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Μοριακή διερεύνηση παραλλαγών σε ασθενείς με νεφρωσικό σύνδρομο (Bachelor thesis)

Καλογήρου, Αναστασία/ Kalogirou, Anastasia

Nephrotic syndrome represents a heterogeneous group of glomerular disorders characterized by disruption of the integrity of the glomerular filtration barrier, resulting in significant proteinuria, hypoalbuminemia, generalized edema, and hyperlipidemia. Contemporary understanding of nephrotic syndrome as a podocytopathy highlights the central role of podocytes and slit diaphragm-associated proteins in maintaining normal glomerular function. Among the key genes implicated in steroid-resistant nephrotic syndrome, NPHS2, encoding podocin, is of major clinical and genetic relevance. The aim of the present study was to investigate the inheritance pattern and intrafamilial phenotypic heterogeneity of pathogenic NPHS2 variants in a family diagnosed with focal segmental glomerulosclerosis (FSGS) and clinical suspicion of hereditary steroid-resistant nephrotic syndrome, as well as to highlight the contribution of molecular genetic analysis to genotype phenotype correlation. Genomic DNA was extracted from peripheral blood samples. Target regions were amplified by polymerase chain reaction (PCR), and Sanger sequencing was performed for validation of variants initially identified by Next-Generation Sequencing (NGS), specifically Whole Exome Sequencing (WES). Molecular analysis identified the pathogenic NPHS2 variants c.868G>A p.(Val290Met) and c.871C>T p.(Arg291Trp) in compound heterozygosity in the affected offspring. The c.871C>T variant was detected in the mother in a heterozygous state, whereas the c.868G>A variant was identified in the father in a homozygous state, supporting the inherited origin of the variants. Notably, marked intrafamilial phenotypic heterogeneity was observed, as the father did not exhibit any overt clinical manifestations of nephrotic syndrome. These findings underscore the complexity of genotype–phenotype correlations in NPHS2 associated disease. Furthermore, they emphasize the critical role of molecular genetic testing in diagnostic evaluation, genetic counseling, and personalized clinical management of patients with hereditary nephrotic syndrome.