Familial non-syndromic macular pseudocoloboma secondary to homozygous CLDN19 mutation

Purpose: The purpose of this study is to uncover the genetic cause for non-syndromic macular “coloboma” (pseudocoloboma) in three brothers from a consanguineous family. Methods: Homozygosity mapping for the three affected brothers and whole-exome sequencing in one affected brother, followed by confirmatory Sanger sequencing and segregation analysis of the candidate gene for all immediate family members; molecular modeling of the candidate mutation; and review of clinical, imaging, and laboratory findings. Results: Three otherwise-healthy brothers (age 10, 10, and 6 years) had macular pseudocoloboma. Both parents and the fourth brother were not affected. Parents were first cousins. A novel homozygous missense variant in claudin 19 (CLND19: NM_148960.2:c. 263T>A; p.Val88Glu) segregated with the phenotype, and molecular modeling predicts an unfavorable effect to protein function. All prior reported biallelic CLND19 mutations cause symptomatic hypomagnesemia with hypercalciuria and nephrocalcinosis, often with concurrent macular pseudocoloboma. However, general physical assessment, metabolic profile, and renal imaging for the three affected brothers were normal. Conclusions: A homozygous CLDN19 mutation can cause macular pseudocoloboma without evidence for systemic disease in children. This is the first reported family with CLDN19 mutations to have an ocular phenotype only; however, those identified to harbor biallelic CLDN19 mutations should be considered at risk for the extraocular manifestations that have previously been associated with mutations in the gene.