Case report: Novel ACTN4 variant of uncertain significance in a pediatric case of steroid-resistant nephrotic syndrome requesting kidney transplantation
BackgroundSteroid-resistant nephrotic syndrome (SRNS) is a rare kidney disease commonly characterized histopathologically by focal and segmental glomerulosclerosis (FSGS) or minimal change disease. One-third of SRNS-FSGS cases are attributed to a genetic cause ultimately leading to end-stage kidney...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Nephrology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneph.2024.1375538/full |
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| author | Ignacio Alarcón Carolina Peralta Francisco Cammarata-Scalisi Maykol Araya Castillo Francisco Cano Francisco Cano Angélica Rojo María Luisa Ceballos María Luisa Ceballos Paola Krall Paola Krall |
| author_facet | Ignacio Alarcón Carolina Peralta Francisco Cammarata-Scalisi Maykol Araya Castillo Francisco Cano Francisco Cano Angélica Rojo María Luisa Ceballos María Luisa Ceballos Paola Krall Paola Krall |
| author_sort | Ignacio Alarcón |
| collection | DOAJ |
| description | BackgroundSteroid-resistant nephrotic syndrome (SRNS) is a rare kidney disease commonly characterized histopathologically by focal and segmental glomerulosclerosis (FSGS) or minimal change disease. One-third of SRNS-FSGS cases are attributed to a genetic cause ultimately leading to end-stage kidney disease (ESKD) during childhood or adulthood. ACTN4 variants, although rare, typically manifest in early adulthood as SRNS-FSGS with autosomal dominant inheritance pattern and are associated with variable progression toward ESKD.Case–diagnosis/treatmentA 10-year-old Chilean male patient, born to a complicated pregnancy without any history of prenatal care, was incidentally found to have mild proteinuria during pre-surgery analysis. He was diagnosed with nephrotic syndrome and treatment with prednisone was started, but 12 months later, he persisted with hyperlipidemia, hypoalbuminemia, and proteinuria. Within a few weeks, proteinuria rapidly increased, and a kidney biopsy exhibited FSGS features. At the age of 12, he reached ESKD and initiated peritoneal dialysis, experiencing an episode of posterior reversible encephalopathy syndrome. Exome sequencing identified a novel variant of uncertain significance (VUS), ACTN4 c.625_633del that predicted the in-frame deletion p.L209_E211del in a highly conserved functional domain. He requested to be considered for kidney transplantation and the VUS in ACTN4 was re-analyzed to assess potential risks, resulting in a reclassification as likely pathogenic (PM1+PM2+PM4 criteria). At 14 years old, he received a deceased donor kidney allograft without recurrence during the subsequent 5 months.ConclusionsIdentifying VUS is a recurring challenge in routine clinical genetics, particularly for patients with rare diseases or atypical phenotypes in underrepresented populations. This case underscores the benefit of timely genetic diagnosis taking into account the patient’s request. VUS reassessment becomes more relevant when considering a kidney transplant not only as an appropriate procedure, but as the therapy of choice, especially considering the patient’s history of complications with variable long-term consequences. |
| format | Article |
| id | doaj-art-42629bc76f934a728f42959dc4b6d7b4 |
| institution | Kabale University |
| issn | 2813-0626 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Nephrology |
| spelling | doaj-art-42629bc76f934a728f42959dc4b6d7b42025-01-31T10:51:13ZengFrontiers Media S.A.Frontiers in Nephrology2813-06262025-01-01410.3389/fneph.2024.13755381375538Case report: Novel ACTN4 variant of uncertain significance in a pediatric case of steroid-resistant nephrotic syndrome requesting kidney transplantationIgnacio Alarcón0Carolina Peralta1Francisco Cammarata-Scalisi2Maykol Araya Castillo3Francisco Cano4Francisco Cano5Angélica Rojo6María Luisa Ceballos7María Luisa Ceballos8Paola Krall9Paola Krall10Escuela de Medicina, Facultad de Medicina, Universidad de Chile, Santiago, ChileServicio de Pediatría, Hospital de Antofagasta, Antofagasta, ChileServicio de Pediatría, Hospital de Antofagasta, Antofagasta, ChileLaboratorio Clínico, Hospital de Antofagasta, Antofagasta, ChileDepartamento de Pediatría y Cirugía Infantil Oriente, Facultad de Medicina, Universidad de Chile, Santiago, ChileUnidad de Nefrología, Hospital Luis Calvo Mackenna, Santiago, ChileUnidad de Nefrología, Hospital Luis Calvo Mackenna, Santiago, ChileDepartamento de Pediatría y Cirugía Infantil Oriente, Facultad de