Comparative Analysis of Aipl1 Mutations in Recessive Inherited Retinal Dystrophies

Abstract

Purpose: : To investigate the prevalence of sequence variants in AIPL1 in a large cohort of DNA from patients with Lebers Congenital Amaurosis (LCA) and autosomal recessive severe childhood onset retinal dystrophy and to compare this with that seen in the normal population.

Methods: : 268 DNA samples were obtained from unrelated probands with a clinical diagnosis of LCA or childhood onset autosomal recessive retinal dystrophy. The samples were screened for mutations in AIPL1 using a combination of microarray LCA chip analysis (Asper-Ophthalmics) and direct sequencing. The entire AIPL1 coding sequence was assayed, including the intron/exon junctions. Direct sequencing of AIPL1 was also performed in 96 control DNA samples.

Results: : Microarray LCA chip analysis detected homozygous mutations in 2 subjects and one compound heterozygote. A single AIPL1 allele was found in 13 patients. Of these, a second allele was identified using the same array in another LCA gene (RPGRIP, RDH12, CRB1) in 5 patients. Direct sequencing in 147 probands identified 11 subjects who had previously reported mutations in the AIPL1 gene. Four were homozygous for the mutations. Seven subjects were compound heterozygotes, each had a previously published mutation combined with a novel sequence variant. Three subjects had compound heterozygous changes, both of which were novel. A total of 9 previously unreported sequence variants were found. Sequencing of control DNA did not detect any of the novel variants found in the patient panel. Overall sequencing of the 147 probands revealed AIPL1 variants (reported and unreported) in at least one allele in 106 subjects. Sequencing of 96 controls identified sequence variants in 38 subjects, 5 of which were novel.

Conclusions: : AIPL1 appears to be polymorphic in the general population but sequence variants are more common in the population of patients with childhood retinal dystrophies. It may be difficult in individual patients to determine whether sequence variants in AIPL1 are pathogenic.

Keywords: gene screening • retinal degenerations: hereditary • candidate gene analysis