Targeted next generation sequencing and family survey enable correct genetic diagnosis in CRX associated macular dystrophy \u2013 a case report

Saoud Al-Khuzaei,Karl A Z Hudspith,Morag E Shanks,Andrea H Németh,Stephanie Halford,Penny Clouston,Susan M Downes,Suzanne Broadgate

doi:10.1186/s12886-021-01919-1

Abstract

BackgroundWe present 3 members of a family with macular dystrophy, originally diagnosed as Stargardt disease, with a significantly variable age at onset, caused by a heterozygous mutation in CRX.Case presentationA 43-year-old female with bull’s eye maculopathy, whose sister was diagnosed with Stargardt disease previously at another centre, was found to have a single ABCA4 variant. Further examination of the family revealed that the asymptomatic father was also affected, indicating a dominant pattern of inheritance. In addition, the ABCA4 variant was not identified in the sister originally diagnosed with Stargardt disease. Next generation sequencing identified a heterozygous c.121C > T, p.R41W missense mutation in CRX in all 3 affected members.ConclusionsWe describe a common phenotype, but with variable age at onset, with autosomal dominant inheritance and reduced penetrance in a family found to have a pathogenic sequence variant in CRX. This illustrates the importance of panel based molecular genetic testing accompanied by family studies to establish a definitive diagnosis.

Highlights

We present 3 members of a family with macular dystrophy, originally diagnosed as Stargardt disease, with a significantly variable age at onset, caused by a heterozygous mutation in cone-rod homeobox (CRX).Case presentation: A 43-year-old female with bull’s eye maculopathy, whose sister was diagnosed with Stargardt disease previously at another centre, was found to have a single ATP binding cassette subfamily A member 4 (ABCA4) variant
Autofluorescence (AF) shows loss of signal centrally corresponding to atrophy with a surrounding band of increased autofluorescence imaging (AF) within the arcades (c and d. optical coherence tomography (OCT) imaging showing the temporal extent of the loss of the ellipsoid zone demarcated by yellow arrows. e and f
Single ABCA4 variants are frequently identified in patients phenotypically diagnosed with Stargardt macular dystrophy (STGD1) [2,3,4], ABCA4 testing was undertaken because of the family history of Stargardt disease (STGD1) and because the siblings had a bull’s eye macular dystrophy (BEM) appearance, which has been reported with ABCA4 variants [7]

Summary

Conclusions

We describe a common phenotype, but with variable age at onset, with autosomal dominant inheritance and reduced penetrance in a family found to have a pathogenic sequence variant in CRX.

Background

Discussion and conclusions