An extremely mild clinical course in a case with LAMB2-associated nephritis diagnosed with next-generation sequencing

Abstract

Biallelic pathogenic variants in the laminin β2 (LAMB2) gene, which encodes laminin β2, are associated with Pierson syndrome characterized by a congenital nephrotic syndrome that rapidly progresses to end-stage renal disease, distinct ocular maldevelopment with bilateral microcoria, and neurodevelopmental deficits. However, the phenotypic spectrum of LAMB2-associated disorder is broader than expected, and cases with milder phenotypes such as isolated congenital or infantile nephrotic syndrome have also been reported. We report a patient with LAMB2-associated renal disorder showing an extremely mild phenotype. A 5-year-old girl presented with asymptomatic proteinuria and hematuria detected by urinalysis screening. She had been previously healthy without any additional renal symptoms. The serum albumin and creatinine levels were normal. Renal biopsy revealed minor glomerular abnormalities with occasional focal mesangial proliferation. Electron microscopy showed no structural changes in the glomerular basement membrane. Targeted sequencing of podocyte-related genes using next-generation sequencing was performed. As a result, previously reported biallelic pathogenic variants of the truncating variant (c.5073_5076dupCCAG) and a splice site variant (c.3797 + 5G > A) in the LAMB2 gene were detected, and the patient was diagnosed with LAMB2-associated renal disorder. Interestingly, a previously reported case with this splicing variant also showed an atypically mild phenotype. We suggest that clinicians should consider LAMB2-associated nephritis as an important differential diagnosis in children with asymptomatic proteinuria and microscopic hematuria if there is no structural change in the glomerular basement membrane. A comprehensive gene-screening system using next-generation sequencing is useful for diagnosing these atypical cases with isolated urine abnormalities.

Keywords: LAMB2; LAMB2-associated renal disorder; Next-generation sequencing; Pierson syndrome.

Fig. 1

Renal biopsy findings of the patient. a, b Light microscopy findings. In total, 23 glomeruli were observed. a Mild mesangial cell proliferation was observed in three glomeruli. (PAS staining, × 100). b Duplication of GBM was observed (arrowheads) (PAM staining, × 100). c, d Electron microscopy appearance of glomeruli. c Partially loss of fenestra was observed; black bar 10.0 μm. (Magnification × 600). d There are no lamellation or wrinkling of GBM. Foot processes were predominantly intact without effacement; black bar 2.0 μm. (Magnification × 4000)

Fig. 2

A splice site variant (c.3797 + 5G > A) and truncating variant (c.5073_5076dupCCAG) were detected. Red arrows point the variants. In the left panel, the red arrow points G > A single base substitution. In the right panel, the red arrow points the start point of duplication