Can a single gene deficiency help explain problems affecting the intestine, limbs and heart in the same patient?

Details

The Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene was first identified as a cause of lethal congenital contracture syndrome (OMIM 607598). A recent study reported six additional patients carrying ERBB3 variants who had distinct clinical features, including evident intestinal dysmotility (OMIM 243180). The potential connection between these phenotypes remained unknown, and the range of ERBB3-related features needed better characterization.

In this single-patient genetic and functional study, researchers described a patient with a multisystem syndrome that included skip segment Hirschsprung disease, bilateral clubfoot deformity and a cardiac defect. Trio-whole exome sequencing identified a novel compound heterozygous combination of variants in the patient's ERBB3 gene: c.1914-7C>G and c.2942_2945del.

RT-PCR and in vitro minigene analysis demonstrated that c.1914-7C>G caused abnormal mRNA splicing. Both variants resulted in a premature termination codon and complete loss of ERBB3 function.

In zebrafish, erbb3b knockdown simultaneously caused fewer enteric neurons in the distal intestine, craniofacial cartilage defects and micrognathia. These changes phenotypically mimicked ERBB3-related intestinal dysmotility and some features of lethal congenital contracture syndrome in human patients.

Together, the findings provide further patient and animal evidence supporting that ERBB3 deficiency causes a complex syndrome affecting multiple systems, with features that vary between individuals.