A 57 kB Genomic Deletion Causing CTNS Loss of Function Contributes to the CTNS Mutational Spectrum in the Middle East

Abstract

Background: Nephropathic Cystinosis, the most common cause of renal Fanconi syndrome, is a lysosomal transport disorder with an autosomal recessive inheritance pattern. A large number of mutations in CTNS have been identified as causative to date. A 57 kb deletion encompassing parts of CTNS is most commonly identified in Caucasians but this allele has not been identified in individuals of Eastern Mediterranean, Middle Eastern, Persian, or Arab origin to date. Methods and Results: Implementing whole exome sequencing (WES) in a consanguineous Iranian family, we identified this large deletion affecting CTNS in a patient initially presenting with hypokalemic metabolic alkalosis symptoms and considerable proteinuria. Conclusion: We show WES is a cost and time efficient genetic diagnostics modality to identify the underlying molecular pathology in Cystinosis individuals and provide a summary of all previously reported CTNS alleles in the Middle east population. Our work also highlights the importance to consider the 57-kb deletion as underlying genetic cause in non-European populations, including the Middle East. Limited diagnostic modalities for Cystinosis in developing countries could account for the lack of previously reported cases in these populations carrying this allele. Further, our findings emphasize the utility of WES to define genetic causes in clinically poorly defined phenotypes and demonstrate the requirement of Copy number variation (CNV) analysis of WES data.

Keywords: CTNS deletion; Cystinosis; Iran; Middle East population; tubulopathy.

Figure 1

WES identifies a homozygous deletion encompassing large parts of CTNS. (A) Pedigree of the Iranian family, DNA of individual IV3 was analyzed by WES (arrow) while no DNA of other family members was available. Females are marked with circle, males with square, solid filling marks affected individuals, crossed symbols marks a deceased individual, double lines between individuals mark a consang. marriage and single lines mark non-consang.-marriages. (B) WES revealed a large genomic deletion for individual IV.3 encompassing parts of TRPV1, all of CARKL/SHPK and large parts of CTNS as visualized in the BAM file generated from WES data. Read alignment of a control person is shown above for comparison. (C) Breakpoint confirmation by Sanger sequencing confirms presence of the homozygous deletion and reveals a random insertion shown in black.

Figure 2

CTNS gene structure and visualization of alleles detected in individuals of Middle-Eastern ethnical origin. (A) Visualization of the genomic location of CTNS and genomic breakpoints of the 57 kb deletion. (B) Localizations of CTNS alleles described in cystinosis patients from the Middle East.