeletal system, teeth, hair, nails and eyes. The ocular phenotype observed in IP can often resemble that found in FEVR. The purpose of this study was to genetically investigate a family segregating both these disorders.

Methods: : Family members underwent ophthalmic examination including fluorescein angiography in key individuals. The common NEMO deletion was screened by PCR and the coding sequence of LRP5, TSPAN12, FZD4 and NDP were PCR amplified and directly sequenced.

Results: : The female proband and her mother were examined in an ophthalmic clinic and presented with a classic FEVR phenotype and no systemic IP features. Family history showed that the proband’s sister and two nieces were reported to have IP. Genetic screening revealed the presence of a large deletion spanning exons 4-10 of the NEMO gene in all family members apart from the proband. Screening of the known FEVR genes in the proband revealed no clear mutation but a polymorphic variant of unknown significance in LRP5 (c.34CTG[6]+[9]). Subsequently, a large cohort of unrelated female FEVR patients was excluded for the presence of the NEMO deletion.

Conclusions: : We have identified a family with members affected by IP and FEVR. Genetic screening identified a common NEMO deletion, which is found in 70% of IP cases, in all family members apart from the proband. As the mother carried this deletion but only showed an ocular phenotype we speculated that other cases diagnosed as FEVR might also have the NEMO deletion. However, screening of our cohort failed to identify additional cases. Screening of the known FEVR genes in the proband didn’t reveal a clear mutation so the genetic basis of the ocular phenotype in this patient remains unknown. Further investigation is required to understand the possible mechanisms underlying the genotype/phenotype observed in this family. [email protected]

Keywords: gene screening • retina