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.

Genetic analysis of two Iranian patients affected with cystinosis identified a novel CTNS mutation: case report

“…In Iran, a patient was reported with this mutation. Hence this 57-kb deletion is extremely rare in cases reported from in the Middle East [20].…”

Unveiling cystinosis in India

“…The most common genetic alteration, a 57-kb deletion affecting the gene's promoter and initial exons, is predominantly found in individuals of North European descent due to a potential founder effect. However, this genetic variation is less prevalent among populations from the Middle East, Asia, and Africa [33]. Two out of four of our patients underwent genetic testing, revealing a homozygous pathogenic variant c.18_21delGACT (p.Thr7PhefsX7) in the CTNS gene.…”

Genetic Landscape of Nephropathic Cystinosis in Russian Children

“…The pathogenic c.1015G > A variant, which leads to the p.G339R amino acid residue replacement and was previously described in American, Turkish, and Iranian patients with infantile cystinosis ( Topaloglu et al, 2012 ; Zykovich et al, 2015 ; Ghazi et al, 2017 ), was detected on 10 alleles (12.5%) in children from six non-related families of Karachay ethnicity from the Republic of Karachay-Cherkessia, Kabardino-Balkaria, and Stavropol Krai. The nucleotide variant c.433C > T, which leads to p.Q145* premature translation termination and was described in an Iranian patient ( Najafi et al, 2019 ), was detected on five alleles in four (10.0%) patients from various regions of Russia. A previously non-described с.785G > A nucleotide variant, which leads to a p.W262* premature translation termination, was detected in four patients from three families from Tatarstan, Bashkortostan, and Moscow Oblast.…”