Identification of a rare LAMB4 variant associated with familial diverticulitis through exome sequencing

Abstract

Diverticulitis is a chronic disease of the colon in which diverticuli, or outpouching through the colonic wall, become inflamed. Although recent observations suggest that genetic factors may play a significant role in diverticulitis, few genes have yet been implicated in disease pathogenesis and familial cases are uncommon. Here, we report results of whole exome sequencing performed on members from a single multi-generational family with early onset diverticulitis in order to identify a genetic component of the disease. We identified a rare single nucleotide variant in the laminin β 4 gene (LAMB4) that segregated with disease in a dominant pattern and causes a damaging missense substitution (D435N). Targeted sequencing of LAMB4 in 148 non-familial and unrelated sporadic diverticulitis patients identified two additional rare variants in the gene. Immunohistochemistry indicated that LAMB4 localizes to the myenteric plexus of colonic tissue and patients harboring LAMB4 variants exhibited reduced LAMB4 protein levels relative to controls. Laminins are constituents of the extracellular matrix and play a major role in regulating the development and function of the enteric nervous system. Reduced LAMB4 levels may therefore alter innervation and morphology of the enteric nervous system, which may contribute to colonic dysmotility associated with diverticulitis.

Epidemiology, Pathophysiology, and Treatment of Diverticulitis

“…A study of 5 members of a family with early-onset diverticulitis identified a rare single-nucleotide polymorphisms in the laminin subunit beta 4 (LAMB4). 100 Laminins are part of the extracellular matrix and involved in development of the enteric nervous system.…”

Recent advances in understanding and managing diverticulitis

“…Finally, recent studies corroborate the previous observation of a strong familial aggregation both in diverticulosis and in diverticular complications, suggesting a role for genetic factors 51 . A relationship has been reported between complicated diverticulitis and a single nuclear polymorphism in the TFNSF15 gene, a T-cell maturation receptor gene associated with other colonic inflammatory diseases 52 , and between early onset diverticulitis or unrelated sporadic diverticulitis and variants in the laminin β4 gene ( LAMB4 ), which codes for constituents of the extracellular matrix that regulate the function of the enteric nervous system 53 .…”

Role of Inflammation in Pathophysiology of Colonic Disease: An Update

“…These include the SNP rs7848647, upstream of the Tumour necrosis factor (TNF)-like cytokine 1A (TL1A)/TNF superfamily member 15 (TNFSF15) genes [20]. Other SNPs include: SNP rs4662344 located in the gene for Rho-GTPase-activating protein 15 (ARHGAP15), which plays an important role in selective neutrophil functions [21]; the SNP rs7609897 in the gene for collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) important for neuromuscular junctions [21]; a rare SNP encoding a D435N substitution in laminin beta 4 (LAMB4) known for its role in the intestinal barrier function [22], and rs67153654 in FAM155A (unknown function) [21]. In addition to these SNPs, genome wide association studies (GWAS) from the United States, UK, and Europe identified 25 common susceptibility loci with diverticulitis from genes that were associated with roles in immunity, extracellular matrix biology, cell adhesion, membrane transport, and intestinal motility [23,24].…”