Exome Sequencing in a Swiss Childhood Glaucoma Cohort Reveals CYP1B1 and FOXC1 Variants as Most Frequent Causes.

Elena Lang, Samuel Koller, Luzy Bähr, Marc Töteberg-Harms, David Atac, Françoise Roulez, Angela Bahr, Katharina Steindl, Silke Feil, Wolfgang Berger, Christina Gerth-Kahlert

Translational vision science & technology 2020 Jun

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The aim of this study was to investigate the molecular basis of childhood glaucoma in Switzerland to recommend future targeted genetic analysis in the Swiss population. Whole-exome sequencing and copy number variation (CNV) analysis was performed in a Swiss cohort of 18 patients from 14 unrelated families. Identified variants were validated by Sanger sequencing and multiplex ligation-dependent probe amplification. Breakpoints of structural variants were determined by a microarray. A minigene assay was conducted for functional analysis of a splice site variant. A diagnosis of primary congenital glaucoma was made in 14 patients, of which six (43%) harbored pathogenic variants in CYP1B1, one (7%) a frameshift variant in FOXC1, and seven (50%) remained without a genetic diagnosis. Three patients were diagnosed with glaucoma associated with nonacquired ocular anomalies, of which two patients with mild ocular features of Axenfeld-Rieger syndrome harbored a FOXC1 duplication plus an additional FOXC1 missense variant, and one patient with a Barkan membrane remained without genetic diagnosis. A diagnosis of juvenile open-angle glaucoma was made in one patient, and genetic analysis revealed a FOXC1 duplication. Sequencing of CYP1B1 and FOXC1 , as well as analysis of CNVs in FOXC1, should be performed before extended gene panel sequencing. The identification of the molecular cause of childhood glaucoma is a prerequisite for genetic counseling and personalized care for patients and families. Copyright 2020 The Authors.

Citation

Elena Lang, Samuel Koller, Luzy Bähr, Marc Töteberg-Harms, David Atac, Françoise Roulez, Angela Bahr, Katharina Steindl, Silke Feil, Wolfgang Berger, Christina Gerth-Kahlert. Exome Sequencing in a Swiss Childhood Glaucoma Cohort Reveals CYP1B1 and FOXC1 Variants as Most Frequent Causes. Translational vision science & technology. 2020 Jun;9(7):47