Identification of a dominant MYH11 causal variant in chronic intestinal pseudo‐obstruction: Results of whole‐exome sequencing

Abstract Chronic Intestinal Pseudo‐Obstruction (CIPO) is a rare gastrointestinal disorder, which affects the smooth muscle contractions of the gastrointestinal tract. Dominant mutations in the smooth muscle actin gene, ACTG2 , accounts for 44%‐50% of CIPO patients. Other recessive or X‐linked genes, including MYLK , LMOD1 , RAD21 , MYH11 , MYL9 , and FLNA were reported in single cases. In this study, we used Whole‐Exome Sequencing (WES) to study 23 independent CIPO families including one extended family with 13 affected members. A dominantly inherited rare mutation, c.5819delC (p.Pro1940HisfsTer91), in the smooth muscle myosin gene, MYH11 , was found in the extended family, shared by 7 affected family members but not by 3 unaffected family members with available DNA, suggesting a high probability of genetic linkage. Gene burden analysis indicates that additional genes, COL4A1 , FBLN1 and HK2 , may be associated with the disease. This study expanded our understanding of CIPO etiology and provided additional genetic evidence to physicians and genetic counselors for CIPO diagnosis.