Heterozygous variants of uncertain significance in NPHS1 and CRB2 in a newborn with congenital nephrotic syndrome of the Finnish type and multiple fetal anomalies: a case report.

Background: Congenital nephrotic syndrome of the Finnish type (CNF) is an autosomal recessive disorder resulting from mutations in the NPHS1 gene, which encodes nephrin, an essential protein in the podocyte slit diaphragm. Pathogenic mutations of NPHS1 cause substantial proteinuria detectable at birth. Variants of uncertain significance (VUS) are recognized mutations, but their effects on health are not yet understood. This uncertainty makes it challenging to identify specific types of VUS that may contribute to disease development. The association of CNF with NPHS1 VUS remains unclear.

Case description: We describe the salient features of a newborn with CNF and multiple fetal anomalies based on clinical risk factors discovered by ultrasound (US) and X-rays, which include cardiomegaly, polycystic kidney disease, and renal dysplasia. Biochemical tests showed substantial proteinuria and excess protein in the urine detected at birth; this condition caused albuminuria, hypoalbuminemia, edema, and additional symptoms. The patient underwent treatment to reduce the risks of proteinuria, hypertension, infection, and other symptoms. The next generation sequencing (NGS) analysis revealed that the infant had five previously unreported heterozygous missense variants classified as VUS in NPHS1, NUP160, ALG1, and CRB2. The NPHS1 c.2150A>G and CRB2 c.1654G>T may lead to defects in the CTCF (CCCTC binding factor) and exonic splicing enhancer (ESE) motifs, respectively, which could account for the observed clinical features in the newborn.

Conclusions: The infant's illness may be related to changes in exonic splicing caused by NPHS1-VUS and CRB2-VUS. NPHS1 encodes the nephrin protein, which is crucial for the slit diaphragm of podocytes, while CRB2 is essential for slit diaphragm formation and is linked to cystic kidney disease.