Whole Exome Sequencing for Sjögren’s Reticular Dystrophy

Abstract

Purpose: To apply the methods of whole exome sequencing to search for candidate gene mutations underlying Sjogren’s reticular dystrophy of the retina.

Methods: Patients with Sjogren’s reticular dystrophy of the retina were identified from two unrelated families: two affected non-identical siblings with unrelated, unaffected parents, and a simplex case from another, unrelated family. Whole exome sequencing was performed on DNA samples from the two affected siblings and their parents, and the other affected patient and one parent. The mutations identified in the candidate gene were confirmed by Sanger sequencing.

Results: Initial comparison of the sequences from the two affected siblings and their parents identified with the reference genome revealed approximately 115,000 high quality variants. Of these, some 17,000 were categorized as “rare” and were considered further. Of these, approximately 1,900 variants were considered potentially “deleterious”; of these, only one protein-coding gene with mutations inherited in concordance with the apparent autosomal recessive pattern in this family was identified, which is thus a candidate gene for Sjogren’s reticular dystrophy. These mutations occurred as a compound heterozygous nonsense variant in the KATNA1 gene on chromosome 6 (6q25.1). Comparison with the unrelated patient found a very rare heterozygous variant, possibly pathogenic, in the KATNA1 gene in both the mother and the affected patient. All the candidate variants were confirmed by Sanger sequencing.

Conclusions: We have identified KATNA1 as a candidate gene for Sjogren’s reticular dystrophy on the basis of whole exome screening of two unrelated families. Further studies, including in vivo studies of animal models, and sequencing of unrelated families may be of value to confirm the role of this gene in the pathogenesis of this very rare retinal disorder.

Keywords: 539 genetics • 696 retinal degenerations: hereditary