Genetic stratification reveals COL4A variants and spontaneous remission in Egyptian children with proteinuria in the first 2 years of life

Abstract

Aim The earlier the onset of proteinuria, the higher the incidence of genetic forms. Therefore, we aimed to analyse the spectrum of monogenic proteinuria in Egyptian children presenting at age <2 years. Methods The results of 27‐gene panel or whole‐exome sequencing were correlated with phenotype and treatment outcomes in 54 patients from 45 families. Results Disease‐causing variants were identified in 29/45 (64.4%) families. Mutations often occurred in three podocytopathy genes: NPHS1, NPHS2 and PLCE1 (19 families). Some showed extrarenal manifestations. Additionally, mutations were detected in 10 other genes, including novel variants of OSGEP, SGPL1 and SYNPO2. COL4A variants phenocopied isolated steroid‐resistant nephrotic syndrome (2/29 families, 6.9%). NPHS2 M1L was the single most common genetic finding beyond the age of 3 months (4/18 families, 22.2%). Biopsy results did not correlate with genotypes (n = 30). On renin–angiotensin–aldosterone system antagonists alone, partial and complete remission occurred in 3/24 (12.5%) patients with monogenic proteinuria each, whereas 6.3% (1/16) achieved complete remission on immunosuppression. Conclusion Genotyping is mandatory to avoid biopsies and immunosuppression when proteinuria presents at age <2 years. Even with such a presentation, COL4A genes should be included. NPHS2 M1L was prevalent in Egyptian children (4 months–2 years) with proteinuria, demonstrating precision diagnostic utility.

Synaptopodin-2 Isoforms Have Specific Binding Partners and Display Distinct, Muscle Cell Type-Specific Expression Patterns

“…Additional evidence supporting the importance of SYNPO2 comes from ClinVar ( (accessed on 22 September 2023)), which lists 52 different SYNPO2 variations in humans, which are all described as either “uncertain significance” or “benign”, but no data concerning potential associated phenotypes are currently available. The few variations that have been reported so far to be true human disease candidates, indeed result in a phenotype (in this case monogenic nephrotic syndrome, proteinuria) when they are homozygous [ 16 , 17 ]. Our work therefore paves the way for future detailed analyses of mouse models and/or patients.…”

“…The phenotype of mice homozygous for the Synpo2 tm1b(EUCOMM)Wtsi allele was described as preweaning lethality with complete penetrance, indicating that SYNPO2 is crucial for mouse embryonic development. In humans, SYNPO2 variants were presented as candidates of monogenic nephrotic syndrome and proteinuria [ 16 , 17 ]. In addition, SYNPO2 was described to play a role in several aspects of tumor development (for review, see [ 18 ]).…”