Congenital Nephrotic Syndrome in a Hispanic Neonate Due to a Rare NPHS1 c.3024A>G Variant

Introduction: Congenital nephrotic syndrome (CNS) typically emerges within the first months of life with proteinuria, hypoalbuminemia, and edema. Most cases arise from pathogenic NPHS1 variants, yet synonymous substitutions are seldom reported, leaving clinical relevance unclear. We present a patient with CNS caused by in-trans homozygous NPHS1 c.3024A>G (p.Arg1008=) variants and describe a nephrectomy-free management. Case Description: A microcephalic, edema-free Hispanic and Guatemalan male infant was admitted on day-of-life (DOL) 8 after a brief resolved unexplained event. Urinalysis showed 3+ protein and 3+ glucose; random urine protein-to-creatinine ratio was 59mg/mg and serum albumin was <2g/dL. Given the unusual presentation, a genome trio was sent and identified 2 homozygous NPHS1 c.3024A>G variants, each inherited from a parent (in-trans) with no other variants in relevant genes. ClinVar NCBI lists 6 cases of the c.3024A>G variant which were all reported as a variant of uncertain significance. The sole published case (DOI: 10.3892/br.2021.1487) proposed that this synonymous change disrupts FOX1L1/FOXC1 binding in exon 22, dysregulating nephrin expression. The performing lab found in-silico evidence predicting alteration in splicing. RNA sequencing generated a premature stop codon demonstrating pathogenicity. The patient eventually developed edema at approximately DOL 21 and therapy comprised IV albumin infusions along with furosemide, metolazone, indomethacin, captopril, and enoxaparin. With optimization of medical management, nephrectomy was avoided and albumin was weaned off. At around DOL 150 he remains stable with minimal edema. Discussion: This case highlights two lessons. First, we describe a “silent” NPHS1 variant that is likely pathogenic; early genetic testing is therefore essential for accurate diagnosis and counseling. Second, family-centered and multidisciplinary approach can achieve patient stability with medical management alone, especially in rare genetic diseases.