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

Maryam Najafi,Zeineb Bakey,Dor Mohammad Kordi Tamandani,Ehsan Ghayoor Karimiani,Isabel Schüle,Miriam Schmidts,Farkhondeh Behjati,Simin Sadeghi-Bojd,Anoush Azarfar,Dinu Antony

doi:10.3389/fped.2019.00089

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.

Highlights

Cystinosis is an autosomal recessive lysosomal storage disorder caused by mutation of the CTNS gene (1, 2)
At the age of nearly 5 months, he was hospitalized due to recurrent vomiting, polydipsia, and polyuria, failure to thrive was noted since the 4th month of life with a length of 62.2 cm (
The biochemical findings of mild hypokalemic alkalosis together with severe growth retardation, polydipsia and polyuria as well as the urine findings suggested a renal tubulopathy such as Bartter syndrome or Fanconi syndrome

Summary

Introduction

Cystinosis is an autosomal recessive lysosomal storage disorder (general incidence of 1:100,000–200,000 live births) caused by mutation of the CTNS gene (1, 2). Based on the age at onset and the severity of clinical disease, three cystinosis subtypes are distinguished: the most severe subtype is nephropathic cystinosis (OMIM#219800) which is known as infantile onset renal tubular fanconi syndrome that affects proximal renal tubular function and results in failure to thrive, polyuria, and polydipsia with a disease onset between age 6 and 18 months on average. This is the most frequent manifestation of cystinosis accounting for up to 95% of all cases (6). 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

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Discussion

Conclusion