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 factorsmay 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 onmembers froma singlemulti-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 segregatedwith disease in a dominant pattern and causes a damagingmissense 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 themyenteric plexus of colonic tissue and patients harboring LAMB4 variants exhibited reduced LAMB4 protein levels relative to controls. Laminins are constituents of the extracellularmatrix and play amajor role in regulating the development and function of the enteric nervous system. Reduced LAMB4 levelsmay therefore alter innervation and morphology of the enteric nervous system, whichmay contribute to colonic dysmotility associated with diverticulitis.