Abstract: PO1352
Genetic Analysis of a Brazilian Nephropathic Cystinosis Cohort Reveals Novel CTNS Variants Mostly of Non-European Origin
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Vaisbich, Maria H, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
- Nunes, Kelly, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
- R Santos, A., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
- Ferreira, Juliana Caires, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
- Nunes, F. M., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
- Watanabe, Andreia, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
- Onuchic, Luiz F., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
Background
Nephropathic Cystinosis (NC) is a severe autosomal recessive disease caused by intralysosomal cystine deposition. Most CTNS variants have been described in Europe and North America, where a specific 57kb deletion (del) is the most frequent one. In this study, we seeked to characterize the CTNS variants and their genetic ancestry profiles in a NC Brazilian cohort, an admixed population.
Methods
61 NC patients were studied, both sexes, <21 years old, followed at the University of Sao Paulo Medical Center. Mutation analysis was performed by gel electrophoresis and/or MLPA to assess the 57kb del, and NGS targeted sequencing. To characterize the genetic ancestry profiles, 48 patients were genotyped with a high-density SNP array. The average genomic ancestry was inferred using ADMIXTURE and the ancestry of the CTNS gene region using RFMIX.
Results
Two disease-causing variants were identified in 58/61 patients, followed by segregation analysis whenever possible. The detected variants included 9 previously reported and 7 novel ones. All previously reported variants were observed in European genomic segments, except the African ancestry-linked variant c.62-2A>G. Among the novel variants, 4 are in genomic segments of African origin (del exons 2,4,5; c.227delT:p.V76fs; c.T412C:p.W138R and c.A457T:p.K153X), 1 in Native American (c.16_19del:p.L6fs), 1 in a European-ancestry segment (c.*262_*266delinsCGGAC), and 1 could not be determined (c.158delC:p.W53fs). The highest allele frequencies were 57kb del (55.7%), c.C382T (14.0%), c.16_19del (7.4%) and c.611_613del (5.7%). Analyses of LD decay support that 57kb del, c.C382T and c.611_613del originated in Europe at least 1,750 years (250-3,750), 1,050 years (550-1,550) and 275 years ago (75-1,200), respectively, and suggest that c.16_19del likely originated in America 15,025 years ago (5,775-41,000).
Conclusion
57kb del was the most frequent CTNS variant in this Brazilian NC cohort. However, given the admixed nature of the Brazilian population, novel variants with distinct ethnic origins were identified. Indeed, 5 of the 7 novel variants are located in chromosome segments of non-European ancestry. This finding raises the possibility that the novel non-European CTNS variants may be present in other South American and African populations.