Pierson Syndrome and Congenital Nephrotic Syndrome via the LAMB2 Gene

Defects in the LAMB2 gene can cause congenital nephrotic syndrome with or without ocular abnormalities (Matejas et al. 2010). Nephrotic syndrome is a genetically heterogeneous disease defined by proteinuria, hypoalbuminemia, hyperlipidemia, and edema (Benoit et al. 2010; Santín et al. 2011; Saleem 2012). Approximately 20% of cases are steroid-resistant nephrotic syndrome (SRNS), characterized by resistance to steroid treatment and rapid progression to end-stage renal failure. The prevalent histological feature of SRNS is focal segmental glomerulosclerosis (FSGS), which has been seen in approximately 60% of SRNS cases. Diffuse mesangial sclerosis (DMS) is the other important histological feature associated with SRNS. The clinical courses of SRNS vary greatly with a wide range of age at onset from birth to adulthood.

When distinct ocular abnormalities (featured by microcoria and hypoplasia of the ciliary and pupillary muscles) present alongside congenital nephrotic syndrome with diffuse mesangial sclerosis (DMS) histologically, Pierson syndrome due to a complete loss of LAMB2 expression resulted from null alleles should be suspected (Zenker et al. 2004). Severe neurodevelopmental abnormalities including congenital muscular weakness/myasthenia and developmental retardation are also commonly seen in Pierson syndrome.

Different from those with Pierson syndrome, patients with compound heterozygous or homozygous missense variants in the LAMB2 gene generally only develop congenital nephrotic syndrome with minor ocular abnormalities or isolated congenital nephrotic syndrome (Hasselbacher et al. 2006).

The LAMB2 gene (32 coding exons) encodes the basement membrane protein laminin beta2. Both Pierson syndrome and LAMB2-related congenital nephrotic syndrome are autosomal recessive disorders due to LAMB2 defects, caused by null alleles and missense variants, respectively (Zenker et al. 2004; Hasselbacher et al. 2006; Matejas et al. 2010). Notably, genetic modifiers have been suspected to exist to explain some genotype-phenotype discordance (Matejas et al. 2010). To date, documented genetic defects of LAMB2 include missense, nonsense, splicing, regulatory mutations, and small indels (Human Gene Mutation Database). Large deletions and duplications have not been reported.

LAMB2 defects are a rare cause of isolated congenital nephrotic syndrome. In a large European cohort of 89 children from 80 families with nephrotic syndrome manifesting in the first year of life, LAMB2 pathogenic variants were found in only 2.5% of these families (Hinkes et al. 2007).

Mutation detection rate of the LAMB2 gene in a large cohort of patients with Pierson syndrome is unavailable in the literature because pathogenic variants in this gene have only been reported in limited cases from individual studies.

This test provides full coverage of all coding exons of the LAMB2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).