BACKGROUND: Both Pierson syndrome (PS) and isolated nephrotic syndrome can be caused by LAMB2 biallelic pathogenic variants. Only 15 causative splicing variants in the LAMB2 gene have been reported. However, the pathogenicity of most of these variants has not been verified, which may lead to incorrect interpretation of the functional consequence of these variants.
METHODS: Using high-throughput DNA sequencing and Sanger sequencing, we detected variants in a female with clinically suspected PS. A minigene splicing assay was performed to assess the effect of LAMB2 intron 20 c.2885-9C>A on RNA splicing. We also performed the immunohistochemical analysis of laminin beta-2 in kidney tissues.
RESULTS: Two novel LAMB2 heteroallelic variants were found: a paternally inherited variant c.2885-9C>A in intron 20 and a maternally inherited variant c. 3658C>T (p. (Gln1220Ter)). In vitro minigene assay showed that the variant c.2885-9C>A caused erroneous integration of a 7 bp sequence into intron 20. Immunohistochemical analysis revealed the absence of glomerular expression of laminin beta-2, the protein encoded by LAMB2.
CONCLUSIONS: We demonstrated the impact of a novel LAMB2 intronic variant on RNA splicing using the minigene assay firstly. Our results extend the mutational spectrum of LAMB2.

Objective: Pierson syndrome (OMIM 609049) is a rare autosomal recessive disorder characterized by congenital nephrotic syndrome and complex ocular abnormalities. Severe renal symptoms had be associated with truncating mutations. Few Chinese patients from diverse ethnic background had been evaluated and reported with this syndrome. Here we report the first Uyghur patient with typical Pierson syndrome phenotypes and a novel pathogenic homozygous variant in LAMB2 gene. Method: A thirty-nine-day old Uyghur girl was born to consanguineous parents, the girl presented with general edema, severe hypotonia and bilateral microcoria. Laboratory tests revealed severe proteinuria, microscopic haematuria, hypoalbuminaemia. By the age of 74 days, she died of renal failure and respiratory infection. We detected on mutations of LAMB2 gene by the sanger sequencing. Result:Sanger sequencing detected a homozygous 2-bp deletion (c.2044_2045insTT/p.Cys682Phefs*13) in the exon 16 of LAMB2 gene. Both parents are heterozygous carriers. Conclusion: We reported the first Uyghur case of LAMB2 gene homozygous mutation leading to severe phenotype Pierson syndrome. The clinical presentation of the patient and the novel pathogenic variant detected in this patient added to the overall knowledge of this rare condition.

BACKGROUND: LAMB2 mutations cause Pierson syndrome (OMIM 609049), an autosomal recessive genetic disease typically characterized by congenital nephrotic syndrome (CNS) and early onset renal failure, as well as bilateral microcoria. NPHP1 mutations cause familial juvenile nephronophthisis type 1 (NPHP1, OMIM 256100), another autosomal recessive renal disease that usually occurs years after birth. Both Pierson syndrome and nephronophthisis cause end-stage renal disease and rare kidney diseases in children. We report an extremely rare case of concurrent mutations of LAMB2 and NPHP1 in a Chinese girl with isolated CNS and the association of the phenotype with novel non-truncating mutations of LAMB2.
METHODS: A-34-day-old girl presented with CNS but no eye abnormalities, and mild hyperechogenicity of kidneys. A novel c.1176_1178delTCT mutation caused deletion of a glycine in exon 9 of LAMB2, and another mutation c.4923 + 2 T > G led to a splicing error. In addition, compound heterozygous mutations of NPHP1 were identified in this child using next generation sequencing, and confirmed by Sanger sequencing.
CONCLUSIONS: Mutations of the LAMB2 and NPHP1 are present in infants with isolated CNS. Next generation sequencing enabled high-throughput screening for mutant genes promptly, with clinically significant outcomes. In addition, our results expand the phenotype spectrum of LAMB2 mutations as the only renal manifestation.