Systematic Review of Clinical Characteristics and Genotype-Phenotype Correlation in LAMB2-Associated Disease

Abstract

Introduction: Laminin subunit beta-2 (LAMB2)-associated disease, termed Pierson syndrome, presents with congenital nephrotic syndrome, ocular symptoms, and neuromuscular symptoms. In recent years, however, the widespread use of next-generation sequencing (NGS) has helped to discover a variety of phenotypes associated with this disease. Therefore, we conducted this systematic review.

Methods: A literature search of patients with LAMB2 variants was conducted, and 110 patients were investigated, including 12 of our patients. For genotype-phenotype correlation analyses, the extracted data were investigated for pathogenic variant types, the severity of nephropathy, and extrarenal symptoms. Survival analyses were also performed for the onset age of end-stage kidney disease (ESKD).

Results: Among all patients, 81 (78%) presented with congenital nephrotic syndrome, and 52 (55%) developed ESKD within 12 months. The median age at ESKD onset was 6.0 months. Kidney survival analysis showed that patients with biallelic truncating variants had a significantly earlier progression to ESKD than those with other variants (median age 1.2 months vs. 60.0 months, P < 0.05). Although the laminin N-terminal domain is functionally important in laminin proteins, and variants in the laminin N-terminal domain are said to result in a severe kidney phenotype such as earlier onset age and worse prognosis, there were no significant differences in onset age of nephropathy and progression to ESKD between patients with nontruncating variants located in the laminin N-terminal domain and those with variants located outside this domain.

Conclusion: This study revealed a diversity of LAMB2-associated diseases, characteristics of LAMB2 nephropathy, and genotype-phenotype correlations.

Keywords: LAMB2; Pierson syndrome; congenital nephrotic syndrome; end-stage kidney disease; genotype-phenotype correlation; laminin.

Graphical abstract

Figure 1

Flowchart of the literature search. HGMD, Human Gene Mutation Database.

Figure 2

Kidney survival analysis between patients with biallelic truncating variants and those with other variants. The solid black line indicates patients with biallelic truncating variants (n = 53); the median age at end-stage kidney disease development is 1.2 months (log-rank test). The solid red line indicates patients with other variants (n = 41); the median age of end-stage kidney disease development is 60.0 months. The black line group has a significantly earlier progression to end-stage kidney disease than the red line group (P < 0.05).

Figure 3

Kidney survival analysis between patients with neuromuscular symptoms and those without neuromuscular symptoms (left), and between patients with ocular symptoms and those without ocular symptoms (right). The left side (a) shows a solid black line indicating patients with neuromuscular symptoms (n = 27); the median age at end-stage kidney disease development is 3.0 months (log-rank test). The solid red line indicates patients without neuromuscular symptoms (n = 24); the median age of end-stage kidney disease development is 68.4 months. The black line group has a significantly earlier progression to end-stage kidney disease than the red line group (P < 0.05). The right side (b) shows a solid black line indicating patients with ocular symptoms (n = 74); the median age at end-stage kidney disease development is 3.0 months. The solid red line indicates patients without ocular symptoms (n = 9); the median age at end-stage kidney disease development is 48.0 months. The progression to end-stage kidney disease does not significantly differ between the black line and red line groups (P = 0.135).

Figure 4

Kidney survival analysis between patients with biallelic nontruncating variants located in the laminin N-terminal domain and those with both variants located outside the laminin N-terminal domain. The solid black line indicates patients with variants both located in the laminin N-terminal domain (n = 17); the median age at end-stage kidney disease development is not available because the kidney survival rate does not reach 50%. The solid red line indicates patients with variants located outside the LN domain (n = 9); the median age at end-stage kidney disease development is 68.4 months (log-rank test). There are no significant differences in the progression to end-stage kidney disease between the black line group and the red line group (P = 0.316).

Figure 5

Exon and intron structure of LAMB2 with geometric shapes indicating relative positions of different types of variants. The horizontal line in the center is the transcript of LAMB2 (NM_002292.3). Each yellow square represents an exon, and each solid yellow line represents an intron. The gray square shows the position of the laminin N-terminal domain (residue Ser43 to Asn282). The white squares are lined from top to bottom with exons 1, 2, etc. Patients with the severe phenotype (who developed end-stage kidney disease within 12 months) are shown in the upper part, and those with the mild phenotype (whose kidneys survived at least 13 months) in the lower part. Each geometric shape represents a variant type. ▲ indicates missense variants, ▼ indicates in-frame variants because of deletion or insertion, ● indicates nonsense variants, ■ indicates frameshift variants because of deletion, ◆ indicates frameshift variants because of insertion, and ★ indicates splice site variants. Red-colored shapes indicate the variants of patients with biallelic truncating variants, and blue-colored shapes indicate the variants of patients with other types of variants. Most patients follow genotype-phenotype correlations, but a few patients have mild phenotypes regardless of the presence of biallelic truncating variants.