Background/Objectives: Podocalyxin is a sialoprotein mainly expressed in the kidney cortex and lung tissue, which has been described as a component of the podocyte glycocalyx. This protein promotes the reorganization of the podocyte cytoskeleton, as well as the morphogenesis and differentiation of nascent podocytes, actively participating in glomerular filtration. Previous research has suggested that PODXL haploinsufficiency leads to podocytopathy with development of focal segmental glomerulosclerosis, a disorder that has been demonstrated in Podxl-deficient animal models and proposed as a primary cause in human families affected by this condition. However, only a few families have been reported, which limits the understanding about the spectrum of phenotype and prognosis of the disease. Methods: We performed high-throughput sequencing in a cohort of young adults with CKD, describing the clinical scenario of those who harbored truncating variants in the PODXL gene and testing the families for detected variants. Results: The PODXL gene exhibited a slight deviation in loss intolerance probability and moderate deviation in the observed/expected ratio of variation, which is typically observed in dominant genes with age-dependent incomplete penetrance or variable expression. We reported four novel truncating variants in the PODXL gene, along with a collection of previously published monoallelic truncating variants. Conclusions: These findings further support evidence about genetic defects in the PODXL gene associated with a new molecular entity of podocytopathy with adult onset. Additionally, the nucleotide sequence of PODXL contains particularities that require careful analysis to interpret the effect of the variants detected in this gene.

(1) Background: Focal and segmental glomerulosclerosis (FSGS) is a pattern of injury that results from podocyte loss in the setting of a wide variety of injurious mechanisms. These include both acquired and genetic as well as primary and secondary causes, or a combination thereof, without optimal therapy, and a high rate of patients develop end-stage renal disease (ESRD). Genetic studies have helped improve the global understanding of FSGS syndrome; thus, we hypothesize that patients with primary FSGS may have underlying alterations in adhesion molecules or extracellular matrix glycoproteins related to previously unreported mutations that may be studied through next-generation sequencing (NGS). (2) Methods: We developed an NGS panel with 29 genes related to adhesion and extracellular matrix glycoproteins. DNA was extracted from twenty-three FSGS patients diagnosed by renal biopsy; (3) Results: The average number of accumulated variants in FSGS patients was high. We describe the missense variant ITGB3c.1199G>A, which is considered pathogenic; in addition, we discovered the nonsense variant CDH1c.499G>T, which lacks a Reference SNP (rs) Report and is considered likely pathogenic. (4) Conclusions: To the best of our knowledge, this is the first account of a high rate of change in extracellular matrix glycoproteins and adhesion molecules in individuals with adult-onset FSGS. The combined effect of all these variations may result in a genotype that is vulnerable to the pathogenesis of glomerulopathy.