N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population.

Purpose: The study was conducted to resolve the spectrum of ABCA4 mutations in a cohort of unrelated Danish residents with early-onset macular dystrophy.

Methods: A microarray technique was used to analyze known ABCA4 mutations in genomic DNA from a selected group of 161 unrelated individuals referred to the national low vision clinic. The clinical observation time varied from a single examination to follow-up over 35 years.

Results: Fifty-nine allegedly disease-associated ABCA4 variants were found in 197 alleles (61.2%) from 124 (77.0%) patients. Two or three mutations were present in 73 (45.3%) patients, and only one mutation was found in 51 (31.7%) patients. The mutation spectrum included 45 missense mutations, five nonsense mutations, two frame shift deletions, and seven splice site mutations. The relative frequency among the mutations varied considerably. Twenty-eight mutations occurred only once among 197 alleles, while the five most abundant mutations were encountered in 50% of the mutation-carrying alleles. The rate of mutation detection, assessed as the fraction of individuals carrying at least one ABCA4 mutation, varied from 27% to 90% among seven phenotypic groups, and a single mutation, p.N965S (c.2894A>G) in the first nucleotide-binding domain accounted for 16.2% of 197 disease-associated alleles. The mutation causes moderate to serious phenotypes and eventually blindness.

Conclusions: Our study is the first mutation analysis of Stargardt-related retinopathies in a large cohort of patients from a Scandinavian population. The mutation detection rate, performed with an array-based technique, was comparable to that of other microarray-based ABCA4 studies as well as studies using more laborious techniques involving screening methods followed by sequencing. Four out of five of the most prevalent ABCA4 mutations are reported to be frequent in other Western European populations as well. However, the prevalence of the most common Danish mutation, N965S, significantly deviates from the one found in other studies. This underscores that the ABCA4 mutation spectrum within relatively stable populations might be skewed due to founder effects. The clinical spectrum of patients, who are either homozygous or compound heterozygous for the N965S mutation, indicates that this mutation has an early and profound effect on retinal function.