Molecular Etiology of Stargardt Disease in Newfoundland and Labrador

Abstract

Purpose: : to identify mutations in the ABCA4 gene in Newfoundland (NL) families with Stargardt disease (STGD) and related retinal dystrophies.

Methods: : Since 1978, 31 families with STGD have been identified in NL (the island province in eastern Canada), and members of 22 families were available for molecular analysis. DNA was collected from 37 affected and 27 unaffected consenting members of these families and sequenced on the ABI 3130 automated sequencer. Variants were reviewed manually and with Mutation Surveyor, and compared with Asper Ophthalmics and Retina International mutation databases. Clinical records were reviewed for all affected individuals for up to 31 years and phenotypes for each genotype compared. The study was approved by the Human Investigation Committee of Memorial University, Faculty of Medicine.

Results: : Ancestors of 13/22 families studied came from one bay in eastern NL. Two mutations have been identified in 29 patients, a single mutation in three individuals and no mutation for five individuals in five families. The common IVS40+5G>A mutation was homozygous in seven individuals and heterozygous in eleven others all from the eastern bay. A second mutation IVS38 -10T>C was present in seven individuals (three homozygotes and four compound heterozygotes) from the same bay. Twelve other mutations were identified in fewer individuals.

Conclusions: : Multiple mutations were identified in NL families with IVS40+5 G>A being the most common mutation. All individuals with this mutation came from one genetic isolate. IVS40+5G>A homozygotes had less severe disease than compound heterozygotes with this mutation. The IVS38 -10T>C mutation was seen in two families. This presented as typical STGD at a young age with progression to severe disease confirming the cone-rod dystrophy phenotype previously reported with this mutation. As with other hereditary eye diseases in NL, founder effect and diversity of mutations for STGD was found with a high proportion (78%) of affected individuals explained.

Keywords: genetics • retinal degenerations: hereditary • mutations