Medicina, Universidad de Chile, Santiago, ChileUnidad de Nefrología, Hospital Luis Calvo Mackenna, Santiago, ChileDepartamento de Pediatría y Cirugía Infantil Oriente, Facultad de Medicina, Universidad de Chile, Santiago, ChileInstituto de Medicina, Facultad de Medicina, Universidad Austral de Chile, Valdivia, ChileBackgroundSteroid-resistant nephrotic syndrome (SRNS) is a rare kidney disease commonly characterized histopathologically by focal and segmental glomerulosclerosis (FSGS) or minimal change disease. One-third of SRNS-FSGS cases are attributed to a genetic cause ultimately leading to end-stage kidney disease (ESKD) during childhood or adulthood. ACTN4 variants, although rare, typically manifest in early adulthood as SRNS-FSGS with autosomal dominant inheritance pattern and are associated with variable progression toward ESKD.Case–diagnosis/treatmentA 10-year-old Chilean male patient, born to a complicated pregnancy without any history of prenatal care, was incidentally found to have mild proteinuria during pre-surgery analysis. He was diagnosed with nephrotic syndrome and treatment with prednisone was started, but 12 months later, he persisted with hyperlipidemia, hypoalbuminemia, and proteinuria. Within a few weeks, proteinuria rapidly increased, and a kidney biopsy exhibited FSGS features. At the age of 12, he reached ESKD and initiated peritoneal dialysis, experiencing an episode of posterior reversible encephalopathy syndrome. Exome sequencing identified a novel variant of uncertain significance (VUS), ACTN4 c.625_633del that predicted the in-frame deletion p.L209_E211del in a highly conserved functional domain. He requested to be considered for kidney transplantation and the VUS in ACTN4 was re-analyzed to assess potential risks, resulting in a reclassification as likely pathogenic (PM1+PM2+PM4 criteria). At 14 years old, he received a deceased donor kidney allograft without recurrence during the subsequent 5 months.ConclusionsIdentifying VUS is a recurring challenge in routine clinical genetics, particularly for patients with rare diseases or atypical phenotypes in underrepresented populations. This case underscores the benefit of timely genetic diagnosis taking into account the patient’s request. VUS reassessment becomes more relevant when considering a kidney transplant not only as an appropriate procedure, but as the therapy of choice, especially considering the patient’s history of complications with variable long-term consequences.https://www.frontiersin.org/articles/10.3389/fneph.2024.1375538/fullsteroid-resistant nephrotic syndromevariant of uncertain significanceACTN4pediatric kidney transplantationfocal and segmental glomerulosclerosisrecurrence risk |
| spellingShingle | Ignacio Alarcón Carolina Peralta Francisco Cammarata-Scalisi Maykol Araya Castillo Francisco Cano Francisco Cano Angélica Rojo María Luisa Ceballos María Luisa Ceballos Paola Krall Paola Krall Case report: Novel ACTN4 variant of uncertain significance in a pediatric case of steroid-resistant nephrotic syndrome requesting kidney transplantation Frontiers in Nephrology steroid-resistant nephrotic syndrome variant of uncertain significance ACTN4 pediatric kidney transplantation focal and segmental glomerulosclerosis recurrence risk |
| title | Case report: Novel ACTN4 variant of uncertain significance in a pediatric case of steroid-resistant nephrotic syndrome requesting kidney transplantation |
| title_full | Case report: Novel ACTN4 variant of uncertain significance in a pediatric case of steroid-resistant nephrotic syndrome requesting kidney transplantation |
| title_fullStr | Case report: Novel ACTN4 variant of uncertain significance in a pediatric case of steroid-resistant nephrotic syndrome requesting kidney transplantation |
| title_full_unstemmed | Case report: Novel ACTN4 variant of uncertain significance in a pediatric case of steroid-resistant nephrotic syndrome requesting kidney transplantation |
| title_short | Case report: Novel ACTN4 variant of uncertain significance in a pediatric case of steroid-resistant nephrotic syndrome requesting kidney transplantation |
| title_sort | case report novel actn4 variant of uncertain significance in a pediatric case of steroid resistant nephrotic syndrome requesting kidney transplantation |
| topic | steroid-resistant nephrotic syndrome variant of uncertain significance ACTN4 pediatric kidney transplantation focal and segmental glomerulosclerosis recurrence risk |
| url | https://www.frontiersin.org/articles/10.3389/fneph.2024.1375538/full |
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