Candidate gene analysis of germline variants in Finnish patients with juvenile open‐angle glaucoma

Abstract

AbstractPurposeJuvenile open‐angle glaucoma (JOAG) is a rare type of glaucoma diagnosed in children older than 3 years and adults less than 40 years of age. Predisposition to JOAG is generally inherited in an autosomal dominant pattern. Pathogenic MYOC germline variants are reported in 8‐36% of patients. Rarer pathogenic variants in other genes could also predispose to JOAG. Our aim was to detect disease‐associated germline variants in glaucoma candidate genes in Finnish patients with JOAG.MethodsWe studied 46 unrelated patients with JOAG treated between 2010 and 2018 at the Department of Ophthalmology, Helsinki University Hospital, Finland. We first sequenced all exonic regions and flanking splice sites of MYOC using Sanger sequencing. In 42 patients without a pathogenic MYOC germline variant, we then performed whole exome sequencing (WES) to investigate variants in 17 glaucoma‐related genes.ResultsFour probands had a likely pathogenic variant in MYOC: c.1109C>T, p.(Pro370Leu), 1130C>T p.(Thr377Met), 1132G>A p.(Asp378Asn), and c.1204G>A, p.(Val402Ile). Three of these patients had a family history of dominantly inherited JOAG. One patient and his mother with JOAG had a loss‐of‐function variant in the FOXC1 gene, c.G366A, p.(Trp122Ter). One patient with sporadic glaucoma had a homozygous likely pathogenic variant in the LTBP2 gene, c.G3938A, p.(Cys1313Tyr). The frequency of the variant carriers in Finns is 0.03% (the gnomAD database). The frequency of MYOC variants was 9% (4/46; 95% CI, 2‐21). The detected genetic variants explained 13% (6/46; 95% CI 5‐26%) of JOAG in our patient series.ConclusionsGenetic variants in known JOAG‐associated genes seem to be less frequent in Finnish patients, compared to other reported populations. Because of the specific population history of Finland, the genetic background of Finns differs from other European populations. Therefore, it might be possible to identify novel glaucoma genes through our JOAG series in the future.